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ECDC [European Centre for Disease Prevention and Control]
Investigation of the Family Cluster of Human H5N1 Cases in North Sumatra, Indonesia – Investigations by WHO and the Indonesian Ministries of Health and Agriculture. Status July 6th (latest WHO and FAO reports to June 20th)
WHO and the Indonesian Authorities have published progressive reports of the investigation around the cases of H5N1 in Kubu Simbelang village, Karo district of North Sumatra. There are no news of a further evolvement of the cluster since June 20th.
The WHO links are:
http://www.who.int/csr/don/2006_05_31/en/index.html, http://www.who.int/csr/don/2006_05_23/en/index.html and http://www.who.int/csr/don/2006_05_18b/en/index.html.
the FAO view is accessible through
http://www.fao.org/ag/againfo/subjec...ial_avian.html .
A map of the cases is available at
http://www.who.or.id/eng/php/map_avian.php .
A review of the epidemiology and virology of the case was recently undertaken by WHO and other UN Agencies as part of a wider review requested by the Indonesian authorities
http://www.who.int/mediacentre/news/.../en/index.html.
A report of the consultation has not been published yet. Media interviews with the senior WHO staff who attended indicated that a report will not hold many surprises in addition to what appears below.
Outbreak Summary
It is now more than a month since the last case in this family cluster died (May 22nd) and despite intense clinical surveillance around the area no more cases have come to light. This is far more than the usual two incubation periods (two times seven days) that allows it to be said that an outbreak is over.
There are a total of seven cases confirmed at a WHO Reference Laboratory, six of which have died. A possible eighth infection will never be proven as the body was buried before H5N1 infection was suspected and so no specimens are available). It remains the case that there have been no infections beyond a single extended family despite likely exposure of others.
This is the largest reported cluster of H5N1 infections reported worldwide. The initial case in this family cluster was probably a 37 year old woman who became ill on April 24th, was hospitalized on May 2nd and died of respiratory disease on 4 May. Hers is the case where no specimens were obtained before burial, and the cause of her death cannot be confirmed. She had some backyard chickens which came into the house at night and three of these died before she became ill. The seven confirmed cases include the woman’s brother (who died on May 22nd) and her two sons, aged 15 and 17 years, who died on 9 May and 12 May, a 28-year-old sister of the woman who died on 10 May and the sister’s 18-month-old daughter, who died on 14 May. The final confirmed case, who is still alive, is the 25-year-old brother of the initial case. The sixth confirmed case is the 10-year-old nephew of the initial case who died on 13 May.
The source of infection for the additional cases has not yet been determined and multiple hypotheses are being investigated. The cases lived in close proximity to each other and are known to have participated in a family gathering around 29 April. At that time nine family members including three of those who became confirmed cases spent the night in close proximity with the initial case when she was symptomatic and coughing. If transmission took place that night then the incubation period would have been 5 to 6 days. These cases may have acquired their infection from a shared environmental exposure thought the possibility of limited human-to-human transmission seems quite possible. The first case’s sister and that sister’s young daughter (18 months) also developed infection which has been confirmed. Their exposure may have been when the sister was providing personal care of the initial case.
The crucial point however is that there is no evidence that infection has spread beyond members of this single extended family. No influenza-like illness has been identified in health care workers or other persons in close contact with the patients. One of the confirmed cases who subsequently died declined to be hospitalised and moved between villages with his wife (who remains well) and presumably potentially exposed others. There has been intense surveillance in the area and its unlikely that symptomatic infections will have been missed so if human-to-human transmission has occurred, it has not been sustained.
Health care workers have been under especially close surveillance. Earlier this month (first week of June) four nurses who cared for some of the confirmed came to attention because they had developed influenza like illness. They have all been found to be H5N1 negative. One was positive for a seasonal influenza A/H5N1.
Other Animals
There have been reports that some pig samples have tested positive for avian influenza according to media reports. These animals are apparently seropositive to H5 antigen on haemaglutination inhibition testing. However these results have not been verified by reference laboratories as serology for H5N1 infection is difficult to do and interpret. Even if the infection is positive it does not provide information on whether these animals actually carried the virus or infected people.
Virological information
Genetic sequencing of viruses isolated from cases in this cluster has been undertaken by WHO reference laboratories. Sequencing of all the gene segments found no evidence of genetic reassortment with human or pig influenza viruses and no evidence of significant mutations. The viruses also did not showed mutations associated with resistance to the neuraminidase inhibitors, including oseltamivir (Tamiflu). A report in Promed dated June 23rd indicated that there was some evidence of a further mutation of some of the viruses associated with the outbreak. However this did not seem to have been associated with any change in infectiousness or transmissibility.
ECDC Comment
Any large cluster like this is disturbing as increasing cluster size of outbreaks of H5N1 or any other novel influenza infection in humans could be indicative of increasing human to human transmission. However that is not happening here.
Even when investigations are very thorough in practice (and this outbreak seems to be being investigated especially thoroughly) it is often difficult to determine whether or not sporadic person to person transmissions of H5N1 infection have taken place in clusters like these. However sustained transmission would be hard to miss and these reports have consistently made it clear that the joint WHO-Indonesian team could find no evidence of that. A striking feature here and in most other clusters is that they are confined to blood related family members. It is unusual to find infections in other non-family persons who happened to be in the household. This has led to suggestions that there may be a genetic susceptibility operating with some humans being somewhat more vulnerable to infection.
The interest of some in pigs and avian influenza comes from the theory developed in the 1980s that these animals could act as mixing vessels between human, avian (and pig) influenza viruses. However to date there is no convincing evidence that pigs are as yet being significant affected by H5N1, despite extensive exposure in Asia where there are large domestic pig populations.
In the reporting of this outbreak in the media it does not seem to be appreciated that occasional person to person transmissions have been seen since the first H5N1 infections were observed in humans in 1997(1) and such occasional transmissions are permitted within WHO Prepandemic Phase 3.(2) Indeed it is quite likely that we are underestimating the number of occasional person to person transmissions are being underestimated because few clusters have been as well investigated as this one and even when investigations have been more thorough it can be impossible to determine whether a person has been infected from shared exposure or person to person transmission.(3)
However there is absolutely no room for complacency.(4) Veterinary services in Indonesia require considerable strengthening, and devolution of authority for veterinary services to provincial administrations has diluted central coordination and supervision of disease control activities. As a result, the reports to OIE (e.g. http://www.oie.int/eng/info/hebdo/aIS_21.htm#Sec2) are considered to represent only a proportion of the total number of cases of disease and infection. Outbreaks in poultry are continuing due to a range of factors including limited veterinary capacity to implement control programs, incomplete vaccination coverage, possible use of faulty vaccines, and non-reporting of disease by farmers. This means that people in parts of Indonesia are constantly at risk and the possibility of dangerous co-infection of people with H5N1 and human influenza viruses is considerable. It is therefore not surprising that Indonesia alone has accounted for nearly a third of all cases reported to WHO in 2006.
1. Hayden F, Croisier A. Transmission of Avian Influenza Viruses to and between Humans. J Infect Dis. 2005;192:1311-1314.
2. World Health Organization. WHO Global Influenza Preparedness Plan. http://www.who.int/csr/resources/pub...GIP_2005_5.pdf
3 Nicoll A. Human H5N1 infections: so many cases – why so little knowledge? Eurosurveillance 2006;11(5)
4 ECDC The Public Health Risk from Highly Pathogenic Avian Influenza Viruses Emerging in Europe with Specific Reference to type A/H5N1 Interim ECDC Risk Assessment – Revision 20 May 2006 http://www.ecdc.eu.int/avian_influen..._risk_HPAI.pdf
Investigation of the Family Cluster of Human H5N1 Cases in North Sumatra, Indonesia – Investigations by WHO and the Indonesian Ministries of Health and Agriculture. Status July 6th (latest WHO and FAO reports to June 20th)
WHO and the Indonesian Authorities have published progressive reports of the investigation around the cases of H5N1 in Kubu Simbelang village, Karo district of North Sumatra. There are no news of a further evolvement of the cluster since June 20th.
The WHO links are:
http://www.who.int/csr/don/2006_05_31/en/index.html, http://www.who.int/csr/don/2006_05_23/en/index.html and http://www.who.int/csr/don/2006_05_18b/en/index.html.
the FAO view is accessible through
http://www.fao.org/ag/againfo/subjec...ial_avian.html .
A map of the cases is available at
http://www.who.or.id/eng/php/map_avian.php .
A review of the epidemiology and virology of the case was recently undertaken by WHO and other UN Agencies as part of a wider review requested by the Indonesian authorities
http://www.who.int/mediacentre/news/.../en/index.html.
A report of the consultation has not been published yet. Media interviews with the senior WHO staff who attended indicated that a report will not hold many surprises in addition to what appears below.
Outbreak Summary
It is now more than a month since the last case in this family cluster died (May 22nd) and despite intense clinical surveillance around the area no more cases have come to light. This is far more than the usual two incubation periods (two times seven days) that allows it to be said that an outbreak is over.
There are a total of seven cases confirmed at a WHO Reference Laboratory, six of which have died. A possible eighth infection will never be proven as the body was buried before H5N1 infection was suspected and so no specimens are available). It remains the case that there have been no infections beyond a single extended family despite likely exposure of others.
This is the largest reported cluster of H5N1 infections reported worldwide. The initial case in this family cluster was probably a 37 year old woman who became ill on April 24th, was hospitalized on May 2nd and died of respiratory disease on 4 May. Hers is the case where no specimens were obtained before burial, and the cause of her death cannot be confirmed. She had some backyard chickens which came into the house at night and three of these died before she became ill. The seven confirmed cases include the woman’s brother (who died on May 22nd) and her two sons, aged 15 and 17 years, who died on 9 May and 12 May, a 28-year-old sister of the woman who died on 10 May and the sister’s 18-month-old daughter, who died on 14 May. The final confirmed case, who is still alive, is the 25-year-old brother of the initial case. The sixth confirmed case is the 10-year-old nephew of the initial case who died on 13 May.
The source of infection for the additional cases has not yet been determined and multiple hypotheses are being investigated. The cases lived in close proximity to each other and are known to have participated in a family gathering around 29 April. At that time nine family members including three of those who became confirmed cases spent the night in close proximity with the initial case when she was symptomatic and coughing. If transmission took place that night then the incubation period would have been 5 to 6 days. These cases may have acquired their infection from a shared environmental exposure thought the possibility of limited human-to-human transmission seems quite possible. The first case’s sister and that sister’s young daughter (18 months) also developed infection which has been confirmed. Their exposure may have been when the sister was providing personal care of the initial case.
The crucial point however is that there is no evidence that infection has spread beyond members of this single extended family. No influenza-like illness has been identified in health care workers or other persons in close contact with the patients. One of the confirmed cases who subsequently died declined to be hospitalised and moved between villages with his wife (who remains well) and presumably potentially exposed others. There has been intense surveillance in the area and its unlikely that symptomatic infections will have been missed so if human-to-human transmission has occurred, it has not been sustained.
Health care workers have been under especially close surveillance. Earlier this month (first week of June) four nurses who cared for some of the confirmed came to attention because they had developed influenza like illness. They have all been found to be H5N1 negative. One was positive for a seasonal influenza A/H5N1.
Other Animals
There have been reports that some pig samples have tested positive for avian influenza according to media reports. These animals are apparently seropositive to H5 antigen on haemaglutination inhibition testing. However these results have not been verified by reference laboratories as serology for H5N1 infection is difficult to do and interpret. Even if the infection is positive it does not provide information on whether these animals actually carried the virus or infected people.
Virological information
Genetic sequencing of viruses isolated from cases in this cluster has been undertaken by WHO reference laboratories. Sequencing of all the gene segments found no evidence of genetic reassortment with human or pig influenza viruses and no evidence of significant mutations. The viruses also did not showed mutations associated with resistance to the neuraminidase inhibitors, including oseltamivir (Tamiflu). A report in Promed dated June 23rd indicated that there was some evidence of a further mutation of some of the viruses associated with the outbreak. However this did not seem to have been associated with any change in infectiousness or transmissibility.
ECDC Comment
Any large cluster like this is disturbing as increasing cluster size of outbreaks of H5N1 or any other novel influenza infection in humans could be indicative of increasing human to human transmission. However that is not happening here.
Even when investigations are very thorough in practice (and this outbreak seems to be being investigated especially thoroughly) it is often difficult to determine whether or not sporadic person to person transmissions of H5N1 infection have taken place in clusters like these. However sustained transmission would be hard to miss and these reports have consistently made it clear that the joint WHO-Indonesian team could find no evidence of that. A striking feature here and in most other clusters is that they are confined to blood related family members. It is unusual to find infections in other non-family persons who happened to be in the household. This has led to suggestions that there may be a genetic susceptibility operating with some humans being somewhat more vulnerable to infection.
The interest of some in pigs and avian influenza comes from the theory developed in the 1980s that these animals could act as mixing vessels between human, avian (and pig) influenza viruses. However to date there is no convincing evidence that pigs are as yet being significant affected by H5N1, despite extensive exposure in Asia where there are large domestic pig populations.
In the reporting of this outbreak in the media it does not seem to be appreciated that occasional person to person transmissions have been seen since the first H5N1 infections were observed in humans in 1997(1) and such occasional transmissions are permitted within WHO Prepandemic Phase 3.(2) Indeed it is quite likely that we are underestimating the number of occasional person to person transmissions are being underestimated because few clusters have been as well investigated as this one and even when investigations have been more thorough it can be impossible to determine whether a person has been infected from shared exposure or person to person transmission.(3)
However there is absolutely no room for complacency.(4) Veterinary services in Indonesia require considerable strengthening, and devolution of authority for veterinary services to provincial administrations has diluted central coordination and supervision of disease control activities. As a result, the reports to OIE (e.g. http://www.oie.int/eng/info/hebdo/aIS_21.htm#Sec2) are considered to represent only a proportion of the total number of cases of disease and infection. Outbreaks in poultry are continuing due to a range of factors including limited veterinary capacity to implement control programs, incomplete vaccination coverage, possible use of faulty vaccines, and non-reporting of disease by farmers. This means that people in parts of Indonesia are constantly at risk and the possibility of dangerous co-infection of people with H5N1 and human influenza viruses is considerable. It is therefore not surprising that Indonesia alone has accounted for nearly a third of all cases reported to WHO in 2006.
1. Hayden F, Croisier A. Transmission of Avian Influenza Viruses to and between Humans. J Infect Dis. 2005;192:1311-1314.
2. World Health Organization. WHO Global Influenza Preparedness Plan. http://www.who.int/csr/resources/pub...GIP_2005_5.pdf
3 Nicoll A. Human H5N1 infections: so many cases – why so little knowledge? Eurosurveillance 2006;11(5)
4 ECDC The Public Health Risk from Highly Pathogenic Avian Influenza Viruses Emerging in Europe with Specific Reference to type A/H5N1 Interim ECDC Risk Assessment – Revision 20 May 2006 http://www.ecdc.eu.int/avian_influen..._risk_HPAI.pdf
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