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NEJM - March 29 2007 - Human H5N1 Influenza

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  • NEJM - March 29 2007 - Human H5N1 Influenza

    Human H5N1 Influenza
    <table border="0" cellpadding="0" cellspacing="0"><tbody><tr><th align="right" nowrap="nowrap" valign="top">Volume 356:1375-1377</th> <td nowrap="nowrap"></td> <th nowrap="nowrap" valign="top">March 29, 2007</th> <td nowrap="nowrap"></td> <th align="left" nowrap="nowrap" valign="top">Number 13</th></tr></tbody></table>

    As is consistent with previous studies of outbreaks<sup> </sup>of avian influenza A (H5N1) virus, the epidemiologic investigations<sup> </sup>reported by Kandun et al. in Indonesia and by Oner et al. in<sup> </sup>Turkey (Nov. 23 issue)<sup>1</sup><sup>,</sup><sup>2</sup> show that H5N1 virus primarily infects<sup> </sup>young people (median age, 9 years).

    As of late November 2006,<sup> </sup>258 cases of human H5N1 virus infection had been identified.<sup> </sup>More than half of the patients were under the age of 20 years<sup> </sup>(median age, 18.5 years), and 25% of them were under the age<sup> </sup>of 10 years. Although both studies report clusters within families<sup> </sup>and cite exposure to dead poultry as a common risk factor, it<sup> </sup>is unlikely that the intensity of exposure differed among household<sup> </sup>members.

    Rather, higher incidence rates in children may represent<sup> </sup>age-dependent differences in host susceptibility to H5N1 virus<sup> </sup>infection. Human infection is mediated by a receptor recognized<sup> </sup>by avian influenza (2,3-linked sialic acid) that is expressed<sup> </sup>in the lower respiratory tract.<sup>3</sup> In children this receptor may<sup> </sup>be expressed in the upper airway, increasing the risk of infection.<sup> </sup>Indeed, 2,3-linked sialic acids are homogeneously distributed<sup> </sup>in the human fetal lung, and the expression of the receptor<sup> </sup>appears to decrease with age.<sup>4</sup>

    Miguel Goicoechea, M.D.
    University of California, San Diego

    1. <!-- null -->
    2. Kandun IN, Wibisono H, Sedyaningsih ER, et al. Three Indonesian clusters of H5N1 virus infection in 2005. N Engl J Med 2006;355:2186-2194.<!-- HIGHWIRE ID="356:13:1375:1" --> <nobr>[Free Full Text]</nobr><!-- /HIGHWIRE --><!-- null -->
    3. Oner AF, Bay A, Arslan S, et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. N Engl J Med 2006;355:2179-2185.<!-- HIGHWIRE ID="356:13:1375:2" --> <nobr>[Free Full Text]</nobr><!-- /HIGHWIRE --><!-- null -->
    4. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006;440:435-436.<!-- HIGHWIRE ID="356:13:1375:3" --> [CrossRef][ISI][Medline]<!-- /HIGHWIRE --><!-- null -->
    5. Cerna A, Janega P, Martanovic P, Lisy M, Babal P. Changes in sialic acid expression in the lung during intrauterine development of the human fetus. Acta Histochem 2002;104:339-342.<!-- HIGHWIRE ID="356:13:1375:4" --> [CrossRef][ISI][Medline]

    Human H5N1 virus infection can be difficult to<sup> </sup>diagnose. In the report by Oner et al., the results of nasopharyngeal<sup> </sup>swabs were mostly negative. Positive results were obtained on<sup> </sup>polymerase-chain-reaction (PCR) assays of tracheal aspirates<sup> </sup>and lung-tissue samples. These results are predictable, since<sup> </sup>the receptors for the attachment of H5N1 virus are located predominantly<sup> </sup>around alveoli and terminal bronchioles and become progressively<sup> </sup>more rare toward the trachea.<sup>1</sup><sup>

    </sup> <sup> </sup>Jeanne A. Pawitan, M.D., Ph.D.
    University of Indonesia


    <!-- null --><!-- HIGHWIRE ID="356:13:1375:5" --> van Riel D, Munster VJ, de Wit E, et al. H5N1 virus attachment to lower respiratory tract. Science 2006;312:399-399. <nobr>[Free Full Text]</nobr>

    The Perspective article by Webster and Govorkova<sup>1</sup><sup> </sup>accompanying the reports by Kandun et al. and Oner et al. is<sup> </sup>perhaps the best available published summary of the emergence,<sup> </sup>evolution, and proliferation of H5N1 virus, an important emerging<sup> </sup>animal and human pathogen. Nonetheless, the time line that the<sup> </sup>authors provide does not include the four retrospectively confirmed<sup> </sup>cases of human H5N1 virus infection that occurred in Korea between<sup> </sup>December 2003 and March 2004 and another five confirmed cases<sup> </sup>that occurred in Japan during February and March 2004 among<sup> </sup>poultry workers and persons involved in the culling of infected<sup> </sup>poultry.

    The cases in Japan were not reported until 10 months<sup> </sup>after they had been confirmed, and the cases in Korea were not<sup> </sup>confirmed until more than 2 years after they had occurred. The<sup> </sup>existence of these often overlooked nonfatal cases of human<sup> </sup>H5N1 virus infection illustrate the many impediments we face<sup> </sup>in refining our understanding of the epidemiology, risks, and<sup> </sup>potential effects of this disease in human populations.<sup>

    </sup> <sup> </sup>Joseph P. Dudley, Ph.D.
    Science Applications International
    Arlington, VA 22203


    <!-- null --><!-- HIGHWIRE ID="356:13:1375:6" --> Webster RG, Govorkova EA. H5N1 influenza -- continuing evolution and spread. N Engl J Med 2006;355:2174-2177. <nobr>[Free Full Text]</nobr>

    Dr. Oner and colleagues reply: That the expression of 2,3-linked<sup> </sup>sialic acid receptor might be a reason for the high incidence<sup> </sup>of the disease in young patients is theoretical. To assess this<sup> </sup>concern, an understanding of the culture and traditions of the<sup> </sup>countries where avian influenza outbreaks have occurred is required.<sup> </sup>In the families of the patients in our study, exposure was more<sup> </sup>intensive in children than in their parents. People in this<sup> </sup>area of Turkey do not believe that the illness of chickens can<sup> </sup>be transmitted to humans. Therefore, the children played with<sup> </sup>the poultry, kissing and sleeping with them even when the birds<sup> </sup>were ill. However, the parents typically had contact with the<sup> </sup>chickens only while preparing them for cooking and eating them.<sup> </sup>We believe that contact with the secretions of the sick birds<sup> </sup>is an important risk factor and that children had more intensive<sup> </sup>contact with the poultry. Furthermore, if there were a relationship<sup> </sup>between viral-receptor intensity in young children and disease<sup> </sup>incidence, we would expect to see more cases in the first years<sup> </sup>of life, which has not been observed. Cerna et al.<sup>1</sup> have studied<sup> </sup>sialic acid expression in relation to developmental maturity<sup> </sup>of the lung and have shown that there is a slight decrease in<sup> </sup>sialic acid expression in the lungs before birth. Therefore,<sup> </sup>we think that children are affected by avian influenza viruses<sup> </sup>by the same mechanism that mediates adult infection.<sup> </sup> We agree with Pawitan that human H5N1 virus infection is difficult<sup> </sup>to diagnose. Although the results of some nasopharyngeal swabs<sup> </sup>were negative in our study, all tracheal aspirates and lung-tissue<sup> </sup>samples were positive on real-time PCR assay. As Pawitan states,<sup> </sup>the receptors for the attachment of avian influenza virus are<sup> </sup>located mostly around alveoli and terminal bronchioles.<sup>2</sup><sup> </sup>
    <sup> </sup>
    Ahmet Faik Oner, M.D.
    Yuzuncu Yil University
    65200 Van, Turkey

    Mehmet Ceyhan, M.D.
    Hacettepe University<sup> </sup>
    06100 Ankara, Turkey
    Hayrettin Akdeniz, M.D. <sup> </sup>
    Yuzuncu Yil University
    65200 Van, Turkey

    1. <!-- null -->
    2. Cerna A, Janega P, Martanovic P, Lisy M, Babal P. Changes in sialic acid expression in the lung during intrauterine development of the human fetus. Acta Histochem 2002;104:339-342.<!-- HIGHWIRE ID="356:13:1375:7" --> [CrossRef][ISI][Medline]<!-- /HIGHWIRE --><!-- null -->
    3. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006;440:435-436.<!-- HIGHWIRE ID="356:13:1375:8" --> [CrossRef][ISI][Medline]
    Dr. Kandun and colleagues reply: Most human cases of highly<sup> </sup>pathogenic H5N1 virus infection have been sporadic to date,<sup> </sup>but family clusters have occurred in several countries. Direct<sup> </sup>physical contact with sick or dead poultry has been identified<sup> </sup>as the primary risk factor.<sup>1</sup><sup>,</sup><sup>2</sup> The reported intensity of exposure<sup> </sup>to diseased or dead poultry can vary substantially among family<sup> </sup>members in households of patients who have H5N1 virus infection.<sup> </sup>In our study, all three patients and the unaffected family members<sup> </sup>in cluster 3 were similarly exposed to diseased or dead poultry,<sup> </sup>as were many neighbors who never became ill. No patients or<sup> </sup>unaffected family members in clusters 1 and 2 had known contact<sup> </sup>with sick or dead poultry. In addition to exposure to H5N1 virus,<sup> </sup>susceptibility to human infection with H5N1 viruses could be<sup> </sup>mediated by age or immunologic, genetic, or other factors. The<sup> </sup>question of whether genetic or other factors, such as those<sup> </sup>affecting the expression of the host inflammatory response,<sup>3</sup><sup> </sup>might influence the severity of disease after H5N1 virus infection<sup> </sup>should also be investigated.

    <sup> </sup> In our study, throat specimens had a higher yield for detecting<sup> </sup>H5N1 virus than did nasal specimens, and H5N1 viral RNA levels<sup> </sup>were higher in throat specimens than in nasal specimens in another<sup> </sup>study.<sup>3</sup> For detection of H5N1 viral RNA by real-time PCR in<sup> </sup>patients with suspected H5N1 virus infection, specimens should<sup> </sup>be collected from different respiratory sites on multiple days,<sup> </sup>including nasal and throat swabs from patients who are not undergoing<sup> </sup>mechanical ventilation and endotracheal aspirates from intubated<sup> </sup>patients.<sup>4</sup> Testing of nasal-swab specimens from patients with<sup> </sup>suspected H5N1 virus infection can also help detect human influenza<sup> </sup>A and B viruses that bind to 2,6-linked sialic acid receptors<sup> </sup>located primarily in the upper respiratory tract.<sup>5</sup>
    <sup> </sup>
    Two minor inaccuracies appear on page 2188 of our article. In<sup> </sup>Figure 1, the hospitalization date for Patient 2A should have<sup> </sup>been 9/6, rather than 9/3. On the same page, under the heading<sup> </sup>"Cluster 2," line 3 of the second paragraph should have read,<sup> </sup>"Four days after his aunt was hospitalized, he had onset of<sup> </sup>fever," rather than "three days." We regret the errors.<sup> </sup>
    <sup> </sup>
    I. Nyoman Kandun, M.D., M.P.H.
    Ministry of Health
    Jakarta 10560, Indonesia
    <sup> </sup>
    Endang R. Sedyaningsih, M.D., D.P.H. <sup> </sup>
    National Institute of Health Research and Development
    Jakarta 10560, Indonesia
    <sup> </sup>
    Timothy M. Uyeki, M.D., M.P.H.
    Centers for Disease Control<sup> </sup>and Prevention<sup> </sup>
    Atlanta, GA 30333

    <script type="text/javascript"><!-- var u = "tuyeki", d = ""; document.getElementById("em4").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>
    1. <!-- null -->
    2. Areechokchai D, Jiraphongsa C, Laosiritaworn Y, Hanshaoworakul W, O'Reilly M. Investigation of avian influenza (H5N1) outbreak in humans -- Thailand, 2004. MMWR Morb Mortal Wkly Rep 2006;55:Suppl 1:3-6.<!-- HIGHWIRE ID="356:13:1375:9" --><!-- /HIGHWIRE --><!-- null -->
    3. Pham DN, Hoang LT, Nguyen TKT, et al. Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004. Emerg Infect Dis 2006;12:1841-1847.<!-- HIGHWIRE ID="356:13:1375:10" --> [ISI][Medline]<!-- /HIGHWIRE --><!-- null -->
    4. de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006;12:1203-1207.<!-- HIGHWIRE ID="356:13:1375:11" --> [CrossRef][ISI][Medline]<!-- /HIGHWIRE --><!-- null -->
    5. World Health Organization. Collecting, preserving and shipping specimens for the diagnosis of avian influenza A(H5N1) virus infection. Guide for field operations. 2006 (Accessed March 8, 2007, at<!-- HIGHWIRE ID="356:13:1375:12" --><!-- /HIGHWIRE --><!-- null -->
    6. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature 2006;440:435-436.<!-- HIGHWIRE ID="356:13:1375:13" --> [CrossRef][ISI][Medline]<!-- /HIGHWIRE -->
    Drs. Webster and Govorkova reply:

    Dudley raises important unresolved<sup> </sup>issues about the timely detection and reporting of serologically<sup> </sup>confirmed cases of H5N1 infection in humans in South Korea and<sup> </sup>Japan between December 2003 and March 2004.

    Because of limited<sup> </sup>space, our Perspective article did not address the retrospective<sup> </sup>human cases of H5N1 in South Korea and Japan.

    The surprising<sup> </sup>finding is the low incidence of infection among humans after<sup> </sup>contact with infected poultry. The reemergence of H5N1 in poultry<sup> </sup>in both Vietnam and South Korea indicates that H5N1 virus continues<sup> </sup>to emerge and that the focus for eventual control may be domestic<sup> </sup>waterfowl.<sup> </sup> <sup> </sup>
    Robert G. Webster, Ph.D. <sup> </sup>
    Elena A. Govorkova, M.D., Ph.D.
    St. Jude Children's Research Hospital
    Memphis, TN 38105