Pathology, Molecular Biology, and Pathogenesis of Avian Influenza A (H5N1) Infection in Humans
2008; Elsevier BV; Volume: 172; Issue: 5 Linguagem: Inglês
10.2353/ajpath.2008.070791
ISSN1525-2191
Autores Tópico(s)Animal Disease Management and Epidemiology
ResumoH5N1 avian influenza is a highly fatal infectious disease that could cause a potentially devastating pandemic if the H5N1 virus mutates into a form that spreads efficiently among humans. Recent findings have led to a basic understanding of cell and organ histopathology caused by the H5N1 virus. Here we review the pathology of H5N1 avian influenza reported in postmortem and clinical studies and discuss the key pathogenetic mechanisms. Specifically, the virus infects isolated pulmonary epithelial cells and causes diffuse alveolar damage and hemorrhage in the lungs of infected patients. In addition, the virus may infect other organs, including the trachea, the intestines, and the brain, and it may penetrate the placental barrier and infect the fetus. Dysregulation of cytokines and chemokines is likely to be one of the key mechanisms in the pathogenesis of H5N1 influenza. We also review the various molecular determinants of increased pathogenicity that have been identified in recent years and the role of avian and human influenza virus receptors in relation to the transmissibility of the H5N1 virus. A comprehensive appreciation of H5N1 influenza pathogenetic mechanisms should aid in the design of effective strategies for prevention, diagnosis, and treatment of this emerging disease. H5N1 avian influenza is a highly fatal infectious disease that could cause a potentially devastating pandemic if the H5N1 virus mutates into a form that spreads efficiently among humans. Recent findings have led to a basic understanding of cell and organ histopathology caused by the H5N1 virus. Here we review the pathology of H5N1 avian influenza reported in postmortem and clinical studies and discuss the key pathogenetic mechanisms. Specifically, the virus infects isolated pulmonary epithelial cells and causes diffuse alveolar damage and hemorrhage in the lungs of infected patients. In addition, the virus may infect other organs, including the trachea, the intestines, and the brain, and it may penetrate the placental barrier and infect the fetus. Dysregulation of cytokines and chemokines is likely to be one of the key mechanisms in the pathogenesis of H5N1 influenza. We also review the various molecular determinants of increased pathogenicity that have been identified in recent years and the role of avian and human influenza virus receptors in relation to the transmissibility of the H5N1 virus. A comprehensive appreciation of H5N1 influenza pathogenetic mechanisms should aid in the design of effective strategies for prevention, diagnosis, and treatment of this emerging disease. H5N1 avian influenza was initially confined to poultry, but in recent years it has emerged as a highly fatal infectious disease in the human population. In 1997, the avian influenza A virus subtype H5N1 crossed the avian-human species barrier for the first time.1Claas EC Osterhaus AD van Beek R De Jong JC Rimmelzwaan GF Senne DA Krauss S Shortridge KF Webster RG Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus.Lancet. 1998; 351: 472-477Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar Eighteen individuals were infected, six of whom died.2Yuen KY Chan PK Peiris M Tsang DNC Que TL Cheung PT To WK Ho ETF Sung R Cheng AFB Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus.Lancet. 1998; 351: 467-471Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar In January 2003, avian influenza re-emerged among humans in Hong Kong,3Peiris JSM Yu WC Leung CW Cheung CY Ng WF Nicholls JM Ng TK Chan KH Lai ST Lim WL Yuen KY Guan Y Re-emergence of fatal human influenza A subtype H5N1 disease.Lancet. 2004; 363: 617-619Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar and since 2004 numerous human infections have also occurred in other Asian and non-Asian countries. To date, the World Health Organization has reported 348 laboratory-confirmed cases, 216 of which were fatal, resulting in a fatality rate of ∼60% (World Health Organization: http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_01_03/en/index.html; accessed January 2008). Human infections mainly resulted from poultry-to-human transmission. Recently, however, there have been reports of human-to-human transmission,4Ungchusak K Auewarakul P Dowell SF Kitphati R Auwanit W Puthavathana P Uiprasertkul M Boonnak K Pittayawonganon C Cox NJ Zaki SR Thawatsupha P Chittaganpitch M Khontong R Sirnerman JM Chunsutthiwat S Probable person-to-person transmission of avian influenza A (H5N1).N Engl J Med. 2005; 352: 333-340Crossref PubMed Scopus (591) Google Scholar, 5Normile D Human transmission but no pandemic in Indonesia.Science. 2006; 312: 1855Google Scholar increasing fears of a human pandemic. H5N1 influenza is still a relatively novel disease with poorly understood pathology and pathogenesis. During the period from the first known outbreak nearly a decade ago until the present, only a limited number of reports describing pathological findings in human H5N1 cases has been published. Nevertheless, recent studies combined with early findings have gradually resulted in a better understanding of the cell and organ pathology caused by the H5N1 virus, as well as the viral tissue tropism. These findings together with animal and in vitro experiments have also contributed to a basic understanding of the pathogenesis of this disease. On the molecular level, several viral genes and gene products have been identified that may be responsible for the high pathogenicity of H5N1 influenza viruses. Herein, we describe the pathology of H5N1 avian influenza by reviewing the major pathological findings reported in hitherto published postmortem studies of human H5N1 cases as well as some key findings of animal studies. In addition, the major pathogenetic mechanisms and etiological factors of H5N1 influenza are discussed. The various molecular determinants of increased pathogenicity of H5N1 avian influenza viruses that have been identified in recent years are also presented. Finally, we have taken a closer look at the role of avian and human influenza virus receptors in relation to the transmissibility of the H5N1 virus. Thus far the results of only nine full autopsies including one autopsy of a fetus,3Peiris JSM Yu WC Leung CW Cheung CY Ng WF Nicholls JM Ng TK Chan KH Lai ST Lim WL Yuen KY Guan Y Re-emergence of fatal human influenza A subtype H5N1 disease.Lancet. 2004; 363: 617-619Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar, 4Ungchusak K Auewarakul P Dowell SF Kitphati R Auwanit W Puthavathana P Uiprasertkul M Boonnak K Pittayawonganon C Cox NJ Zaki SR Thawatsupha P Chittaganpitch M Khontong R Sirnerman JM Chunsutthiwat S Probable person-to-person transmission of avian influenza A (H5N1).N Engl J Med. 2005; 352: 333-340Crossref PubMed Scopus (591) Google Scholar, 6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar, 7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar, 9Uiprasertkul MP Kitphati R Puthavathana P Kriwong R Kongchanagul A Ungchusak K Angkasekwinai S Chokephaibulkit K Srisook K Vanprapar N Auewarakul P Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans.Emerg Infect Dis. 2007; 13: 708-712Crossref PubMed Google Scholar, 10Chotpitayasunondh T Ungchusak K Hanshaoworakul W Chunsuthiwat S Sawanpayalert P Kijphati R Lochindarat S Srisan P Suwan P Osotthanakorn Y Anantasetagoon T Kanjanawasri S Tanupattarachai S Weerakul J Chaiwirattana R Maneerattanaporn M Poolsavatkitikool R Chokephaibulkit K Apisarnthanarak A Dowellet SF Human disease from influenza A (H5N1).Thailand Emerg Infect Dis. 2004; 11: 201-209Crossref Google Scholar three limited autopsies (only the lungs and spleen),10Chotpitayasunondh T Ungchusak K Hanshaoworakul W Chunsuthiwat S Sawanpayalert P Kijphati R Lochindarat S Srisan P Suwan P Osotthanakorn Y Anantasetagoon T Kanjanawasri S Tanupattarachai S Weerakul J Chaiwirattana R Maneerattanaporn M Poolsavatkitikool R Chokephaibulkit K Apisarnthanarak A Dowellet SF Human disease from influenza A (H5N1).Thailand Emerg Infect Dis. 2004; 11: 201-209Crossref Google Scholar and two cases of postmortem organ biopsies11Chan PK Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.Clin Infect Dis. 2002; 34: S58-S64Crossref PubMed Scopus (233) Google Scholar, 12Subbarao K Klimov A Katz J Regnery H Lim W Hall H Perdue M Swayne D Bender C Huang J Hemphill M Rowe T Shaw M Xu X Fukuda K Cox N Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness.Science. 1998; 279: 393-396Crossref PubMed Scopus (868) Google Scholar, 13Ku AS Chan LT The first case of H5N1 avian influenza infection in a human with complications of adult respiratory distress syndrome and Reye's syndrome.J Paediatr Child Health. 1999; 35: 207-209Crossref PubMed Google Scholar have been reported. The main histopathological findings for each of these reports are summarized in Table 1 and discussed below.Table 1Summary of Published Autopsy Reports and Their Main Histopathological FindingsNumber of cases*FA, full autopsy; LA, limited autopsy; B, biopsies.Disease duration/sex/age†Disease duration before death in days (d); sex: female (F), male (M).Main histopathological findingsRegion/country/period/reference (no.)2 (FA)29 days/F/13 years (case 1); 28 days/F/25 years (case 2)Lungs: DAD, interstitial fibrosis, reactive pneumocytes, interstitial lymphoplasmacytic infiltration, few histiocytes with reactive hemophagocytic activity, cystically dilated air spaces. Liver: central lobular necrosis. Kidneys: acute tubular necrosis. Brain: edema, demyelinated areas (not observed in case 2). Bone marrow: hypoplastic (case 1), hyperplastic (case 2), reactive histiocytes with reactive hemophagocytic activity. Lymph nodes: hemophagocytosis. Spleen: white pulp atrophy, reactive hemophagocytosisHong Kong/1997/(6)1 (B)11 days‡This patient died of H5N1 infection and the complications of Reye's syndrome./M/3 yearsLiver: microvesicular fatty changes (consistent with Reye's syndrome), multiple Councilman bodies with some inflammatory cells. Kidneys: vacuolation, vesicular changes in proximal tubules (consistent with Reye's syndrome). Bone marrow: occasional hemophagocytic activity, reactive changesHong Kong/1997/(12,13)1 (B)11 days/M/54 yearsLungs: reactive pneumocytes, hemorrhage, fibrinous exudates, sparse lymphocytic infiltration. Kidneys: acute tubular necrosis. Bone marrow: hypercellular, reactive hemophagocytosisHong Kong/1997/(11)1 (FA)6 days/M/33 yearsLungs: edema, hemorrhage, fibrin exudation, pneumocytes hyperplasia, intra-alveolar macrophages, interstitial T lymphocytes. Bronchial and hilar lymph nodes: reactive histiocytes with hemophagocytic activity. Bone marrow: hypercellular, hemophagocytosis. Spleen: lymphoid depletion. Other organs: no remarkable findingsHong Kong/2003/(3,14)1 (FA)9 days/F/26 yearsLungs: DAD and interstitial pneumonia. Liver: cholestasis, hemophagocytic activity. Spleen: congestion, depletion of lymphocytesThailand/2004/(4)1 (FA)6 days/M/48 yearsLungs: DAD (exudative phase), atypical pneumocytes, bronchiolitis, pleuritis. Hemophagic activity in lungs, liver, and bone marrowThailand/¶Not specified./(9)1 (FA)17 days/M/6 yearsLungs: DAD (proliferative phase), interstitial pneumonia, focal hemorrhage, reactive pneumocytes, superimposed fungal infection, bronchiolitis. Lymph nodes, spleen, and bone marrow: slight histiocytic hyperplasia without hemophagocytic activity. Liver: mild fatty changes, activated Kupffer cells, lymphoid infiltration. Brain: edema, small foci of necrosis. Other organs: no remarkable findingsThailand/2004/(8)3 (FA)9 days/F/24 years (case 1)§This patient was 4 months pregnant at the time of death.; 27 days/M/35 years (case 2)Lungs: DAD, edema, intra-alveolar macrophages, desquamation of epithelial cells, foci with bronchopneumonia, areas with fibrosis (case 2). Spleen: massive depletion in white and red pulp. Lymph nodes: loss of germinal centers. Liver: edema, single cell hepatocyte necrosis. Kidneys: tubular necrosis. Brain (case 2): edema. Placenta (case 1): syncytiocytotrophoblast necrosis, diffuse villitis, necrotizing deciduitis. Other organs: no remarkable findings. Fetus: lungs: edema, features of mild interstitial pneumonitis. Liver: rare multinucleate giant cells. Other organs: no remarkable findingsChina/2005/(7)3 (LA)NS∥Lungs: DAD, reactive fibroblasts, hemorrhage. Spleen: atypical lymphocytesThailand/2004/(10)* FA, full autopsy; LA, limited autopsy; B, biopsies.† Disease duration before death in days (d); sex: female (F), male (M).‡ This patient died of H5N1 infection and the complications of Reye's syndrome.§ This patient was 4 months pregnant at the time of death.¶ Not specified. Open table in a new tab The lungs typically show diffuse alveolar damage.3Peiris JSM Yu WC Leung CW Cheung CY Ng WF Nicholls JM Ng TK Chan KH Lai ST Lim WL Yuen KY Guan Y Re-emergence of fatal human influenza A subtype H5N1 disease.Lancet. 2004; 363: 617-619Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar, 4Ungchusak K Auewarakul P Dowell SF Kitphati R Auwanit W Puthavathana P Uiprasertkul M Boonnak K Pittayawonganon C Cox NJ Zaki SR Thawatsupha P Chittaganpitch M Khontong R Sirnerman JM Chunsutthiwat S Probable person-to-person transmission of avian influenza A (H5N1).N Engl J Med. 2005; 352: 333-340Crossref PubMed Scopus (591) Google Scholar, 6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar, 7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar, 9Uiprasertkul MP Kitphati R Puthavathana P Kriwong R Kongchanagul A Ungchusak K Angkasekwinai S Chokephaibulkit K Srisook K Vanprapar N Auewarakul P Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans.Emerg Infect Dis. 2007; 13: 708-712Crossref PubMed Google Scholar, 10Chotpitayasunondh T Ungchusak K Hanshaoworakul W Chunsuthiwat S Sawanpayalert P Kijphati R Lochindarat S Srisan P Suwan P Osotthanakorn Y Anantasetagoon T Kanjanawasri S Tanupattarachai S Weerakul J Chaiwirattana R Maneerattanaporn M Poolsavatkitikool R Chokephaibulkit K Apisarnthanarak A Dowellet SF Human disease from influenza A (H5N1).Thailand Emerg Infect Dis. 2004; 11: 201-209Crossref Google Scholar In cases with a short disease duration (<10 to 12 days), features of the exudative inflammatory phase of diffuse alveolar damage (edema, fibrous exudates, hyaline membranes) are predominant (Figure 1A).3Peiris JSM Yu WC Leung CW Cheung CY Ng WF Nicholls JM Ng TK Chan KH Lai ST Lim WL Yuen KY Guan Y Re-emergence of fatal human influenza A subtype H5N1 disease.Lancet. 2004; 363: 617-619Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar, 7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 9Uiprasertkul MP Kitphati R Puthavathana P Kriwong R Kongchanagul A Ungchusak K Angkasekwinai S Chokephaibulkit K Srisook K Vanprapar N Auewarakul P Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans.Emerg Infect Dis. 2007; 13: 708-712Crossref PubMed Google Scholar, 11Chan PK Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.Clin Infect Dis. 2002; 34: S58-S64Crossref PubMed Scopus (233) Google Scholar In cases with a longer disease duration, changes consistent with the fibrous proliferative phase (organizing diffuse alveolar damage) and the final fibrotic stage (interstitial fibrosis) have been observed.6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar, 7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar, 14Ng WF To KF Lam WW Ng TK Lee KC The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1—a review.Hum Pathol. 2006; 37: 381-390Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Hyperplasia of type II pneumocytes has been demonstrated in most autopsy cases.3Peiris JSM Yu WC Leung CW Cheung CY Ng WF Nicholls JM Ng TK Chan KH Lai ST Lim WL Yuen KY Guan Y Re-emergence of fatal human influenza A subtype H5N1 disease.Lancet. 2004; 363: 617-619Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar, 6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar, 11Chan PK Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.Clin Infect Dis. 2002; 34: S58-S64Crossref PubMed Scopus (233) Google Scholar Viral inclusions or other cytopathic changes have not been observed in pneumocytes.6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar, 11Chan PK Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.Clin Infect Dis. 2002; 34: S58-S64Crossref PubMed Scopus (233) Google Scholar, 14Ng WF To KF Lam WW Ng TK Lee KC The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1—a review.Hum Pathol. 2006; 37: 381-390Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Macrophages appeared to be the predominant cells within the alveoli,3Peiris JSM Yu WC Leung CW Cheung CY Ng WF Nicholls JM Ng TK Chan KH Lai ST Lim WL Yuen KY Guan Y Re-emergence of fatal human influenza A subtype H5N1 disease.Lancet. 2004; 363: 617-619Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar, 7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar whereas in the interstitium T lymphocytes, with or without neutrophils, are present.3Peiris JSM Yu WC Leung CW Cheung CY Ng WF Nicholls JM Ng TK Chan KH Lai ST Lim WL Yuen KY Guan Y Re-emergence of fatal human influenza A subtype H5N1 disease.Lancet. 2004; 363: 617-619Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar, 6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar, 7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 11Chan PK Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.Clin Infect Dis. 2002; 34: S58-S64Crossref PubMed Scopus (233) Google Scholar Scattered histiocytes with hemophagocytic activity have been observed in the lungs of some cases.6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar The following additional histopathological features have also been reported: 1) desquamation of epithelial cells into alveolar spaces4Ungchusak K Auewarakul P Dowell SF Kitphati R Auwanit W Puthavathana P Uiprasertkul M Boonnak K Pittayawonganon C Cox NJ Zaki SR Thawatsupha P Chittaganpitch M Khontong R Sirnerman JM Chunsutthiwat S Probable person-to-person transmission of avian influenza A (H5N1).N Engl J Med. 2005; 352: 333-340Crossref PubMed Scopus (591) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar; 2) bronchiolitis8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar, 9Uiprasertkul MP Kitphati R Puthavathana P Kriwong R Kongchanagul A Ungchusak K Angkasekwinai S Chokephaibulkit K Srisook K Vanprapar N Auewarakul P Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans.Emerg Infect Dis. 2007; 13: 708-712Crossref PubMed Google Scholar; 3) cystically dilated air spaces6To KF Chan PKS Chan KF Lee WK Lam WY Wong KF Tang NLS Tsang DNC Sung RYT Buckley TA Tam JS Cheng AF Pathology of fatal human infection associated with avian influenza A H5N1 virus.J Med Virol. 2001; 63: 242-246Crossref PubMed Scopus (293) Google Scholar; 4) hemorrhage,8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar, 10Chotpitayasunondh T Ungchusak K Hanshaoworakul W Chunsuthiwat S Sawanpayalert P Kijphati R Lochindarat S Srisan P Suwan P Osotthanakorn Y Anantasetagoon T Kanjanawasri S Tanupattarachai S Weerakul J Chaiwirattana R Maneerattanaporn M Poolsavatkitikool R Chokephaibulkit K Apisarnthanarak A Dowellet SF Human disease from influenza A (H5N1).Thailand Emerg Infect Dis. 2004; 11: 201-209Crossref Google Scholar, 11Chan PK Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997.Clin Infect Dis. 2002; 34: S58-S64Crossref PubMed Scopus (233) Google Scholar 5) pleuritis9Uiprasertkul MP Kitphati R Puthavathana P Kriwong R Kongchanagul A Ungchusak K Angkasekwinai S Chokephaibulkit K Srisook K Vanprapar N Auewarakul P Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans.Emerg Infect Dis. 2007; 13: 708-712Crossref PubMed Google Scholar; 6) features of interstitial pneumonitis,4Ungchusak K Auewarakul P Dowell SF Kitphati R Auwanit W Puthavathana P Uiprasertkul M Boonnak K Pittayawonganon C Cox NJ Zaki SR Thawatsupha P Chittaganpitch M Khontong R Sirnerman JM Chunsutthiwat S Probable person-to-person transmission of avian influenza A (H5N1).N Engl J Med. 2005; 352: 333-340Crossref PubMed Scopus (591) Google Scholar, 7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar and 7) apoptosis in alveolar epithelial cells and leukocytes.9Uiprasertkul MP Kitphati R Puthavathana P Kriwong R Kongchanagul A Ungchusak K Angkasekwinai S Chokephaibulkit K Srisook K Vanprapar N Auewarakul P Apoptosis and pathogenesis of avian influenza A (H5N1) virus in humans.Emerg Infect Dis. 2007; 13: 708-712Crossref PubMed Google Scholar Two cases of possible superinfections caused by fungi have been reported.7Gu J Xie Z Gao Z Liu J Korteweg C Ye J Lau LT Lu J Gao Z Zhang B McNutt MA Lu M Anderson VM Gong E Yu AC Lipkin WI H5N1 infection of the respiratory tract and beyond.Lancet. 2007; 370: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 8Uiprasertkul MP Puthavathana K Sangsiriwut P Pooruk P Srisook K Peiris M Nicholls JM Chokephaibulkit K Vanprapar N Auewarakul P Influenza A H5N1 replication sites in humans.Emerg Infect Dis. 2005; 11: 1036-1041Crossref PubMed Google Scholar Because the above histopathological features are not unique to H5N1 influenza, it may be difficult to distinguish diffuse alveolar damage caused by H5N1 virus infections from diffuse alveolar damage caused by other microorganisms such as severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) or by other factors such as aspiration or oxygen toxicity. More specific tests such as in situ hybridization, reverse transcription-polymerase chain reaction (RT-PCR), and virus isolation are required to confirm H5N1 infection. 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