To the Editor: As is consistent with previous studies of outbreaksof avian influenza A (H5N1) virus, the epidemiologic investigationsreported by Kandun et al. in Indonesia and by Oner et al. inTurkey (Nov. 23 issue)1,2 show that H5N1 virus primarily infectsyoung people (median age, 9 years). As of late November 2006,258 cases of human H5N1 virus infection had been identified.More than half of the patients were under the age of 20 years(median age, 18.5 years), and 25% of them were under the ageof 10 years. Although both studies report clusters within familiesand cite exposure to dead poultry as a common risk factor, itis unlikely that the intensity of exposure differed among householdmembers. Rather, higher incidence rates in children may representage-dependent differences in host susceptibility to H5N1 virusinfection. Human infection is mediated by a receptor recognizedby avian influenza (2,3-linked sialic acid) that is expressedin the lower respiratory tract.3 In children this receptor maybe expressed in the upper airway, increasing the risk of infection.Indeed, 2,3-linked sialic acids are homogeneously distributedin the human fetal lung, and the expression of the receptorappears to decrease with age.4
Miguel Goicoechea, M.D. University of California, San Diego San Diego, CA 92103 mgoicoechea{at}ucsd.edu
References
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. [Free Full Text]
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. [Free Full Text]
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. [CrossRef][Medline]
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. [CrossRef][ISI][Medline]
To the Editor: Human H5N1 virus infection can be difficult todiagnose. In the report by Oner et al., the results of nasopharyngealswabs were mostly negative. Positive results were obtained onpolymerase-chain-reaction (PCR) assays of tracheal aspiratesand lung-tissue samples. These results are predictable, sincethe receptors for the attachment of H5N1 virus are located predominantlyaround alveoli and terminal bronchioles and become progressivelymore rare toward the trachea.1
Jeanne A. Pawitan, M.D., Ph.D. University of Indonesia Jakarta 10430, Indonesia jeanneadiwip{at}yahoo.com
References
van Riel D, Munster VJ, de Wit E, et al. H5N1 virus attachment to lower respiratory tract. Science 2006;312:399-399. [Free Full Text]
To the Editor: The Perspective article by Webster and Govorkova1accompanying the reports by Kandun et al. and Oner et al. isperhaps the best available published summary of the emergence,evolution, and proliferation of H5N1 virus, an important emerginganimal and human pathogen. Nonetheless, the time line that theauthors provide does not include the four retrospectively confirmedcases of human H5N1 virus infection that occurred in Korea betweenDecember 2003 and March 2004 and another five confirmed casesthat occurred in Japan during February and March 2004 amongpoultry workers and persons involved in the culling of infectedpoultry. The cases in Japan were not reported until 10 monthsafter they had been confirmed, and the cases in Korea were notconfirmed until more than 2 years after they had occurred. Theexistence of these often overlooked nonfatal cases of humanH5N1 virus infection illustrate the many impediments we facein refining our understanding of the epidemiology, risks, andpotential effects of this disease in human populations.
Joseph P. Dudley, Ph.D. Science Applications International Arlington, VA 22203 dudleyjp{at}saic.com
References
Webster RG, Govorkova EA. H5N1 influenza -- continuing evolution and spread. N Engl J Med 2006;355:2174-2177. [Free Full Text]
Dr. Oner and colleagues reply: That the expression of 2,3-linkedsialic acid receptor might be a reason for the high incidenceof the disease in young patients is theoretical. To assess thisconcern, an understanding of the culture and traditions of thecountries where avian influenza outbreaks have occurred is required.In the families of the patients in our study, exposure was moreintensive in children than in their parents. People in thisarea of Turkey do not believe that the illness of chickens canbe transmitted to humans. Therefore, the children played withthe poultry, kissing and sleeping with them even when the birdswere ill. However, the parents typically had contact with thechickens only while preparing them for cooking and eating them.We believe that contact with the secretions of the sick birdsis an important risk factor and that children had more intensivecontact with the poultry. Furthermore, if there were a relationshipbetween viral-receptor intensity in young children and diseaseincidence, we would expect to see more cases in the first yearsof life, which has not been observed. Cerna et al.1 have studiedsialic acid expression in relation to developmental maturityof the lung and have shown that there is a slight decrease insialic acid expression in the lungs before birth. Therefore,we think that children are affected by avian influenza virusesby the same mechanism that mediates adult infection.
We agree with Pawitan that human H5N1 virus infection is difficultto diagnose. Although the results of some nasopharyngeal swabswere negative in our study, all tracheal aspirates and lung-tissuesamples were positive on real-time PCR assay. As Pawitan states,the receptors for the attachment of avian influenza virus arelocated mostly around alveoli and terminal bronchioles.2
Ahmet Faik Oner, M.D. Yuzuncu Yil University 65200 Van, Turkey afo59{at}yahoo.com
Mehmet Ceyhan, M.D. Hacettepe University 06100 Ankara, Turkey
Hayrettin Akdeniz, M.D. Yuzuncu Yil University 65200 Van, Turkey
References
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. [CrossRef][ISI][Medline]
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. [CrossRef][Medline]
Dr. Kandun and colleagues reply: Most human cases of highlypathogenic H5N1 virus infection have been sporadic to date,but family clusters have occurred in several countries. Directphysical contact with sick or dead poultry has been identifiedas the primary risk factor.1,2 The reported intensity of exposureto diseased or dead poultry can vary substantially among familymembers in households of patients who have H5N1 virus infection.In our study, all three patients and the unaffected family membersin cluster 3 were similarly exposed to diseased or dead poultry,as were many neighbors who never became ill. No patients orunaffected family members in clusters 1 and 2 had known contactwith sick or dead poultry. In addition to exposure to H5N1 virus,susceptibility to human infection with H5N1 viruses could bemediated by age or immunologic, genetic, or other factors. Thequestion of whether genetic or other factors, such as thoseaffecting the expression of the host inflammatory response,3might influence the severity of disease after H5N1 virus infectionshould also be investigated.
In our study, throat specimens had a higher yield for detectingH5N1 virus than did nasal specimens, and H5N1 viral RNA levelswere higher in throat specimens than in nasal specimens in anotherstudy.3 For detection of H5N1 viral RNA by real-time PCR inpatients with suspected H5N1 virus infection, specimens shouldbe collected from different respiratory sites on multiple days,including nasal and throat swabs from patients who are not undergoingmechanical ventilation and endotracheal aspirates from intubatedpatients.4 Testing of nasal-swab specimens from patients withsuspected H5N1 virus infection can also help detect human influenzaA and B viruses that bind to 2,6-linked sialic acid receptorslocated primarily in the upper respiratory tract.5
Two minor inaccuracies appear on page 2188 of our article. InFigure 1, the hospitalization date for Patient 2A should havebeen 9/6, rather than 9/3. On the same page, under the heading"Cluster 2," line 3 of the second paragraph should have read,"Four days after his aunt was hospitalized, he had onset offever," rather than "three days." We regret the errors.
I. Nyoman Kandun, M.D., M.P.H. Ministry of Health Jakarta 10560, Indonesia
Endang R. Sedyaningsih, M.D., D.P.H. National Institute of Health Research and Development Jakarta 10560, Indonesia
Timothy M. Uyeki, M.D., M.P.H. Centers for Disease Controland Prevention Atlanta, GA 30333 tuyeki{at}cdc.gov
References
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.
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. [ISI][Medline]
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. [CrossRef][ISI][Medline]
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. [CrossRef][Medline]
Drs. Webster and Govorkova reply: Dudley raises important unresolvedissues about the timely detection and reporting of serologicallyconfirmed cases of H5N1 infection in humans in South Korea andJapan between December 2003 and March 2004. Because of limitedspace, our Perspective article did not address the retrospectivehuman cases of H5N1 in South Korea and Japan. The surprisingfinding is the low incidence of infection among humans aftercontact with infected poultry. The reemergence of H5N1 in poultryin both Vietnam and South Korea indicates that H5N1 virus continuesto emerge and that the focus for eventual control may be domesticwaterfowl.
Robert G. Webster, Ph.D. Elena A. Govorkova, M.D., Ph.D. St. Jude Children's Research Hospital Memphis, TN 38105
Correction
to
Kandun et al., 
2,3-linked sialic acid) that is expressed in the lower respiratory tract.3 In children this receptor may be expressed in the upper airway, increasing the risk of infection. Indeed, 
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