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WER. Summary of human infection with highly pathogenic avian influenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases

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  • WER. Summary of human infection with highly pathogenic avian influenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases

    Summary of human infection with highly pathogenic avian influenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases

    Weekly epidemiological record 15 JANUARY 2010, 85th YEAR
    No. 3, 2010, 85, 13–20 http://www.who.int/wer

    Full pdf at: http://www.who.int/wer/2010/wer8503.pdf

    excerpt


    . . .
    During 2003–2009, 480 confirmed (n=443) or probable (n=37) human cases of H5N1 virus infection were identified and reported to WHO. Of these, 54 clusters were identified involving 138 cases (29% of cases; 104 cases confirmed and 34 probable); the remaining 342 cases (71% of cases) were sporadic (339 confirmed cases and 3 probable).
    . . .

    Case investigation

    For 44 clusters, information was available on whether the primary case (that is, the case with the earliest onset) triggered an investigation that led to the identification of additional cases. During 2003–2004, an investigation was triggered for 1/4 clusters (25%), compared with 6/12 (50%) during 2005, 7/18 (39%) during 2006, 3/5 (67%) during 2007, and 3/5 (67%) during 2008–2009.

    Discussion

    This analysis demonstrates the importance of clusters in the overall epidemiology of human H5N1 virus infection; almost one third of cases occurred in a cluster. Detection of the primary case often triggered an investigation that led to identification of other cases.

    Clustering suggests that there is the potential for wide-spread transmission of the virus. In this context, it is reassuring that the absolute number of clusters and the proportion of all cases associated with clusters have both decreased; only 2 countries (Indonesia and Viet Nam) have reported the clustering of cases for an extended time. It also is reassuring that only 3 clusters had cases occurring beyond 2 weeks; none lasted beyond 23 days.
    . . .
    http://novel-infectious-diseases.blogspot.com/

  • #2
    Re: WER. Summary of human infection with highly pathogenic avian influenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases

    Summary of human infection with highly pathogenic avian influenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases (WHO WER, edited)

    [Source Full PDF Document: LINK. EDITED.]

    Weekly epidemiological record - 15 JANUARY 2010, 85th YEAR - No. 3, 2010, 85, 13–20
    http://www.who.int/wer

    Summary of human infection with highly pathogenic avian influenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases


    Background

    In 1969, WHO developed International Health Regulations, a legally binding international agreement, to prevent the global spread of disease. The 2005 revision – known as IHR (2005) – entered into force in June 2007 and expands the scope of the original regulations from the diseases cholera, plague and yellow fever to include any public health event, irrespective of its origin or source, that presents a significant threat to global health.1 Annex 2 of IHR (2005) provides a framework for defining public health emergencies that are of international concern; this framework includes individual cases and the clustering of cases or outbreaks of human infection with highly pathogenic avian influenza A (H5N1) virus because the clustering of cases or outbreaks signifies the potential for human-to-human transmission of the virus, greater viral transmissibility and potentially the start of an influenza A (H5N1) pandemic. A key feature of IHR (2005) is the obligation of Member States to increase their public health capacity for investigating health threats and reporting these to WHO.

    Human clusters of H5N1 virus infection are also of interest because they may provide information on the likelihood of genetic susceptibility to infection or severe disease, and the dynamics of viral transmission within households. For example, investigators in China and Thailand have used results from cluster investigations to argue for the likelihood of human-to-human transmission.2,3 Investigators in Indonesia have postulated that people whose cases occur as part of a cluster have a lower risk of death than people whose cases occur sporadically.4 WHO has received reports of human H5N1 virus infection from Member States since 2003 and has participated in subsequent investigations of clusters. Most data reported to WHO have been presented separately in publications developed by individual countries,5–18 but no summary of clusters worldwide has been presented.

    While reports from individual countries provide detailed descriptions of cases, the goal of this analysis was to present a description of the global epidemiology of cluster-associated cases that have occurred until the end of August 2009.


    Methods

    Data reported to WHO arise from investigations conducted by individual countries and those countries’ willingness to share data. In some cases, data were not included in this analysis owing to the difficulty of conducting comprehensive evaluations in some settings or the incompleteness of the data. Where data were missing, we have reported the denominator. In particular, comprehensive data on exposure were available only for the years 2003–2007.

    Specific case-definitions used in this investigation have been published (See LINK). We included both confi rmed and probable cases of H5N1 virus infection. In brief, a probable case met 1 of 2 definitions:

    • (i) a person meeting the definition of a suspected case plus either radiographic evidence of pneumonia and respiratory failure, or laboratory identification of influenza A but insufficient evidence of H5N1 virus infection or
    • (ii) a person dying of an unexplained acute respiratory illness linked epidemiologically to a probable or confirmed case.

    Confirmation existed when a person met the clinical definition of a suspected or probable case and 1 of the following laboratory criteria:
    • (i) H5N1 virus was isolated;
    • (ii) polymerase chain reaction (PCR) testing using of acute serum specimens (collected <7 days after symptom onset) and convalescent serum specimens (the convalescent neutralizing antibody titre must have been 1:80 or higher); or
    • (iv) a microneutralization antibody titre for H5N1 virus of >1:80 was found in a single serum specimen collected at day 14 (or later) after symptom onset and a positive result was also found using a different serological assay (for example, a horse red blood cell haemagglutination inhibition titre of >1:160 was found or an H5-specific western blot result was positive).

    A cluster was defined as a group composed of >1 confirmed cases of H5N1 virus infection and additional confirmed or probable cases associated with a specific setting, such as a household, extended family, hospital, other residential institution, military barracks or recreational camp, with the onset of cases occurring within 2 weeks of each other.19

    To evaluate human exposure, proximity to an ill case was defined as an instance or instances where people lived within 500 metres of an earlier case. Direct human contact was defined as having touched, slept in the same bed with, or provided bedside care to any confirmed or probable case, or handling or kissing the body of a deceased confirmed or probable case. Indirect contact was defined as sharing a household with a confirmed or probable case, visiting a hospital or home, or socializing with a confirmed or probable case.

    To evaluate exposure to birds, direct contact was defined as activities that implied touching a bird before the onset of illness or when the terminology “direct contact” or “close contact” was used in a case report. Proximity to a bird was defined as the presence of birds in a home or in nearby homes, or as visiting another household where birds were raised on site or nearby before the onset of illness. People were considered to have been exposed to a sick or dead bird if the bird showed any signs of illness, died of an unknown cause or was known to be infected with H5N1 virus.


    Results

    Background and demographic information

    During 2003–2009, 480 confirmed (n=443) or probable (n=37) human cases of H5N1 virus infection were identified and reported to WHO. Of these, 54 clusters were identified involving 138 cases (29% of cases; 104 cases confirmed and 34 probable); the remaining 342 cases (71% of cases) were sporadic (339 confirmed cases and 3 probable).

    During 2003–2006 the percentage of all cases identified as cluster-associated was 39% (115/294); during 2007–2009 the percentage of cluster-associated cases declined to 12% (23/186) (Fig. 1). The percentage of all cases occurring in clusters was relatively stable by country except in those countries with only a few reported cases (Table 1). The average cluster size was 2.5 cases (median, 2 cases; range 2–8); this remained stable by country (Table 1). During 2003–2006, the average number of people in a cluster increased (Fig 1). There were 38 clusters with 2 cases, 10 with 3 cases, 3 with 4 cases and 3 with 5, 7 and 8 cases.

    Cluster-associated cases and sporadic cases each occurred in 11 countries; 7 countries reported both types of cases, and these countries accounted for 86% (119/138) of cluster-associated cases and 99% (337/342) of sporadic cases.

    The mean age of cluster-associated cases was 19 years (median, 15 years; range, 4 months–81 years) compared with 22 years for sporadic cases (median, 20 years; range, 1–75 years) (P=0.06). Among cluster-associated cases, 53% (72/137) were female compared with 51% (173/336) of sporadic cases (P=0.92). Table 1 shows the demographic data by country for both types of cases.


    Seasonality, temporal trends, cluster durationand reporting

    Clusters peaked during 2005 and 2006. China, Indonesia and Viet Nam were the only countries to have clusters identified during >2 consecutive years (Fig. 2). Indonesia and Viet Nam had the most clusters, but no seasonality was identified. In 35 clusters, the date of illness onset was known for ≥2 cases and the difference in the date of onset between the index and other cases varied from 0 days (in instances where the date of onset was the same for both cases in a cluster) to 23 days (mean, 6.7 days; median, 6 days). The difference in the date of illness onset was >10 days in 7 clusters and >14 days in 3 clusters.

    The time from the onset of illness in the first case to a report being made to WHO was recorded for 17 clusters; it averaged 10 days (median, 10 days; range, 0–22). The delay from time of illness onset in a second case (that is, the case that indicated the existence of a cluster) to reporting to WHO was known for 19 clusters; it averaged 28 days (median, 8; range, 3–369); and all but 1 of the 19 reports was made at <12 days.


    Mortality

    Among cluster-associated cases, the case-fatality ratio (CFR) was 64%; the CFR varied by country, from 43% in Egypt to 100% in Cambodia and Nigeria (Table 1).

    The CFR was similar for sporadic cases and clusterassociated cases.

    For cluster-associated cases, the CFR was 74% (n=83) among those aged 10–39 years compared with 42% (n=36) among those aged <10 years (rate ratio [RR], 1.7; 95% confidence interval [CI], 1.2–2.7) and 63% (n=8) among those aged >40 years (RR, 1.2; 95% CI, 0.7–2.0). Among sporadic cases, the CFR was 77% (n=187) for those aged 10–39 years compared with 45% (n=76) among those aged <10 years (RR, 1.7; 95% CI, 1.3–2.2) and 47% (n=32) among those aged >40 years (RR, 1.6; 95% CI, 1.1–2.4). Among cluster-associated cases, the CFR was high regardless of the time from symptom onset to hospitalization, although earlier hospitalization appeared to have some benefit. The CFR was 50% for those who were not hospitalized (n=6), 50% for those for whom there was a delay of <2 days (n=12), 62% for those with a delay of 2–3 days (n=21), 74% for those with a delay of 4–5 days (n=35), 70% for a delay of 6–7 days (n=23) and 40% for a delay of >8 days (n=10).

    The CFRs were similar for sporadic cases except for those hospitalized earliest: the CFR was 19% for those with a delay of <2 days (n=48), 62% for a delay of 2–3 days (n=53), 79% for a delay of 4–5 days (n=56), 70% for a delay of 6–7 days (n=41) and 40% for a delay of >8 days (n=31). According to the data, all sporadic cases were hospitalized.

    For all cases combined, the CFR was 32% among those hospitalized following a delay of <2 days compared with 61% for a delay of 2–3 days (RR, 0.5; 95% CI, 0.3–0.8) and 70% for a delay of >3 days or for those who were not hospitalized (RR, 0.5; 95% CI, 0.3–0.7).

    For cluster-associated cases, the CFR was 74% for females (n=72) and 54% for males (n=65) (RR, 1.4; 95% CI, 1.1–1.8). In the 7 countries with >5 cases, the CFR was similar for females and males in 3 of them: Azerbaijan (67% for males and females), Thailand (75% males versus 67% females) and Egypt (40% males versus 50% females). The CFR was higher for females than males in the 4 remaining countries: China (80% females versus 33% males), Viet Nam (61% females versus 46% males), Indonesia (85% females versus 59% males), and Turkey (75% females versus 33% males).

    For sporadic cases, the CFR was similar for females (66%; n=177) and males (57%; n=164) (RR, 1.1; 95% CI, 0.97–1.4).

    Among cluster-associated cases, death was associated with case order among 129 cases for whom this information existed, including 51/62 (82%) primary or coprimary cases, 28/47 (60%) second cases, 6/12 (50%) third cases and 3/8 (38%) fourth or fifth cases.


    Households and exposures

    For 41/54 clusters, information on household residence was known. In 30 instances (73%) all cluster members lived in 1 house; in 7 clusters (17%) all lived in 2 houses; and in 4 clusters (10%) members lived in 3–6 houses. For all 54 clusters, the relationship between affected people was known, and in 50 clusters everyone was a blood relative. In the 4 remaining clusters, 2 clusters that included >3 people, 9/11 people were blood relatives; and in 2 clusters, each contained 2 unrelated people.

    A total of 68 secondary cases were identified; for 55 there was information on human exposure. For 54/55 (98%) there was documented exposure or the possibility of having been exposed to an ill person before symptom onset. Of the 54 cases with actual or potential human exposure, for 25 (46%) exposure was direct contact; for 29 (54%) the contact was indirect. A total of 116 cases were classified as either primary or secondary (having had exposure to an ill person); however exposure to birds was documented for almost all of these cases (Table 2).


    Case investigation

    For 44 clusters, information was available on whether the primary case (that is, the case with the earliest onset) triggered an investigation that led to the identification of additional cases. During 2003–2004, an investigation was triggered for 1/4 clusters (25%), compared with 6/12 (50%) during 2005, 7/18 (39%) during 2006, 3/5 (67%) during 2007, and 3/5 (67%) during 2008–2009.


    Discussion

    This analysis demonstrates the importance of clusters in the overall epidemiology of human H5N1 virus infection; almost one third of cases occurred in a cluster. Detection of the primary case often triggered an investigation that led to identification of other cases.

    Clustering suggests that there is the potential for widespread transmission of the virus. In this context, it is reassuring that the absolute number of clusters and the proportion of all cases associated with clusters have both decreased; only 2 countries (Indonesia and Viet Nam) have reported the clustering of cases for an extended time. It also is reassuring that only 3 clusters had cases occurring beyond 2 weeks; none lasted beyond 23 days.

    Based on the lack of knowledge about exposure to avian sources, 3 published studies have postulated the existence of human-to-human transmission during illness clusters. These studies occurred in China, Pakistan and Thailand.2,3,18 All of the cases in these clusters are included in this analysis. Nevertheless, the information reported to WHO is not as detailed as that available to local investigators, and thus its difficult to draw firm conclusions about human-to-human transmission from this analysis. The data are clear: the majority of clusterassociated cases have occurred in people with documented exposure to birds.

    Although some variation in mortality was identified, mortality was uniformly high regardless of country, age group and time from symptom onset to presentation at hospital. Nevertheless, early presentation at a hospital appeared to substantially reduce mortality. A report from Indonesia found a small association between a delay in presentation and fatality, with a stronger association documented between the delay between the time of symptom onset and the start of oseltamivir treatment.4

    We found a higher CFR among females but this was not uniform across countries. It is not clear whether this association was due to
    • (i) genetic differences;
    • (ii) differences in environmental circumstances, such as more intense exposure to birds owing to different roles played by men and women in the poultry industry or more intense exposure to primary cases due to differences in caretaking practices; or
    • (iii) differences in access to care by sex. We also identified an association between fatality and the order in which a case occurred in a cluster.


    Cluster-associated cases are common but decreasing.

    Despite this, national authorities should be aware of the data presented here and rigorously investigate the contacts of known H5N1 cases to determine whether there is a common source of exposure or human-to-human transmission. Additionally, national authorities are encouraged to collect data on known or possible cases and to continue reporting these data to WHO.

    References

    1 International Health Regulations (2005), Geneva, World Health Organization, 2005 (LINK; accessed December 2009).
    2 Wang H et al. Probable limited person-to-person transmission of highly pathogenic avian influenza A(H5N1) virus in China. Lancet, 2008, 371:1427–1434.
    3 Ungchusak K et al. Probable person-to-person transmission of avian influenza A (H5N1). New England Journal of Medicine, 2005, 352:333–340.
    2 different PCR targets was positive for influenza H5 virus; (iii) there was a fourfold or greater rise in neutralizing antibody titre for H5N1 virus based on testing
    4 Kandun et al. Factors associated with case fatality of human H5N1 virus infections in Indonesia: a case series. Lancet, 2008, 372:744–749.
    5 See No. 18, 2006, pp. 183–188.
    6 Vong S et al. Low frequency of poultry-to-human H5N1 virus transmission, Southern Cambodia, 2005. Emerging Infectious Diseases, 2006, 12:1542–1547.
    7 Kandun IN et al. Three Indonesian clusters of H5N1 virus infection in 2005. New England Journal of Medicine, 2006, 355:2186–2194.
    8 Ortiz JR et al. Lack of evidence of avian-to-human transmission of avian influenza A (H5N1) virus among poultry workers, Kano, Nigeria, 2006. Journal of Infectious Diseases, 2007, 196:1685–1691.
    9 Oner AF et al. Avian influenza A(H5N1) infection in Eastern Turkey in 2006. New England Journal of Medicine, 2006, 355:2179–2185.
    10 Hien TT et al. Avian uenza A(H5N1) in 10 patients in Vietnam. New England Journal of Medicine, 2004, 350:1179–1188.
    11 See No. 42, 2006, p. 397.
    12 See No. 50/51, 2006, pp. 465–468.
    13 See No. 8, 2006, p. 71.
    14 See No. 12, 2006, pp. 105–106.
    15 See No. 19, 2006, pp. 189.
    16 See No. 21, 2006, p. 209.
    17 See No. 9, 2006, pp. 81–82.
    18 See No. 40, 2008, pp. 359–364.
    19 WHO case definitions for human infections with influenza A(H5N1) virus. Geneva, World Health Organization, 2006 (LINK; accessed December 2009).

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    Comment


    • #3
      Re: WER. Summary of human infection with highly pathogenic avian influenza A (H5N1) virus reported to WHO, January 2003–March 2009: cluster-associated cases

      Comment

      This is perhaps most the significant WHO report on human avian influenza cases since 2003. This report is a tacit admission that H5N1 is capable of human to human transmission. Not only does human to human transmission occur but it occurs fairly regularly. The report states that “Cluster-associated cases are common but decreasing.” The report did not suggest a cause or mechanism for this decline. However, the perceived decline may simply be an artifact of the data set. The world is currently preoccupied with an H1N1 pandemic and surveillance resources have been committed to tracking H1N1 infections. So H5N1 infections may be being missed. Also the recent failure of some of nations to report human H5N1 cases and clusters may also skew the data set.
      <o:p> </o:p>
      This should be a reminder that H5N1 has not gone away and still has the potential to cause a new influenza pandemic.
      http://novel-infectious-diseases.blogspot.com/

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