Nosocomial outbreak of the pandemic Influenza A (H1N1) 2009 in critical hematologic patients during seasonal influenza 2010-2011: detection of oseltamivir resistant variant viruses

BMC Infectious Diseases

Carlo Bonfanti¹  Dolores De Tomasi¹  Silvia Corbellini¹  Francesca Perandin¹  Chiara Cattaneo³  Giuseppe Rossi³  Giorgio Piccinelli¹  Caterina P Pollara² 

[1] Laboratory of Microbiology and Virology, A. O. Spedali Civili, Brescia, University of Brescia, Brescia, Italy;Institute of Microbiology, A. O. Spedali Civili, Brescia, University of Brescia, P.le Spedali Civili, 1 25123 Brescia, Italy;Department of Haematology, A. O. Spedali Civili, Brescia, Italy

关键词: Resistance;    Oseltamivir;    H1N1;    Pandemic;   

Others  :  1170996
DOI  :  10.1186/1471-2334-13-127

 received in 2012-03-08, accepted in 2013-02-25,  发布年份 2013

【 摘 要 】

Background

The pandemic influenza A (H1N1) 2009 (H1N1pdm09) virus infection caused illness and death among people worldwide, particularly in hematologic/oncologic patients because influenza infected individuals can shed virus for prolonged periods, thus increasing the chances for the development of drug-resistant strains such as oseltamivir-resistant (OST-r) variant.

Methods

The aim of our study was to retrospectively evaluate the clinical importance of OST-r variant in circulating strains of the pandemic H1N1pdm09 virus. By means of RT-PCR and Sanger sequencing we analysed the presence of OST-r variant in 76 H1N1pdm09 laboratory-confirmed cases, hospitalized at the hematologic/oncologic ward at Spedali Civili of Brescia –Italy.

Results

Out of 76 hospitalized hematologic/oncologic patients, 23 patients (30.2%) were infected by H1N1pdm09 virus. Further investigation revealed that 3 patients were positive for the OST-r variant carrying the H275Y mutation. All the 23 infected patients were immuno-compromised, and were under treatment or had been treated previously with oseltamivir. Three patients died (13%) after admission to intensive care unit and only one of them developed H275Y mutation.

Conclusions

Our retrospective observational study shows that pandemic influenza A (H1N1) 2009 virus can cause significant morbidity and even mortality in hematologic/oncologic patients and confirms the high rate of nosocomial transmission of pandemic H1N1pdm09 virus in these critical subjects. Indeed, the reduction in host defences in these hospitalized patients favoured the prolonged use of antiviral therapy and permitted the development of OST-r strain. Strategies as diagnostic vigilance, early isolation of patients and seasonal influenza A(H1N1) vaccination may prevent transmission of influenza in high risk individuals.

【 授权许可】

   
2013 Pollara et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Weinstock DM, Gubarera LV, Zuccotti G: Prolonged shedding of multidrug-resistant influenza A virus in immunocompromised patient. N Eng J Med 2003, 27:348-867.
• [2]Kumar D, Michaels MG, Morris MI, Green M, Avery RK, Liu C: Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis 2010, 10(8):521-526.
• [3]Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, Uyeki TM: Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Eng J Med 2010, 362(18):1708-1719.
• [4]Le QM, Wertheim HF, Tran ND, van Doorn HR, Nguyen TH, Horby P: A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med 2010, 362(1):86-87.
• [5]Centers for Disease Control Prevention: Swine influenza A (H1N1) infection in two children–Southern California, March-April 2009. MMWR Morb Mortal Wkly Rep 2009, 58:400-402.
• [6]World Health Organization: Pandemic (H1N1) 2009. Update 60. Laboratory-confirmed cases of pandemic (H1N1) 2009 as officially reported to WHO by states parties to the IHR (2005). 2009. July 2009. Available at http://www.who.int/csr/don/2009_08_04/en/index.html webcite
• [7]Dawood FS: Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2019, 360:2605-2615.
• [8]Jain R, Goldman RD: Novel influenza A (H1N1):clinical presentation, diagnosis, and management. Pediatr Emerg Carc 2009, 25:791-796.
• [9]Centers for Disease Control and Prevention: Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. Wkly Epidemiol Rec 2009, 84:453-459.
• [10]Centers for Disease Control Prevention: Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis–North Carolina, 2009. MMWR Morb Mortal Wkly Rep 2009, 58:969-972.
• [11]World Health Organization: Sequencing primers and protocol. Geneva, Switzerland: World Health Organization; 2009. http://www.who.int/csr/resources/publications/swineflu/GenomePrimers_20090512.pdf webcite. Accessed 15 July 2009
• [12]Peramivir (Neuraminidase Inhibitor): BioCryst Pharmaceuticals. Inc. 2010. [Accessed 27 July 2010]. Available from: http://www.biocryst.com/peramivir webcite
• [13]Sheu TG, Deyde VM, Okomo-Adhiambo M: Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother 2008, 52:3284-3292.
• [14]Barr IG, Cui L, Komadina N, Lee RT, Lin RT: A new pandemic influenza A (H1N1) genetic variant predominated in the winter 2010 influenza season in Australia, New Zealand and Singapore. Euro Surveill 2010, 15:pii = 19692.
• [15]Esposito S, Molteni CG, Daleno C, Valzano A, Fossali E, Da Dalt L, Cecinati V, Bruzzese E, Giacchino R, Giaquinto C, Galeone C, Lackenby A, Principi N: Clinical importance and impact on the households of oseltamivir-resistant seasonal A/H1N1 influenza virus in healthy children in Italy. Virol J 2010, 7:202. BioMed Central Full Text
• [16]Campanini G, Piralla A, Rovida F, Puzelli S, Facchini M, Locatelli F, Minoli L, Percivalle E, Donatelli I, Baldanti F: Surveillance Group for New Influenza A/H1N1v Investigation in Italy. First case in Italy of acquired resistance to oseltamivir in an immunocompromised patient with influenza A/H1N1v infection. J Clin Virol 2010, 48(3):220-222.
• [17]Puzelli S, Facchini M, De Marco MA, Palmieri A, Spagnolo D, Boros S, Corcioli F, Trotta D, Bagnarelli P, Azzi A, Cassone A, Rezza G, Pompa MG, Oleari F, Donatelli I: Molecular surveillance of pandemic influenza A(H1N1) viruses circulating in Italy from May 2009 to February 2010: association between haemagglutinin mutations and clinical outcome. Euro Surveill 2010, 15(43):pii: 19696.
• [18]Souza TM, Salluh JI, Bozza FA, Mesquita M, Soares M, Motta FC, Pitrowsky MT, de Lourdes Oliveira M, Mishin VP, Gubareva LV, Whitney A, Rocco SA, Gonçalves VM, Marques VP, Velasco E, Siqueira MM: H1N1pdm influenza infection in hospitalized cancer patients: clinical evolution and viral analysis. PLoS One 2010, 5(11):e14158. 30
• [19]Choi SM, Boudreault AA, Xie H, Englund JA, Corey L, Boeckh M: Differences in clinical outcomes following 2009 influenza A/H1N1 and seasonal influenza among hematopoietic cell transplant recipients. Blood 2011, 117(19):5050-5060.
• [20]Renaud C, Boudreault AA, Kuypers J, Lofy KH, Corey L, Boeckh MJ: H275Y mutant pandemic (H1N1) 2009 virus in immunocompromised patients. Emerg Infect Dis 2011, 17:653-660.
• [21]Wolfe C, Greenwald I, Chen L: Pandemic (H1N1) 2009 and oseltamivir resistance in hematology/oncology patients. Emerg Infect Dis 2010, 16:1809-1811.
• [22]Chen LF, Dailey NJM, Rao AK, Fleischauer AT, Ian G, Deyde VM, Moore ZS, Anderson DJ, Jonathan D, Gubareva LV, Sexton DJ, Fry AM, Arjun S, Wolf CR: Cluster of Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Virus Infections on a Hospital Ward among Immunocompromised Patients—North Carolina. JID 2009, 2011:203.
• [23]Wong S, Pabbaraju K, Wong A, Fonseca K, Drews ST: Development of a real-time RT-PCR assay for detection of resistance to oseltamivir in Influenza A (H1N1) 2009 virus using single nucleotide polymorphism probes. J Virol Meth 2011, 30:11469-11476.
• [24]Deng YM, Caldwella N, Hurt A, Shaw T, Kelso A, Chidlow G, Williams S, Smith D, Dwyer DE, Barr I: A comparison of pyrosequencing and neuraminidase inhibition assays for the detection of oseltamivir-resistant pandemic influenza A(H1N1) 2009 viruses. Ant Res 2011, 30:2276-2281.
• [25]Ghedin E, Laplante J, De Passe J, Wentworth DE, Santos RP, Lepow ML, Porter J, Stellrecht K, Lin X, Operario D, Griesemer S, Fitch A, Halpin RA, Stockwell TB, Spiro DJ, Holmes EC, St George K: Deep Sequencing Reveals Mixed Infection with 2009 Pandemic Influenza A (H1N1) Virus Strains and the Emergence of Oseltamivir Resistance. JID 2011, 203(2):168-174.
• [26]Okomo-Adhiambo M, Nguyen HT, Sleeman K, Sheu TG, Deyde VR, Garten RJ, Xu X, Shaw MW, Klimov AW, Gubareva LV: Host cell selection of influenza neuraminidase variants: Implications for drug resistance monitoring in A(H1N1) viruses. Ant Res 2010, 85:381-388.
• [27]Hurt AC, Holien JK, Parker M, Barr IG: Oseltamivir resistance and the H274Y neuraminidase mutation in seasonal, pandemic and highly pathogenic influenza yiruses. Drugs 2009, 69(18):2523-2531.
• [28]Centers for Disease Control and Prevention: Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients—Seattle, Washington, 2009. MMWR Morb Mortal Wkly Rep 2009, 58:893-896.
• [29]Hurt AC, Deng YM, Ernest J, Caldwell N, Leang L, Iannello P, Komadina N, Shaw R, Smith D, Dwyer DE, Tramontana AR, Lin RT, Freeman K, Kelso A, Barr IG: Oseltamivir-resistant influenza viruses circulating during the first year of the influenza A(H1N1)2009 pandemic in the Asia-Pacific region, March 2009 to March 2010. Euro Surveill 2011. http://www.eurosurveillance.org/viewarticle.aspx?articleid=19770 webcite
• [30]Redelman-Sidi G, Sepkowitz KA, Huang CK: H1N1 influenza infection in cancer patients and hematopoietic stem cell transplant recipients. J Infect 2009, 2010(60):257-263.
• [31]Duan S, Boltz DA, Seiler P, Li J, Bragstad K, Nielsen LP: Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets. PLoS Pathog 2010, 6:e1001022.
• [32]Baz M, Abed Y, Simon P, Hamelin ME, Boivin G: Effect of the neuraminidase mutation H274Y conferring resistance to oseltamivir on the replicative capacity and virulence of old and recent human influenza A(H1N1) viruses. J Infect Dis 2010, 201:740-745.
• [33]Van der Vries E, Van den Berg B, Schutten M: Fatal oseltamivir-resistant influenza virus infection. N Engl J Med 2008, 359:1074-1076.
• [34]Gooskens JL, Jonges EC, Claas MJ, Meijer A, Van den Broek PJ, Kroes ACM: Morbidity and Mortality Associated With Nosocomial Transmission of Oseltamivir-Resistant Influenza A(H1N1) Virus. JAMA 2009, 301(10):1042-1046.
• [35]Centers for Disease Control and Prevention: Prevention strategies for seasonal influenza in healthcare settings. 2010. http://www.cdc.gov/flu/professionals/infectioncontrol/healthcaresettings.htm webcite
• [36]Pebody RG, McLean E, Zhao H, Cleary P, Bracebridge S, Foster K: Pandemic Influenza A (H1N1) 2009 and mortality in the United Kingdom: risk factors for death, April 2009 to March 2010. Euro Surveill 2010. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19571 webcite