EPIDEMIOLOGY OF INFLUENZAVIRUS A (H5N1)ref : a digital archive of all suspected and laboratory confirmed human cases reported by the media. All readers are encouraged to signal eventual mistakes by posting referenced corrections to my e-mail.

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Table of contents :

  • 1997 and Feb 2003 Hong Kong outbreaks
  • 2003-2005 outbreak
  • Czech Republic
  • Croatia
  • Lithuania
  • Poland
  • Switzerland
  • Italy
  • Germany
  • Denmark
  • The Netherlands
  • Belgium
  • Sweden
  • Finland
  • France
  • Spain
  • Portugal
  • UK
  • Ireland
  • Africa :
  • Lybia
  • Zimbabwe
  • Malawi
  • Algeria
  • Morocco
  • Nigeria
  • Egypt
  • Mauritania
  • Chad
  • Congo
  • Niger
  • Cameroon
  • Senegal
  • Ethiopia
  • Uganda
  • Kenya
  • Botswana
  • Burkina Faso
  • Ivory Coast
  • Sudan
  • Djibouti
  • Oceania :
  • Australia
  • Fiji
  • Americas
  • Canada
  • USA
  • Bahamas
  • Brazil
  • maps
  • summary of H5N1-susceptible animals
  • summary H5N1 clusters in humans
  • web resources

  • On 6 Mar 2006, WHO spokeswoman Maria Cheng said told H5N1 poses a greater challenge to the world than any infectious disease, including AIDS, and has cost 300 million farmers more than $10 billion in its spread through poultry around the worldref.
    > 209 million poultry have died or been culled since January 2004 to July 2006 worldwide
    WHO case definitionsref :
  • SUSPECTED H5N1 CASE : a person presenting with unexplained acute lower respiratory illness with fever (>38 C) and cough, shortness of breath or difficulty breathing AND one or more of the following exposures in the 7 days prior to symptom onset:
  • (a) close contact (within 1 m) with a person (for example: caring for, speaking with, or touching) who is a suspected, probable, or confirmed H5N1 case;
  • (b) exposure (for example: handling, slaughtering, defeathering, butchering, preparation for consumption) to poultry or wild birds or their remains or to environments contaminated by their feces in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month;
  • (c) consumption of raw or undercooked poultry products in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month;
  • (d) close contact with a confirmed H5N1 infected animal other than poultry or wild birds (e.g. cat or pig);
  • (e) handling samples (animal or human) suspected of containing H5N1 virus in a laboratory or other setting.
  • PROBABLE H5N1 CASE (notify WHO)
  • Probable definition 1: a person meeting the criteria for a suspected case AND one of the following additional criteria:
  • a. infiltrates or evidence of an acute pneumonia on chest radiograph plus evidence of respiratory failure (hypoxemia, severe tachypnea) OR
  • b. positive laboratory confirmation of an influenza A infection but insufficient laboratory evidence for H5N1 infection.
  • Probable definition 2: a person dying of an unexplained acute respiratory illness who is considered to be epidemiologically linked by time, place, and exposure to a probable or confirmed H5N1 case.
  • CONFIRMED H5N1 CASE (NOTIFY WHO) : a person meeting the criteria for a suspected or probable case AND one of the following positive results conducted in a national, regional or international influenza laboratory whose H5N1 test results are accepted by WHO as confirmatory:
  • However, the following references indicate that atypical infections (encephalitis, diarrheal, gastrointestinal illness) are a serious concern associated with outbreaks of avian influenza A subtype H5N1 worldwideref1, ref2. Furthermore, European researchers have reported what they call the first evidence that low-pathogenic avian influenza (LPAI) viruses, and not just highly pathogenic (HPAI) strains like H5N1, can infect humans. The finding, in a study of Italian poultry workers, suggests that avian influenza viruses have more chances than previously suspected to mix with human influenza viruses, potentially creating hybrids that could trigger a human influenza pandemicref. Diarrhea and the detection of viral RNA in most fecal samples tested has been a frequent observation suggesting that H5N1 virus may replicate in the human gastrointestinal tract. This raises the
    question of whether human feces could be a source of transmissionref. Examples of asymptomatic human infection : WHO guidelines for investigation of human cases of avian influenza A(H5N1) - October 2006

    While much has been made of the fulminant cases of presumed viral pneumonia in 1918, Dr. Brundage's research indicates that the majority of pneumonia cases, even in 1918, were either secondary bacterial pneumonias following an influenza infection or mixed viral and bacterial pneumonias. In the pre-antibiotic era, these cases of bacterial pneumonia carried a very high mortality rate; however, with appropriate antibiotic therapy, many such patients may be saved. There is still a deficit of comprehensive seroprevalence data to establish the true frequency of subclinical infections and the relevance of these sporadic accounts of atypical infections listed above.

  • epidemics in Hong Kong :
  • since late 2003, the flu has struck hundreds of thousands of birds and prompted widespread poultry culls in Eastern Asiaref1, ref2. The current AI A/Vietnam/1196/2004(H5N1) virus HA nucleotide sequence is 97% identical to the one discovered at a goose farm in China's Guangdong Province in 1996 (A/Goose/Guangdong/1/96(H5N1) or Gd96), the same which led to the outbreak of AI in Hong Kong in 1997 and the death of a man in Feb 2003, Japanese researchers said on Thu 5 Feb 2004. In Hong Kong, the Gd96 virus has been continually found in ducks and geese exported from China since 1997. Governments throughout the region have slaughtered 100 million chickens, ducks, and other poultry in efforts to keep the virus from spreading. Phylogenetic analyses of the H5 HA genes from the 2004 and 2005 outbreak showed 2 different lineages of HA genes, termed clades 1 and 2. Viruses in each of these clades are distributed in non-overlapping geographic regions of Asia. The H5N1 viruses from the Indochina peninsula are tightly clustered within clade 1, whereas H5N1 isolates from several surrounding countries are distinct from clade 1 isolates and belong in the more divergent clade 2. Clade 1 H5N1 viruses were isolated from humans and birds in Viet Nam, Thailand, and Cambodia but only from birds in Laos and Malaysia. The clade 2 viruses were found in viruses isolated exclusively from birds in China, Indonesia, Japan, and South Korea. Viruses isolated from birds and humans in Hong Kong in 2003 and 1997 made up clades 1* and 3, respectively. he HA genes from H5N1 viruses isolated from human specimens were closely related to HA genes from H5N1 viruses of avian origin; human HA gene sequences differ from the nearest gene from avian isolates from the sameyear in 2-14 nucleotides (<1% divergence). These findings are consistent with the epidemiologic data that suggest that humans acquired their infections by direct or indirect contact with poultry or poultry products. Analysis of the amino acid sequences showed that both clades of H5 HAs from the 2004-2005 outbreak have a multiple basic amino acid motif at thecleavage site, a defining feature of HPAI viruses. Among all H5N1 isolates collected in east Asia since 1997, only those in clades 1, 1*, and 3 appear to be associated with fatal human infections. NA genes from human and related avian H5N1 isolates from 2003-2005 as well as clade 3 isolates were characterized by deletions in the stalk region of the protein (positions 49-68 for clades 1-2 and 54-72 for clade 3). Deletions in the stalk of the NA are thought to increase retention of virions at the plasma membrane to balance weaker binding of sialic acid receptors by the HA with newly acquired N154 glycosylation. The phylogenetic tree of the M genes resembled that of the HA genes, indicating coevolution of these genes. The amino acid sequence of the M2 protein of clade 1 viruses as well as of HK/213/03 indicated a serine-to-asparagine substitution at residue 31 (S31N), known to confer resistance to adamantanes (including amantadine and rimantadine). All the currently circulating clade 1 isolates are resistant to adamantanes.  The PB2, PB1, and PA polymerase genes from 2003-2005 H5N1 isolates from humans constitute a single clade and have coevolved with the respective HA genes. No evidence of reassortment with polymerase genes from circulating H1N1 or H3N2 human influenza virus was found. The phylogenies of the NP and NS genes also supported the avian origin of these genes, indicating that all the genes from the human H5N1 isolates analyzed are of avian origin, which confirms the absence of reassortment with human influenza genes. Taken together, the phylogenies of the 8 genomic segments show that the H5N1 viruses from human infections and the closely related avian viruses isolated in 2004 and 2005 belong to a single genotype, often referred to as genotype Z. H5N1 isolates collected in 2004 and 2005 analyzed by the HI test showed reactivity patterns that correlated with the 3 main clades of recent isolates identified in the HA gene phylogeny. Viruses from humans and birds in clade 1 were found to constitute a relatively homogeneous and distinct antigenic group characterized by poor inhibition by ferret antisera to isolates from other clades, in particular by the ferret antiserum raised to HK/213/03 (64-fold reduction compared to the homologous titer). The latter isolate was previously used to develop a vaccine reference strain in response to 2 confirmed H5N1 human infections in February 2003. Antigenic analysis of human isolates from 2005 provided evidence of antigenic drift among the most recently circulating H5N1 strains. Inactivated influenza vaccines are manufactured from reassortant viruses obtained by transferring the HA and NA genes with the desired antigenic properties into a high-growth strain such as PR8. However, reassortants with H5-derived HA with a polybasic cleavage site are potentially hazardous for animal health. Because the high pathogenicity of the H5N1 viruses in poultry, mice, and ferrets depends primarily on the polybasic cleavage site in the HA molecule, a derivative with a deletion of this motif was engineered in cloned HA cDNAs. 3 high-growth reassortant influenza viruses were developed: NIBRG-14 (NIBSC), VN/04xPR8-rg (SJCRH), and VNH5N1-PR8/CDC-rg (CDC). These candidate vaccine strains, bearing mutant H5 HA, intact NA, and the internal genes from PR8, were generated by a reverse genetics approach using Vero cells and laboratory protocols compatible with eventual use of the vaccine in human subjects. These 3 vaccine candidates were characterized genetically (nucleotide sequencing of HA and NA) and antigenically in HI assays to confirm that their antigenicity remained unchanged relative to the wildtype virus. The candidate reference stocks had molecular and antigenic properties equivalent to parental H5N1 donor strains and lacked virulence in chicken, mouse, and ferret models. The origin of the HA genes of the 2004-2005 outbreak as well as an earlier isolate from a fatal human infection in Hong Kong in 2003 (clade 1*) can be traced back to viruses isolated in 1997 in Hong Kong (clade 3) and from geese in China (goose/Guangdong/96). The phylogeny also shows that viruses with HK/97-like HA may have circulated in avian hosts continuously after 1997 without causing any reported human infections until the 2 confirmed cases in Hong Kong in February 2003.  Genetic and antigenic analyses have shown that, compared to previous H5N1 isolates, 2004-2005 isolates share several amino acid changes that modulate antigenicity and perhaps other biological functions. Furthermore, molecular analysis of the HA from isolates collected in 2005 suggests that several amino acids located near the receptor-binding site are undergoing change, some of which may have an affect on antigenicity or transmissibility. Further surveillance to determine the prevalence of such variants in poultry will be critical to determine whether these variants compromise the efficacy of the candidate vaccine or increase the efficiency of transmission. The phylogenies of the 8 genomic segments from the clade 1 and 2 isolates from 2004-2005 showed that all genes are of avian origin. All H5N1 isolates from both clades belong to one of the genotypes recently circulating in Eastern and Southern Asia, e.g., genotypes V and Z. An effective H5N1 vaccine is a public health priority and the cornerstone for pandemic prevention and control. Reverse genetics approaches allow the rapid production of high-growth PR8 reassortant viruses by engineering a virus with a homologous HA gene lacking the polybasic amino acids associated with high virulence. These candidate H5N1 pandemic vaccine viruses have been made available to vaccine manufacturers to produce pilot lots for clinical trials and are available for possible large-scale manufacturing, should the need ariseref. Perhaps one of the most significant aspects of this analysis is the finding that antigenic drift is occurring and that some recent isolates are distinguishable from virus isolates that were chosen as the candidate vaccine antigens. This identifies a need for continued surveillance of poultry for the appearance of antigenic variants which may compromise the effectiveness of the current vaccine under development. A rolling program of vaccine development may be required to take account of possible changes in the antigenicity of the virus. 37 countries/territories are known to be have been infected by HPAI H5N1 virus since the start of the panzootic in December 2003 to Feb 2006 (alphabetical order): Albania, Austria, Azerbaijan, Bulgaria, Cambodia, China (People's Rep.), Croatia, Denmark, Egypt, France, Germany, Greece, Hong Kong (SARPRC), Hungary, India, Indonesia, Iraq, Iran, Italy, Japan, Kazakhstan, South Korea, Laos, Malaysia, Mongolia, Myanmar, Nigeria, Poland, Romania, Russia, Serbia and Montenegro, Slovakia, Slovenia, Switzerland, Thailand, Turkey, Ukraine, Vietnamref. In addition, the following 5 countries have officially reported H5 in avians: Bosnia & Herzegovina, Georgia, Laos, Pakistan & the Philippines.