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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2010, Vol. 4 Issue (2) : 147-156
Research articles
Pathogenesis of pandemic H1N1 2009 influenza virus infection and the implication on management
Kelvin Kai-Wang TO FRCPath,Iris Wai-Sum LI FRCP,Ivan Fan-Ngai HUNG FRCP,Vincent Chi-Chung CHENG FRCPath,Kwok-Yung YUEN MD,
Carol Yu Center for Infection, Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China;
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Abstract The pandemic H1N1 2009 influenza virus has caused the first influenza pandemic of the 21st century, leading to disproportionate fatalities in the low-risk population despite the generally mild nature of the illness. Advances in sci
Keywords influenza A virus, H1N1 subtype      pandemic      pathogenesis      virulence factors      immunity      management, antiviral      
Issue Date: 05 June 2010
 Cite this article:   
Kelvin Kai-Wang TO FRCPath,Ivan Fan-Ngai HUNG FRCP,Iris Wai-Sum LI FRCP, et al. Pathogenesis of pandemic H1N1 2009 influenza virus infection and the implication on management[J]. Front. Med., 2010, 4(2): 147-156.
Yuen K Y, Chan P K, Peiris M, Tsang D N, Que T L, Shortridge K F, Cheung P T, To W K, Ho E T, Sung R, Cheng A F. Clinical features and rapid viral diagnosisof human disease associated with avian influenza A H5N1 virus. Lancet, 1998, 351(9101): 467―471
Peiris J S, Chu C M, Cheng V C, Chan K S, Hung I F, Poon L L, Law K I, Tang B S, Hon T Y, Chan C S, Chan K H, Ng J S, Zheng B J, Ng W L, Lai R W, Guan Y, Yuen K Y; HKU/UCH SARSStudy Group. Clinical progression and viral load in a community outbreakof coronavirus-associated SARS pneumonia: a prospective study. Lancet, 2003, 361(9371): 1767―1772
Coker R, Mounier-Jack S. Pandemicinfluenza preparedness in the Asia-Pacific region. Lancet, 2006, 368(9538): 886―889
Novel Swine-Origin InfluenzaA (H1N1) Virus Investigation Team, Dawood F S, Jain S, Finelli L, Shaw M W, Lindstrom S, Garten R J, Gubareva L V, Xu X, Bridges C B, Uyeki T M. Emergence of a novel swine-origininfluenza A (H1N1) virus in humans. N EnglJ Med, 2009, 360(25): 2605―2615
World Health Organization. Transmission dynamics and impact of pandemic influenzaA (H1N1) 2009 virus. Wkly Epidemiol Rec, 2009, 84(46): 481―484
Cao B, Li X W, Mao Y, Wang J, Lu H Z, Chen Y S, Liang Z A, Liang L, Zhang S J, Zhang B, Gu L, Lu L H, Wang D Y, Wang C; NationalInfluenza A Pandemic (H1N1) 2009 Clinical Investigation Group of China.Clinical features of the initial cases of 2009 pandemic influenzaA (H1N1) virus infection in China. N EnglJ Med, 2009, 361(26): 2507―2517
Domínguez-Cherit G, Lapinsky S E, Macias A E, Pinto R, Espinosa-Perez L, de la Torre A, Poblano-Morales M, Baltazar-Torres J A, Bautista E, Martinez A, Martinez M A, Rivero E, Valdez R, Ruiz-Palacios G, Hernández M, Stewart T E, Fowler R A. Critically ill patients with 2009 influenza A(H1N1) inMexico. JAMA, 2009, 302(17): 1880―1887
Centers for Disease Controland Prevention (CDC). Intensive-care patientswith severe novel influenza A (H1N1) virus infection- Michigan, June2009. MMWR Morb Mortal Wkly Rep, 2009, 58(27): 749―752
Hewagama S, Walker S P, Stuart R L, Gordon C, Johnson P D, Friedman N D, O'Reilly M, Cheng A C, Giles M L. 2009 H1N1 Influenza A and Pregnancy Outcomesin Victoria, Australia. Clin Infect Dis, 2010, 50(5): 686―690
Jamieson D J, Honein M A, Rasmussen S A, Williams J L, Swerdlow D L, Biggerstaff M S, Lindstrom S, Louie J K, Christ C M, Bohm S R, Fonseca V P, Ritger K A, Kuhles D J, Eggers P, Bruce H, Davidson H A, Lutterloh E, Harris M L, Burke C, Cocoros N, Finelli L, MacFarlane K F, Shu B, Olsen S J; NovelInfluenza A (H1N1) Pregnancy Working Group. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet, 2009, 374: 451―458
Louie J K, Acosta M, Jamieson D J, Honein M A; California Pandemic (H1N1) Working Group. Severe 2009H1N1 influenza in pregnant and postpartum women in California. N Engl J Med, 2010, 362(1): 27―35
Vaillant L, La Ruche G, Tarantola A, Barboza P; epidemic intelligence team at InVS. Epidemiology of fatalcases associated with pandemic H1N1 influenza 2009. Euro Surveill, 2009, 14(33), pii: 19309
Maines T R, Jayaraman A, Belser J A, Wadford D A, Pappas C, Zeng H, Gustin K M, Pearce M B, Viswanathan K, Shriver Z H, Raman R, Cox N J, Sasisekharan R, Katz J M, Tumpey T M. Transmission and pathogenesis of swine-origin 2009 A(H1N1)influenza viruses in ferrets and mice. Science, 2009, 325(5939): 484―487
Munster V J, de Wit E, van den Brand J M, Herfst S, Schrauwen E J, Bestebroer T M, van de Vijver D, Boucher C A, Koopmans M, Rimmelzwaan G F, Kuiken T, Osterhaus A D, Fouchier R A. Pathogenesis and transmission of swine-origin 2009 A(H1N1)influenza virus in ferrets. Science, 2009, 325(5939): 481―483
Yeh E, Luo R F, Dyner L, Hong D K, Banaei N, Baron E J, Pinsky B A. Preferential lower respiratory tract infection in swine-origin 2009A(H1N1) influenza. Clin Infect Dis, 2010, 50(3): 391―394

doi: 10.1086/649875
Glaser L, Stevens J, Zamarin D, Wilson I A, García-Sastre A, Tumpey T M, Basler C F, Taubenberger J K, Palese P. A single amino acid substitutionin 1918 influenza virus hemagglutinin changes receptor binding specificity. J Virol, 2005, 79(17): 11533―11536

doi: 10.1128/JVI.79.17.11533-11536.2005
Stevens J, Blixt O, Glaser L, Taubenberger J K, Palese P, Paulson J C, Wilson I A. Glycan microarray analysis of the hemagglutinins from modern andpandemic influenza viruses reveals different receptor specificities. J Mol Biol, 2006, 355(5): 1143―1155

doi: 10.1016/j.jmb.2005.11.002
Tumpey T M, Maines T R, Van Hoeven N, Glaser L, Solórzano A, Pappas C, Cox N J, Swayne D E, Palese P, Katz J M, García-Sastre A. Atwo-amino acid change in the hemagglutinin of the 1918 influenza virusabolishes transmission. Science, 2007, 315(5812): 655―659

doi: 10.1126/science.1136212
Matrosovich M N, Matrosovich T Y, Gray T, Roberts N A, Klenk H D. Human andavian influenza viruses target different cell types in cultures ofhuman airway epithelium. Proc Natl AcadSci U S A, 2004, 101(13): 4620―4624

doi: 10.1073/pnas.0308001101
Soundararajan V, Tharakaraman K, Raman R, Raguram S, Shriver Z, Sasisekharan V, Sasisekharan R. Extrapolating from sequence--the 2009 H1N1 'swine' influenzavirus. Nat Biotechnol, 2009, 27(6): 510―513

doi: 10.1038/nbt0609-510
Childs R A, Palma A S, Wharton S, Matrosovich T, Liu Y, Chai W, Campanero-Rhodes M A, Zhang Y, Eickmann M, Kiso M, Hay A, Matrosovich M, Feizi T. Receptor-binding specificityof pandemic influenza A (H1N1) 2009 virus determined by carbohydratemicroarray. Nat Biotechnol, 2009, 27(9): 797―799

doi: 10.1038/nbt0909-797
Yamada S, Suzuki Y, Suzuki T, Le M Q, Nidom C A, Sakai-Tagawa Y, Muramoto Y, Ito M, Kiso M, Horimoto T, Shinya K, Sawada T, Kiso M, Usui T, Murata T, Lin Y, Hay A, Haire L F, Stevens D J, Russell R J, Gamblin S J, Skehel J J, Kawaoka Y. Haemagglutininmutations responsible for the binding of H5N1 influenza A virusesto human-type receptors. Nature, 2006, 444(7117): 378―382

doi: 10.1038/nature05264
Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y. Avian flu: influenza virus receptors in the human airway. Nature, 2006, 440(7083): 435―436

doi: 10.1038/440435a
Chan M C, Chan R W, Yu W C, Ho C C, Yuen K M, Fong J H, Tang L L, Lai W W, Lo A C, Chui W H, Sihoe A D, Kwong D L, Wong D S, Tsao G S, Poon L L, Guan Y, Nicholls J M, Peiris J S. Tropism and innate host responsesof the 2009 pandemic H1N1 influenza virus in ex vivo and in vitro cultures of human conjunctiva and respiratory tract. Am J Pathol, 2010, 176(4): 1828–1840

doi: 10.2353/ajpath.2010.091087
Li I W, Chan K H, To K W, Wong S S, Ho P L, Lau S K, Woo P C, Tsoi H W, Chan J F, Cheng V C, Zheng B J, Chen H, Yuen K Y. Differential susceptibility of differentcell lines to swine-origin influenza A H1N1, seasonal human influenzaA H1N1, and avian influenza A H5N1 viruses. J Clin Virol, 2009, 46(4): 325―330

doi: 10.1016/j.jcv.2009.09.013
Ayala E, Kagawa F T, Wehner J H, Tam J, Upadhyay D. Rhabdomyolysisassociated with 2009 influenza A(H1N1). JAMA, 2009, 302(17): 1863―1864

doi: 10.1001/jama.2009.1582
D'Silva D, Hewagama S, Doherty R, Korman T M, Buttery J. Meltingmuscles: novel H1N1 influenza A associated rhabdomyolysis. J Pediatr Infect Dis, 2009, 28(12): 1138―1139

doi: 10.1097/INF.0b013e3181c03cf2
Parikh M, Dolson G, Ramanathan V, Sangsiraprapha W. Novel H1N1-associated rhabdomyolysisleading to acute renal failure. Clin Microbiol Infect, 2010, 16(4): 330–332

doi: 10.1111/j.1469-0691.2010.03185.x
Riquelme A, Alvarez-Lobos M, Pavez C, Hasbun P, Dabanch J, Cofré C, Jimenez J, Calvo M. Gastrointestinalmanifestations among Chilean patients infected with novel influenzaA (H1N1) 2009 virus. Gut, 2009, 58(11): 1567―1568

doi: 10.1136/gut.2009.194746
To K K, Chan K H, Li I W, Tsang T Y, Tse H, Chan J F, Hung I F, Lai S T, Leung C W, Kwan Y W, Lau Y L, Ng T K, Cheng V C, Peiris J S, Yuen K Y. Viral load in patients infectedwith pandemic H1N1 2009 influenza A virus. J Med Virol, 2010, 82(1): 1―7

doi: 10.1002/jmv.21664
To K K, Hung I F, Li I W, Lee K L, Koo C K, Yan W W, Liu R, Ho K Y, Chu K H, Watt C L, Luk W K, Lai K Y, Chow F L, Mok T, Buckley T, Chan J F, Wong S S, Zheng B, Chen H, Lau C C, Tse H, Cheng V C, Chan K H, Yuen K Y. Delayed clearance of viral load and marked cytokine activation insevere cases of pandemic H1N1 2009 influenza virus infection. Clin Infect Dis, 2010, 50(6): 850―859

doi: 10.1086/650581
World Health Organization. Preliminary review of D222G amino acid substitution inthe haemagglutinin of pandemic influenza A (H1N1) 2009 viruses. Wkly Epidemiol Rec, 2010, 85(4): 21―22
Veljkovic V, Niman H L, Glisic S, Veljkovic N, Perovic V, Muller C P. Identification of hemagglutinin structural domain andpolymorphisms which may modulate swine H1N1 interactions with humanreceptor. BMC Struct Biol, 2009, 9: 62

doi: 10.1186/1472-6807-9-62
Neumann G, Noda T, Kawaoka Y. Emergence and pandemic potential of swine-originH1N1 influenza virus. Nature, 2009, 459(7249): 931―939

doi: 10.1038/nature08157
Tumpey TM, Belser JA. Resurrected pandemic influenza viruses. Annu Rev Microbiol, 2009, 63: 79―98

doi: 10.1146/annurev.micro.091208.073359
Herfst S, Chutinimitkul S, Ye J, de Wit E, Munster V J, Schrauwen E J, Bestebroer T M, Jonges M, Meijer A, Koopmans M, Rimmelzwaan G F, Osterhaus A D, Perez D R, Fouchier R A. Introduction of virulence markers in PB2 of pandemic swine-origininfluenza virus does not result in enhanced virulence or transmission. J Virol, 2010, 84(8): 3752–3758

doi: 10.1128/JVI.02634-09
Mehle A, Doudna J A. Adaptive strategies of the influenza virus polymerase for replicationin humans. Proc Natl Acad Sci U S A, 2009, 106(50): 21312―21316

doi: 10.1073/pnas.0911915106
de Jong M D, Simmons C P, Thanh T T, Hien V M, Smith G J, Chau T N, Hoang D M, Chau N V, Khanh T H, Dong V C, Qui P T, Cam B V, Ha do Q, Guan Y, Peiris J S, Chinh N T, Hien T T, Farrar J. Fataloutcome of human influenza A (H5N1) is associated with high viralload and hypercytokinemia. Nat Med, 2006, 12(10): 1203―1207

doi: 10.1038/nm1477
Martin E T, Kuypers J, Heugel J, Englund J A. Clinical disease and viral load in children infectedwith respiratory syncytial virus or human metapneumovirus. Diagn Microbiol Infect Dis, 2008, 62(4): 382―388

doi: 10.1016/j.diagmicrobio.2008.08.002
Moltedo B, Lopez C B, Pazos M, Becker M I, Hermesh T, Moran T M. Cutting edge: stealth influenza virus replication precedesthe initiation of adaptive immunity. JImmunol, 2009, 183(6): 3569―3573

doi: 10.4049/jimmunol.0900091
Smith G J, Vijaykrishna D, Bahl J, Lycett S J, Worobey M, Pybus O G, Ma S K, Cheung C L, Raghwani J, Bhatt S, Peiris J S, Guan Y, Rambaut A. Origins and evolutionary genomics of the 2009 swine-originH1N1 influenza A epidemic. Nature, 2009, 459(7250): 1122―1125

doi: 10.1038/nature08182
Hancock K, Veguilla V, Lu X, Zhong W, Butler E N, Sun H, Liu F, Dong L, DeVos J R, Gargiullo P M, Brammer T L, Cox N J, Tumpey T M, Katz J M. Cross-reactive antibody responsesto the 2009 pandemic H1N1 influenza virus. N Engl J Med, 2009, 361(20): 1945―1952

doi: 10.1056/NEJMoa0906453
Potter C W, Oxford J S. Determinants of immunity to influenza infection in man. Br Med Bull, 1979, 35(1): 69―75
Miller E, Hoschler K, Hardelid P, Stanford E, Andrews N, Zambon M. Incidence of 2009 pandemicinfluenza A H1N1 infection in England: a cross-sectional serologicalstudy. Lancet, 2010, 375(9720): 1100–1108

doi: 10.1016/S0140-6736(09)62126-7
Ikonen N, Strengell M, Kinnunen L, Osterlund P, Pirhonen J, Broman M, Davidkin I, Ziegler T, Julkunen I. High frequency of cross-reactingantibodies against 2009 pandemic influenza A(H1N1) virus among theelderly in Finland. Euro Surveill, 2010, 15(5). pii: 19478
Chen H, Wang Y, Liu W, Zhang J, Dong B, Fan X, de Jong M D, Farrar J, Riley S, Smith G J, Guan Y. Serologic survey of pandemic (H1N1) 2009virus, Guangxi Province, China. Emerg InfectDis, 2009, 15(11): 1849―1850
Zhu F C, Wang H, Fang H H, Yang J G, Lin X J, Liang X F, Zhang X F, Pan H X, Meng F Y, Hu Y M, Liu W D, Li C G, Li W, Zhang X, Hu J M, Peng W B, Yang B P, Xi P, Wang H Q, Zheng J S. A novel influenza A (H1N1) vaccine invarious age groups. N Engl J Med, 2009, 361(25): 2414―2423

doi: 10.1056/NEJMoa0908535
Liang X F, Wang H Q, Wang J Z, Fang H H, Wu J, Zhu F C, Li R C, Xia S L, Zhao Y L, Li F J, Yan S H, Yin W D, An K, Feng D J, Cui X L, Qi F C, Ju C J, Zhang Y H, Guo Z J, Chen P Y, Chen Z, Yan K M, Wang Y. Safety and immunogenicity of 2009 pandemic influenzaA H1N1 vaccines in China: a multicentre, double-blind, randomised,placebo-controlled trial. Lancet, 2010, 375(9708): 56―66

doi: 10.1016/S0140-6736(09)62003-1
Krause J C, Tumpey T M, Huffman C J, McGraw P A, Pearce M B, Tsibane T, Hai R, Basler C F, Crowe J E Jr. Naturally occurring humanmonoclonal antibodies neutralize both 1918 and 2009 pandemic influenzaA (H1N1) viruses. J Virol, 2010, 84(6): 3127―3130

doi: 10.1128/JVI.02184-09
Manicassamy B, Medina R A, Hai R, Tsibane T, Stertz S, Nistal-Villán E, Palese P, Basler C F, García-Sastre A. Protectionof mice against lethal challenge with 2009 H1N1 influenza A virusby 1918-like and classical swine H1N1 based vaccines. PLoS Pathog, 2010, 6(1): e1000745

doi: 10.1371/journal.ppat.1000745
Bishop J F, Murnane M P, Owen R. Australia's winter with the2009 pandemic influenza A (H1N1) virus. N Engl J Med, 2009, 361(27): 2591―2594

doi: 10.1056/NEJMp0910445
Chang Y S, van Hal S J, Spencer P M, Gosbell I B, Collett P W. Comparison of adult patients hospitalised with pandemic (H1N1) 2009influenza and seasonal influenza during the "PROTECT" phase of thepandemic response. Med J Aust, 2010, 192(2): 90―93
Rothberg M B, Haessler S D. Complications of seasonal and pandemic influenza. Crit Care Med, 2010, 38(4 suppl): e91–97

doi: 10.1097/CCM.0b013e3181c92eeb
Greenbaum J A, Kotturi M F, Kim Y, Oseroff C, Vaughan K, Salimi N, Vita R, Ponomarenko J, Scheuermann R H, Sette A, Peters B. Pre-existingimmunity against swine-origin H1N1 influenza viruses in the generalhuman population. Proc Natl Acad Sci US A, 2009, 106(48): 20365―20370

doi: 10.1073/pnas.0911580106
Xing Z, Cardona C J. Preexisting immunity to pandemic (H1N1) 2009. Emerg Infect Dis, 2009, 15(11): 1847―1849
Ge X, Tan V, Bollyky P L, Standifer N E, James E A, Kwok W W. Assessment of seasonal influenza A specific CD4 T cellresponses to 2009 pandemic H1N1 swine-origin influenza A virus. J Virol, 2010, 84(7): 3312–3319

doi: 10.1128/JVI.02226-09
McMichael A J, Gotch F M, Noble G R, Beare P A. Cytotoxic T-cell immunity to influenza. N Engl J Med, 1983, 309(1): 13―17
Doherty P C, Turner S J, Webby R G, Thomas PG. Influenza andthe challenge for immunology. Nat Immunol, 2006, 7(5): 449―455

doi: 10.1038/ni1343
Achdout H, Meningher T, Hirsh S, Glasner A, Bar-On Y, Gur C, Porgador A, Mendelson M, Mandelboim M, Mandelboim O. Killing of avian and swine influenza by natural killercells. J Virol, 2010, 84(8): 3993–4001

doi: 10.1128/JVI.02289-09
Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J, Luo W, Chen T, Qin Q, Deng P. Characterization of cytokine/chemokineprofiles of severe acute respiratory syndrome. Am J Respir Crit Care Med, 2005, 171(8): 850―857

doi: 10.1164/rccm.200407-857OC
Woo P C, Tung E T, Chan K H, Lau C C, Lau S K, Yuen K Y. Cytokine profiles induced by the novel swine-origin influenzaA/H1N1 virus: implications for treatment strategies. J Infect Dis, 2010, 201(3): 346―353

doi: 10.1086/649785
Osterlund P, Pirhonen J, Ikonen N, Rönkkö E, Strengell M, Mäkelä S M, Broman M, Hamming O J, Hartmann R, Ziegler T, Julkunen I. PandemicH1N1 2009 influenza A virus induces weak cytokine responses in humanmacrophages and dendritic cells and is highly sensitive to the antiviralactions of interferons. J Virol, 2010, 84(3): 1414―1422

doi: 10.1128/JVI.01619-09
Lee M H, Arrecubieta C, Martin F J, Prince A, Borczuk A C, Lowy F D. A postinfluenza model ofStaphylococcus aureus pneumonia. J InfectDis, 2010, 201(4): 508―515

doi: 10.1086/650204
Mauad T, Hajjar L A, Callegari G D, da Silva L F, Schout D, Galas F R, Alves V A, Malheiros D M, Auler J O Jr, Ferreira A F, Borsato M R, Bezerra S M, Gutierrez P S, Caldini E T, Pasqualucci C A, Dolhnikoff M, Saldiva P H. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med, 2010, 181(4): 72―79
Srivastava B, Błazejewska P, Hessmann M, Bruder D, Geffers R, Mauel S, Gruber A D, Schughart K. Hostgenetic background strongly influences the response to influenza avirus infections. PLoS One, 2009, 4(3): e4857
Shapira S D, Gat-Viks I, Shum B O, Dricot A, de Grace M M, Wu L, Gupta P B, Hao T, Silver S J, Root D E, Hill D E, Regev A, Hacohen N. Aphysical and regulatory map of host-influenza interactions revealspathways in H1N1 infection. Cell, 2009, 139(7): 1255―1267
Brass A L, Huang I C, Benita Y, John S P, Krishnan M N, Feeley E M, Ryan B J, Weyer J L, van derWeyden L, Fikrig E, Adams D J, Xavier R J, Farzan M, Elledge S J. The IFITM proteins mediatecellular resistance to influenza A H1N1 virus, West Nile virus, anddengue virus. Cell, 2009, 139(7): 1243―1254
Karlas A, Machuy N, Shin Y, Pleissner K P, Artarini A, Heuer D, Becker D, Khalil H, Ogilvie L A, Hess S, Mäurer A P, Müller E, Wolff T, Rudel T, Meyer T F. Genome-wide RNAi screen identifies humanhost factors crucial for influenza virus replication. Nature, 2010, 463(7282): 818―822
König R, Stertz S, Zhou Y, Inoue A, Heinrich Hoffmann H, Bhattacharyya S, Alamares J G, Tscherne D M, Ortigoza M B, Liang Y, Gao Q, Andrews S E, Bandyopadhyay S, De Jesus P, Tu B P, Pache L, Shih C, Orth A, Bonamy G, Miraglia L, Ideker T, García-Sastre A, Young J A, Palese P, Shaw M L, Chanda S K. Human host factors required for influenza virus replication. Nature, 2010, 463(7282): 813―817
Gordon C L, Johnson P D, Permezel M, Holmes N E, Gutteridge G, McDonald C F, Eisen D P, Stewardson A J, Edington J, Charles P G, Crinis N, Black M J, Torresi J, Grayson M L. Association between severe pandemic 2009 influenza A (H1N1) virusinfection and immunoglobulin G(2) subclass deficiency. Clin Infect Dis, 2010, 50(5): 672―678
Watkins J, Tee D E. Catabolismof gamma G-globulin and myeloma proteins of the subclasses gamma G1and gamma G2 in a healthy volunteer. Immunology, 1970, 18(4): 537―543
ANZIC Influenza Investigators, Webb S A, Pettilä V, Seppelt I, Bellomo R, Bailey M, Cooper D J, Cretikos M, Davies A R, Finfer S, Harrigan P W, Hart G K, Howe B, Iredell J R, McArthur C, Mitchell I, Morrison S, Nichol A D, Paterson D L, Peake S, Richards B, Stephens D, Turner A, Yung M. Critical care services and 2009 H1N1 influenza in Australiaand New Zealand. N Engl J Med, 2009, 361(20): 1925―1934
Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, Hernandez M, Quiñones-Falconi F, Bautista E, Ramirez-Venegas A, Rojas-Serrano J, Ormsby C E, Corrales A, Higuera A, Mondragon E, Cordova-Villalobos J A; INER Working Group on Influenza. Pneumoniaand respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med, 2009, 361(7): 680―689
Taubenberger J K, Morens D M. The pathology of influenza virus infections. Annu Rev Pathol, 2008, 3: 499―522
Ulvestad E, Kanestrøm A, Tengnér P, Gjerde S, Sundal J, Haga H J. Anti-cardiolipin autoantibodiesand pulmonary embolism. A case for a common cause. Scand J Rheumatol, 2000, 29(5): 330―333
Gill J R, Sheng Z M, Ely S F, Guinee D G, Beasley M B, Suh J, Deshpande C, Mollura D J, Morens D M, Bray M, Travis W D, Taubenberger J K. Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1viral infections. Arch Pathol Lab Med, 2010, 134(2): 235―243
Centers for Disease Controland Prevention (CDC). Bacterial coinfectionsin lung tissue specimens from fatal cases of 2009 pandemic influenzaA (H1N1) - United States, May-August 2009. MMWR Morb Mortal Wkly Rep, 2009, 58(38): 1071―1074
Cheng V C, Lau Y K, Lee K L, Yiu K H, Chan K H, Ho P L, Yuen K Y. Fatal co-infectionwith swine origin influenza virus A/H1N1 and community-acquired methicillin-resistantStaphylococcus aureus. J Infect, 2009, 59(5): 366―370
Brundage J F. Interactions between influenza and bacterial respiratorypathogens: implications for pandemic preparedness. Lancet Infect Dis, 2006, 6(5): 303―312
Tashiro M, Ciborowski P, Reinacher M, Pulverer G, Klenk H D, Rott R. Synergistic role of staphylococcal proteasesin the induction of influenza virus pathogenicity. Virology, 1987, 157(2): 421―430
Martin S S, Hollingsworth C L, Norfolk S G, Wolfe C R, Hollingsworth J W. Reversible cardiac dysfunction associated with pandemic-2009-H1N1influenza A. Chest, 2010Feb5. [Epub aheadof print]
Silva-Herzog E, Detweiler C S. Intracellular microbes and haemophagocytosis. Cell Microbiol, 2008, 10(11): 2151―2158
World Health Organization. Clinical management of human infection with pandemic(H1N1) 2009: revised guidance. Centers for Disease Controland Prevention (CDC). Update: drug susceptibilityof swine-origin influenza A (H1N1) viruses, April 2009. MMWR Morb Mortal Wkly Rep, 2009, 58(16): 433―435
Jain S, Kamimoto L, Bramley A M, Schmitz A M, Benoit S R, Louie J, Sugerman D E, Druckenmiller J K, Ritger K A, Chugh R, Jasuja S, Deutscher M, Chen S, Walker J D, Duchin J S, Lett S, Soliva S, Wells E V, Swerdlow D, Uyeki T M, Fiore A E, Olsen S J, Fry A M, Bridges C B, Finelli L; 2009Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team.Hospitalized patients with 2009 H1N1 influenza in the United States,April-June 2009. N Engl J Med, 2009, 361(20): 1935―1944
Li I W, Hung I F, To K K, Chan K H, Wong S S, Chan J F, Cheng V C, Tsang O T, Lai S T, Lau Y L, Yuen K Y. The natural viral load profile of patients with pandemicswine-origin influenza A H1N1 2009 (pH1N1) and the effect of oseltamivirtreatment. Chest, 2010, 137(4): 759–768

doi: 10.1378/chest.09-3072
Centers for Disease Controland Prevention (CDC). Oseltamivir-resistantnovel influenza A (H1N1) virus infection in two immunosuppressed patients-Seattle, Washington, 2009. MMWR Morb MortalWkly Rep, 2009, 58(32): 893―896
Centers for Disease Controland Prevention (CDC). Oseltamivir-resistant2009 pandemic influenza A (H1N1) virus infection in two summer campersreceiving prophylaxis--North Carolina, 2009. MMWR Morb Mortal Wkly Rep, 2009, 58(35): 969―972
Chen H, Cheung C L, Tai H, Zhao P, Chan J F, Cheng V C, Chan K H, Yuen K Y. Oseltamivir-resistant influenzaA pandemic (H1N1) 2009 virus, Hong Kong, China. Emerg Infect Dis, 2009, 15(12): 1970―1972

doi: 10.3201/eid1512.091057
Gulland A. First cases of spread of oseltamivir resistant swineflu between patients are reported in Wales. BMJ, 2009, 339: b4975

doi: 10.1136/bmj.b4975
Leung T W, Tai A L, Cheng P K, Kong M S, Lim W. Detection of an oseltamivir-resistantpandemic influenza A/H1N1 virus in Hong Kong. J Clin Virol, 2009, 46(3): 298―299

doi: 10.1016/j.jcv.2009.08.004
Speers D J, Williams S H, Pinder M, Moody H R, Hurt A C, Smith D W. Oseltamivir-resistant pandemic (H1N1)2009 influenza in a severely ill patient: the first Australian case. Med J Aust, 2010, 192(3): 166―168
World Health Organization. Update on oseltamivir-resistant pandemic A (H1N1) 2009influenza virus: January 2010. Wkly EpidemiolRec, 2010, 85(6): 37―40
Le Q M, Wertheim H F, Tran N D, van Doorn H R, Nguyen T H, Horby P; Vietnam H1N1 InvestigationTeam. A community cluster of oseltamivir-resistant cases of 2009 H1N1influenza. N Engl J Med, 2010, 362(1): 86―87

doi: 10.1056/NEJMc0910448
Baz M, Abed Y, Papenburg J, Bouhy X, Hamelin M E, Boivin G. Emergence of oseltamivir-resistant pandemic H1N1 virusduring prophylaxis. N Engl J Med, 2009, 361(23): 2296―2297

doi: 10.1056/NEJMc0910060
Gaur A H, Bagga B, Barman S, Hayden R, Lamptey A, Hoffman J M, Bhojwani D, Flynn P M, Tuomanen E, Webby R. Intravenouszanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med, 2010, 362(1): 88―89

doi: 10.1056/NEJMc0910893
Kidd I M, Down J, Nastouli E, Shulman R, Grant P R, Howell D C, Singer M. H1N1pneumonitis treated with intravenous zanamivir. Lancet, 2009, 374(9694): 1036

doi: 10.1016/S0140-6736(09)61528-2
Hurt A C, Holien J K, Parker M, Kelso A, Barr I G. Zanamivir-resistantinfluenza viruses with a novel neuraminidase mutation. J Virol, 2009, 83(20): 10366―10373

doi: 10.1128/JVI.01200-09
Hayden F. Developing new antiviral agents for influenza treatment:what does the future hold? Clin InfectDis, 2009, 48 Suppl 1: S3―13

doi: 10.1086/591851
Triana-Baltzer G B, Gubareva L V, Nicholls J M, Pearce M B, Mishin V P, Belser J A, Chen L M, Chan R W, Chan M C, Hedlund M, Larson J L, Moss R B, Katz J M, Tumpey T M, Fang F. Novelpandemic influenza A(H1N1) viruses are potently inhibited by DAS181,a sialidase fusion protein. PLoS One, 2009, 4(11): e7788

doi: 10.1371/journal.pone.0007788
Pleschka S, Stein M, Schoop R, Hudson J B. Anti-viral properties and mode of action of standardized Echinaceapurpurea extract against highly pathogenic avian influenza virus (H5N1,H7N7) and swine-origin H1N1 (S-OIV). VirolJ, 2009, 6: 197

doi: 10.1186/1743-422X-6-197
Luke T C, Kilbane E M, Jackson J L, Hoffman S L. Meta-analysis: convalescent blood products for Spanishinfluenza pneumonia: a future H5N1 treatment? Ann Intern Med, 2006, 145(8): 599―609
Zhou B, Zhong N, Guan Y. Treatment with convalescent plasma forinfluenza A (H5N1) infection. N Engl JMed, 2007, 357: 1450―1451

doi: 10.1056/NEJMc070359
Koudstaal W, Koldijk M H, Brakenhoff J P, Cornelissen L A, Weverling G J, Friesen R H, Goudsmit J. Pre- and postexposure use of human monoclonal antibodyagainst H5N1 and H1N1 influenza virus in mice: viable alternativeto oseltamivir. J Infect Dis, 2009, 200(12): 1870―1873

doi: 10.1086/648378
Wu J T, Lee C K, Cowling B J, Yuen K Y. Logistical feasibility and potential benefits of a population-widepassive-immunotherapy program during an influenza pandemic. Proc Natl Acad Sci U S A, 2010, 107(7): 3269―3274

doi: 10.1073/pnas.0911596107
Quispe-Laime A M, Bracco J D, Barberio P A, Campagne C G, Rolfo V E, Umberger R, Meduri G U. H1N1 influenza A virus-associated acute lung injury: response tocombination oseltamivir and prolonged corticosteroid treatment. Intensive Care Med, 2010, 36(1): 33―41

doi: 10.1007/s00134-009-1727-6
Carter M J. A rationale for using steroids in the treatment of severecases of H5N1 avian influenza. J Med Microbiol, 2007, 56(Pt 7): 875―883

doi: 10.1099/jmm.0.47124-0
Zheng B J, Chan K W, Lin Y P, Zhao G Y, Chan C, Zhang H J, Chen H L, Wong S S, Lau S K, Woo P C, Chan K H, Jin D Y, Yuen K Y. Delayed antiviral plus immunomodulatortreatment still reduces mortality in mice infected by high inoculumof influenza A/H5N1 virus. Proc Natl AcadSci U S A, 2008, 105(23): 8091―8096

doi: 10.1073/pnas.0711942105
Fedson D S. Confronting an influenza pandemic with inexpensive genericagents: can it be done? Lancet Infect Dis, 2008, 8(9): 571―576

doi: 10.1016/S1473-3099(08)70070-7
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[7] Tianhua Xu, Zitong Sheng, Li Yao. Obesity-related glomerulopathy: pathogenesis, pathologic, clinical characteristics and treatment[J]. Front. Med., 2017, 11(3): 340-348.
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[10] Lan-Juan LI MD, . Review of hand, foot and mouth disease[J]. Front. Med., 2010, 4(2): 139-146.
[11] Jianqing PAN PhD, Qin ZHANG MD, Daowen WANG MD, PhD, . Construction and humoral immune response of Epstein-Barr virus latent membrane protein 2 DNA vaccine in mice[J]. Front. Med., 2009, 3(4): 390-395.
[12] Geqing XIA, Chaoying WU. Expression of inducible nitric oxide synthase in trophoblasts and deciduas in early medical abortion[J]. Front Med Chin, 2009, 3(2): 216-219.
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