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Update on human cases of influenza at the human–animal interface, 2012 (WHO, March 29 2013)

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  • Update on human cases of influenza at the human–animal interface, 2012 (WHO, March 29 2013)

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

    Weekly epidemiological record / Relevé épidémiologique hebdomadaire

    29 MARCH 2013, 88th year / 29 MARS 2013, 88e année / No. 13, 2013, 88, 137–144 /

    Update on human cases of influenza at the human–animal interface, 2012

    This report describes the epidemiology of the 32 laboratory-confirmed human infections with highly pathogenic avian influenza A(H5N1) virus that were reported to WHO from 6 countries during 2012, and summarizes the information on other zoonotic influenza infections – A(H3N2) variant, A(H1N1), A(H1N2) and A(H7N3) – reported in 2012 in humans.

    Human infection with influenza A(H5N1)

    Temporal and geographical distribution

    In 2012, the number of laboratory-confirmed human cases of A(H5N1) virus infection declined, despite continued widespread circulation of the virus in poultry in some countries. There were 32 human cases reported, down from 62 in 2011, 48 in 2010 and 73 in 2009. Of the 32 cases of A(H5N1), 11 occurred in Egypt, 9 in Indonesia, 4 in Viet Nam, 3 in Cambodia, 3 in Bangladesh and 2 in China.

    According to information from the Food and Agriculture Organization of the United Nations (FAO), influenza A(H5N1) virus is circulating endemically in poultry in Bangladesh, China and Viet Nam.(1) Egypt and Indonesia have officially declared the H5N1 virus endemic in poultry,(2) and a recent study from Institut Pasteur, Cambodia, suggested that the virus is circulating endemically in poultry in Cambodia.(3) All countries reporting human cases in 2012 also reported human cases in previous years.

    The epidemiological curve of human cases follows the same seasonal pattern seen in previous years, with larger numbers of cases in the months December to March (Figure 1). This curve follows the seasonal curve of reported outbreaks in poultry. Of the human cases for the year, 72% (23/32 cases) were reported in the first 3 months of 2012 (1 January to 31 March).

    Distribution by age and sex

    In 2012, most cases occurred in children and young adults; 90% (29/32) were in people aged <40 years and 34% (11/32) in children aged <10 years. Cases ranged in age from 6 months to 45 years, with a median age of 18 years. The median age of reported cases has varied annually since 2009: 5 years of age in 2009, 25 years in 2010 and 13 years in 2011.

    The median age of cases in Egypt remained high for the third consecutive year. The median age in Egypt in 2009 was 3 years but rose to 27 years in 2010 and 21 years in 2011 and continued to increase in 2012 to 31 years.

    In 2012, Egypt reported fewer cases of H5N1 infection (11 cases) compared with previous years (39 cases in 2011, 29 cases in 2010, 39 cases in 2009).

    In the past few years, the trend in Indonesia has been towards progressively younger cases. In 2012, the median age was 12 years, up from 8 years in 2011, but considerably down from 34 years in 2010 and 20 for 2005–2011. Indonesia also reported a relatively low number of human cases in 2012: 9 cases were reported in 2012, 12 cases in 2011, 9 cases in 2010 and 21 cases in 2009, compared with 55 cases reported in 2006.

    In 2012, equal numbers of male and female cases were reported overall, although this pattern was not uniform across countries or age groups. The sex difference was most prominent in Egypt where 82% (9/11) of cases were female. Data from all cases reported during 2003–2012 show a similar 1:1.2 male:female ratio.

    Clinical outcome

    In 2012, the overall proportion of fatal cases among those reported was 62.5% (20/32), slightly higher than in the previous 3 years (55% in 2011, 50% in 2010, 44% in 2009) but similar to the average of all cases reported to WHO since 2003 (59% [360/610]). The proportion of confirmed cases with fatal outcomes varied among countries and age groups. The proportion of fatal cases among those reported was 100% in Indonesia (9/9) and Cambodia (3/3), and 0 (0/3) in Bangladesh. Considerable differences were also found across age groups. In previous years, children younger than 10 years seemed to have a better survival rate than older age groups. In 2012 however, of the 11 children <10 years infected, 6 died (54.5%). This proportion was notably higher than the average of all cases reported to WHO since 2003 (37.3% [71/190]). The proportion also varied by country; all children in Indonesia (4 cases) and Cambodia (2 cases) under 10 died but all 4 in Egypt survived. In 2012, the highest proportion of known cases that died was among those aged 10–19 years (86%, 6/7), similar to the 2003–2012 historical proportion of 74.4% (93/125) in that age group. The lowest proportion of fatal cases was among persons aged 40–49 (33%, 1/3).

    In the past, it has been noted that female cases had a worse outcome than male cases and this trend continued in 2012. In 2012, the median ages for male and female cases were 19.5 years for males and 12.5 years for females; however, 69% (11/16) of females had fatal outcomes compared with 56% (9/16) of male cases. This finding is similar to the 2003–2012 average in which 64% of reported cases in females died and 53% of male cases.

    Of the 32 cases reported in 2012, only 4 were not hospitalized. Of the 4 non-hospitalized cases 3 were detected through an ongoing surveillance project in live bird markets and 1 visited a health-care centre but was not admitted. Data on the time from onset of illness to hospitalization were available for 25 cases and ranged from 0–8 days (median, 4 days); 7 cases (28%) were admitted to hospital <2 days after onset of the illness, while 18 cases (72%) were admitted >2 days after symptom onset. Cases with a fatal outcome were admitted to hospital later (median, 5 days) than those who survived (median, 1 day). In 2012 as in previous years, cases were more likely to survive if they were hospitalized ≤2 days after onset than >2 days (case-fatality rate [CFR]) 3/7 (43%) versus 16/18 (88%); odds-ratio [OR]: 10.6; 95% confidence interval [CI]: 1.3–86.9).

    Since 2003 (n=506) the likelihood of survival is higher for those who were hospitalized within 2 days after onset versus >2 days (CFR: 42/146 (29%) versus 260/360 (72%); OR: 6.4; 95% CI: 4.2–9.8).

    Only 43% (12/28) of cases admitted to hospital received oseltamivir but most (10/12) oseltamivir-treated cases began treatment on the day of admission. Cases treated with oseltamivir within 4 days of onset were more likely to survive than those treated later than 4 days after onset but this finding was not statistically significant.

    Information on time between onset and oseltamivir use is available for 103 cases since 2003. Cases receiving oseltamivir within 4 days after onset had a higher likelihood of survival than those treated after 4 days of onset (CFR 10/53 [19%] versus 35/50 [70%]; OR: 10; CI: 4–25).

    Exposure information

    Of the 32 cases, data on exposure were reported for 29. There were no new clusters reported in 2012, with only 1 case with onset in 2012 linked to an Indonesian cluster from 2011. As in previous years, exposure to sick or dead poultry was the predominant reported exposure, accounting for 11 of the 32 cases. Of these cases, 3 had slaughtered sick birds. Other reported exposures included 8 cases with backyard poultry exposures and 8 cases with visits to live bird markets. The 3 cases from Bangladesh were detected via an ongoing surveillance project in live bird markets; all had mild symptoms and recovered fully.

    Virological information

    Not all viruses from human cases in 2012 have been cultured. Of those isolated and characterized, the viruses belong to clade 1.1 (Cambodia and Viet Nam), clade 2.2.1 (Egypt), clade (Indonesia), clade (Bangladesh and China) and clade (China). In general, the clades of viruses isolated from humans in each country are those circulating in local poultry. Most persons have little or no immunity to influenza A(H5N1), since it is an avian virus with no antigenically related viruses circulating in humans. The genetic and antigenic diversification of circulating influenza A(H5N1) viruses requires the development of multiple A(H5N1) candidate vaccine viruses for purposes of pandemic preparedness. Currently 22 A(H5N1) candidate vaccine viruses are available and new candidates are in development. There is no evidence of increasing antiviral resistance to oseltamivir in influenza A(H5N1) viruses or reassortment with any of the circulating seasonal human influenza viruses.

    Human infections with other influenza viruses circulating in animals

    In 2012, several human infections with influenza viruses currently circulating in animal populations were reported. Transmission of these viruses from animals to humans resulted in sporadic human cases or small clusters among close contacts; epidemiological investigations did not uncover any evidence of community level spread.

    Human infections with A(H3N2)v virus

    In 2012, the United States of America (USA) reported 309 cases of human influenza infection with a non-seasonal variant of A(H3N2) virus (designated A(H3N2)v(4)) that was circulating in swine in that country. In 2011, only 12 cases of A(H3N2)v were reported. From July to December 2012, 16 people were hospitalized with A(H3N2)v infection and there was 1 death. These viruses were first identified in the USA in swine in 2010, and the large majority of cases have been associated with exposure to swine, especially among participants in agricultural fairs during the northern hemisphere’s summer and early autumn months. Although instances of likely human-to-human transmission were identified, no sustained human-to-human transmission was reported. Serological studies(5, 6, 7, 8) indicate that adults may have had previous exposure to an antigenically similar seasonal A(H3N2) virus, however, very little cross-reactive antibody was found in children suggesting that they would have little or no immunity. This finding is consistent with the observation that most cases of A(H3N2)v infection occurred in children. Seasonal vaccines provided a modest boost to the level of antibody to influenza A(H3N2)v in adults and might confer limited protection against A(H3N2)v infection in the adult population. A candidate vaccine virus is available and could be used to produce a specific A(H3N2)v vaccine if necessary. Influenza A(H3N2)v viruses tested are susceptible to the neuraminidase inhibitor drugs oseltamivir and zanamivir. To date, the A(H3N2)v virus does not appear to transmit easily among people and seems to be associated with mild symptoms.

    Human infections with non-seasonal A(H1) viruses

    Two human cases of infection with a non-seasonal variant of A(H1N1) influenza virus that was circulating locally in swine were reported in 2012: 1 from Canada and 1 from the USA. Both cases reported direct contact with swine and both recovered from the illness. No further cases were associated with these 2 cases.

    Three human cases of infection with a variant of A(H1N2) influenza virus circulating in swine were detected in the USA. All 3 had prolonged and direct contact with swine and recovered from the illness, despite 2 having underlying health conditions that put them at risk for complications from influenza infection.

    Serological studies suggest some existing population immunity, since the haemagglutinin (HA) component of the viruses is similar to human seasonal influenza viruses circulating in humans as recently as 2007; however, very young children are likely to have little or no immunity.(9)

    Based on assessment of the public health risks of ongoing spread of these non-seasonal variants of A(H1N1) and A(H1N2) influenza viruses, especially considering their antigenic and genetic characteristics, candidate vaccine viruses were not proposed.(10) Available data indicate that these viruses are likely to be susceptible to treatment with oseltamivir and zanamivir.(9)

    Human infection with A(H7N3) avian influenza viruses

    During 2012, 2 cases of human infection with A(H7N3) viruses were reported in Mexico, associated with a highly pathogenic avian influenza A(H7N3) outbreak in poultry. These human cases were mild, with conjunctivitis as the main clinical sign.(11) Both cases were exposed while working on a farm where poultry was infected with the A(H7N3) virus. No further human cases have been reported. Candidate A(H7) vaccine viruses are available for the development of A(H7) vaccines.


    At present, A(H5N1) remains an avian virus that has not changed substantially in its epidemiological or clinical behaviour since its emergence; human infections remain rare and sporadic. Only 1 cluster was detected in 2012. As in previous years, most human cases of A(H5N1) virus infection are reportedly exposed through direct or indirect contact with household/backyard poultry or contaminated environments, rather than through association with commercial poultry or wild birds. However, identification of the specific exposure leading to human infection is difficult since many people in areas where poultry are affected have multiple exposures to the birds, contaminated environments or live animal markets in their daily lives. The risk of sporadic human A(H5N1) virus infections remains in areas where the virus is circulating in poultry populations and people are exposed to infected birds.

    Although the proportion of reported fatal human cases remains high, the finding of 3 human cases in 2012 with mild infection reinforces concerns that many milder cases of infection occur undetected. Recent reviews of H5 seroprevalence studies found little evidence that large numbers of cases of H5N1 infection are missed.(12, 13)

    However, because of the variation in protocols and standards in the serological studies, as well as persistent questions about serological responses in exposed or infected humans, the frequency of subclinical infection or mild illness remains uncertain. It is also likely that some severe and fatal cases were not diagnosed and thus missed.

    Early recognition of human infection and prompt hospitalization are likely to lead to more favourable outcomes.

    WHO continues to recommend that clinicians in areas with outbreaks of H5N1 influenza in poultry and H5N1-endemic countries be encouraged to consider influenza A(H5N1) infection when patients present with compatible clinical and epidemiological features, and to treat patients as early as possible with appropriate antiviral medications.(14)

    Although influenza A(H5N1) infection in humans seems rare, the prospect that A(H5N1) viruses circulating in animals might evolve and acquire the ability to spread with ease from person to person, while retaining capacity to cause severe disease, is a serious public health concern. During 2011, 2 groups of researchers (one in the Netherlands and the other a joint Japan/USA group) conducted studies(15, 16) to understand better the transmissibility of A(H5N1) influenza viruses. These studies resulted in the creation of laboratory-modified A(H5N1) viruses that can easily transmit in ferrets and demonstrated that relatively few genetic changes in A(H5N1) viruses might enable transmission via the respiratory route. As humans lack immunity to influenza viruses possessing an H5 HA protein, a transmissible H5 virus would likely have pandemic potential. Findings from these studies can be used to improve the impact of public health surveillance by allowing monitoring of these key genetic changes and improving early detection of potentially pandemic H5N1 strains, and might aid the development of vaccines and the assessment of the potential value of other countermeasures.

    In contrast to influenza A(H5N1) infections, human infections with other influenza viruses circulating in animals – A(H3N2)v, variants of A(H1N1), A(H1N2) and A(H7N3) – reported in 2012 in humans were clinically mild.

    Sporadic human cases of influenza A(H7) virus infection linked with outbreaks in poultry have been reported previously: H7N3 in Canada,(17) Italy,(18) and the United Kingdom;(19) H7N2 in the USA(20) and the UK;(21, 22) and H7N7 in the UK and the Netherlands.(23) Most H7 infections previously reported in humans have been mild with the exception of 1 fatal case in the Netherlands, in a veterinarian who had close contact with infected birds. All the A(H3N2)v, variants of A(H1N1) and A(H1N2) viruses associated with human infections in 2012 included the M gene derived from the A(H1N1)pdm09 virus in their genome, probably because of reassortment in swine between the A(H1N1)pdm09 virus and the viruses previously circulating in swine in the USA. Reassortant viruses containing the M gene from the A(H1N1)pdm09 virus have also been circulating increasingly in swine in the USA. The role of the M gene is uncertain; some experimental research has suggested that the M gene from the A(H1N1)pdm09 virus may confer on the virus an increased ability to transmit from animals to humans.(24)

    Sporadic human cases and small clusters of human infection with these non-seasonal influenza viruses might be expected whenever influenza viruses are circulating in animal populations to which humans are directly exposed. To date, none of these viruses has acquired the ability to transmit easily from person to person, and no community level spread has been reported. However, as long as these viruses continue to circulate, public health risks will remain.

    Influenza viruses are unpredictable. Their constant evolving nature raises concerns that these viruses could adapt or reassort with other influenza viruses, thereby gaining potential to become more transmissible to or more pathogenic in humans.

    Continued monitoring of the occurrence of human infections with non-seasonal influenza viruses and ongoing characterization of the viruses to assess their pandemic risk are therefore critically important for public health. Close collaboration with animal health partners allows information regarding viruses circulating in animal populations and human populations worldwide to be shared to improve assessment of global influenza risks to health. WHO continues to stress the importance of global monitoring of influenza viruses and recommends all Member States to strengthen routine influenza surveillance.

    All human infections with non-seasonal influenza viruses should be reported to WHO under the International Health Regulations (2005).

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