The controversy over H5N1 transmissibility research: An opportunity to define a practical response to a global threat

Human Vaccines and Immunotherapeutics

Volumn 9, Issue 5, 2013, Pages 977-986

  Fedson, David S ^a   Opal, Steven M ^b,c  

^a Memorial Hospital of Rhode Island ^*

^b MEMORIAL HOSPITAL OF RHODE ISLAND   (United States)

^c BROWN UNIVERSITY   (United States)

Author keywords

H5N1; Immunomodulatory agents; Influenza; Statins; Transmissibility research

Indexed keywords

ATORVASTATIN; CHEMOKINE; CYTOKINE; FIBRIC ACID DERIVATIVE; GEMFIBROZIL; GLITAZONE DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; PIOGLITAZONE; RESVERATROL; ROSUVASTATIN;

2009 H1N1 INFLUENZA; ACUTE HEART INFARCTION; FATALITY; HEALTH CARE SYSTEM; HUMAN; IMMUNE RESPONSE; INFLUENZA A (H5N1); INFLUENZA VIRUS; INFLUENZA VIRUS A H5N1; MORTALITY; MOUSE; NONHUMAN; OBSERVATIONAL STUDY; PANDEMIC INFLUENZA; PUBLIC HEALTH; RAT; REVIEW; SEASONAL INFLUENZA; VIRUS REPLICATION; VIRUS TRANSMISSION; WORLD HEALTH ORGANIZATION;

H5N1; IMMUNOMODULATORY AGENTS; INFLUENZA; STATINS; TRANSMISSIBILITY RESEARCH;

ANIMALS; ANTIVIRAL AGENTS; BIOMEDICAL RESEARCH; BIRDS; HUMANS; INFLUENZA A VIRUS, H5N1 SUBTYPE; INFLUENZA IN BIRDS; INFLUENZA, HUMAN; PEER REVIEW, RESEARCH; REASSORTANT VIRUSES; ZOONOSES;

EID: 84878793827     PISSN: 21645515     EISSN: 2164554X     Source Type: Journal    
DOI: 10.4161/hv.23869     Document Type: Review

References (129)

1. Fouchier RAM, Herfst S, Osterhaus ADME. Public health and biosecurity. Restricted data on influenza H5N1 virus transmission. Science 2012; 335:662-3; PMID:22267582; http://dx.doi.org/10.1126/science.1218376.
2. Kawaoka Y. H5N1: Flu transmission work is urgent. Nature 2012; 482:155; PMID:22278057.
3. Casadevall A, Shenk T. The H5N1 manuscript redaction controversy. MBio 2012; 3:e00022-12; PMID:22294678; http://dx.doi.org/10.1128/mBio.00022-12.
4. Fouchier RA, García-Sastre A, Kawaoka Y, Barclay WS, Bouvier NM, Brown IH, et al. Pause on avian flu transmission research. Science 2012; 335:400-1; PMID:22282787; http://dx.doi.org/10.1126/science.1219412.
5. Palese P. Don't censor life-saving science. Nature 2012; 481:115; PMID:22237069; http://dx.doi.org/10.1038/481115a.
6. Webster RG. Mammalian-transmissible H5N1 influenza: the dilemma of dual-use research. MBio 2012; 3:e00005-00012; PMID:22294676; http://dx.doi.org/10.1128/mBio.00005-12.
7. Perez DR. Public health and biosecurity. H5N1 debates: hung up on the wrong questions. Science 2012; 335:799-801; PMID:22267585; http://dx.doi.org/10. 1126/science.1219066.
8. Peiris JSM, Poon LLM, Guan Y. Public health. Surveillance of animal influenza for pandemic preparedness. Science 2012; 335:1173-4; PMID:22345402; http://dx.doi.org/10.1126/science.1219936.
9. Herfst S, Osterhaus ADME, Fouchier RAM. The future of research and publication on altered H5N1 viruses. J Infect Dis 2012; 205:1628-31; PMID:22454474; http://dx.doi.org/10.1093/infdis/jis257.
10. Berns KI, Casadevall A, Cohen ML, Ehrlich SA, Enquist LW, Fitch JP, et al. Public health and biosecurity. Adaptations of avian flu virus are a cause for concern. Science 2012; 335:660-1; PMID:22294736; http://dx.doi.org/10.1126/ science.1217994.
11. Keim PS. The NSABB recommendations: rationale, impact, and implications. MBio 2012; 3:e00021-12; PMID:22294677; http://dx.doi.org/10.1128/mBio.00021-12.
12. Osterholm MT, Henderson DA. Public health and biosecurity. Life sciences at a crossroads: respiratory transmissible H5N1. Science 2012; 335:801-2; PMID:22267584; http://dx.doi.org/10.1126/science.1218612.
13. Kraemer JD, Gostin LO. Public Health and biosecurity. The limits of government regulation of science. Science 2012; 335:1047-9; PMID:22267583; http://dx.doi.org/10.1126/science.1219215.
14. Inglesby TV. Engineered H5N1: a rare time for restraint in science. Ann Intern Med 2012; 156:460-2; PMID:22282173.
15. Osterholm MT, Relman DA. Creating a mammalian-transmissible A/H5N1 influenza virus: social contracts, prudence, and alternative perspectives. J Infect Dis 2012; 205:1636-8; PMID:22454472; http://dx.doi.org/10.1093/infdis/ jis259.
16. World Health Organization. 2012. Report on technical consultation on H5N1 research issues. Available at www.who.int/influenza/human-animal-interface/mtg- report-h5n1.pdf.
17. National Science Advisory Board for Biosecurity. Findings and Recommendations. March 29-30, 2012. Available at http://oba.od.nih.gov/ biosecurity/news-events-oba.html#NSABB
18. Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 2012; 486:420-8; PMID:22722205.
19. Herfst S, Schrauwen EJA, Linster M, Chutinimitkul S, de Wit E, Munster VJ, et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 2012; 336:1534-41; PMID:22723413; http://dx.doi.org/10.1126/science. 1213362.
20. United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern. Available at http://oba.od.nih.gov/oba/biosecurity/PDF/ United-States-Government-Policy-for-Oversight-of-DURC-FINAL-version-032812.pdf.
21. Butler D. Caution urged for mutant flu work. Nature 2012; 481:417-8; PMID:22281569; http://dx.doi.org/10.1038/481417a.
22. Butler D. Lab flu may not aid vaccines. Nature 2012; 482:142-3; PMID:22318581; http://dx.doi.org/10.1038/482142a.
23. Ye J, Sorrell EM, Cai Y, Shao H, Xu K, Pena L, et al. Variations in the hemagglutinin of the 2009 H1N1 pandemic virus: potential for strains with altered virulence phenotype? PLoS Pathog 2010; 6:e1001145; PMID:20976194; http://dx.doi.org/10.1371/journal.ppat.1001145.
24. Ilyushina NA, Ducatez MF, Rehg JE, Marathe BM, Marjuki H, Bovin NV, et al. Does pandemic A/H1N1 virus have the potential to become more pathogenic? MBio 2010; 1:e00249-10; PMID:21116343; http://dx.doi.org/10.1128/mBio.00249-10.
25. Schrauwen EJA, Herfst S, Chutinimitkul S, Bestebroer TM, Rimmelzwaan GF, Osterhaus ADME, et al. Possible increased pathogenicity of pandemic (H1N1) 2009 influenza virus upon reassortment. Emerg Infect Dis 2011; 17:200-8; PMID:21291589; http://dx.doi.org/10.3201/eid1702.101268.
26. Jayaraman A, Pappas C, Raman R, Belser JA, Viswanathan K, Shriver Z, et al. A single base-pair change in 2009 H1N1 hemagglutinin increases human receptor affinity and leads to efficient airborne viral transmission in ferrets. PLoS One 2011; 6:e17616; PMID:21407805; http://dx.doi.org/10.1371/journal.pone. 0017616.
27. Chen LM, Blixt O, Stevens J, Lipatov AS, Davis CT, Collins BE, et al. In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity. Virology 2012; 422:105-13; PMID:22056389; http://dx.doi.org/10. 1016/j.virol.2011.10.006.
28. Russell CA, Fonville JM, Brown AEX, Burke DF, Smith DL, James SL, et al. The potential for respiratory droplet-transmissible A/H5N1 influenza virus to evolve in a mammalian host. Science 2012; 336:1541-7; PMID:22723414; http://dx.doi.org/10.1126/science.1222526.
29. Fedson DS, Opal SM. Research into transmissibility of influenza A H5N1: a practical response to the controversy. Lancet Infect Dis 2012; 12:364-5; PMID:22541628; http://dx.doi.org/10.1016/S1473-3099(12)70079-8.
30. Murray CJL, Lopez AD, Chin B, Feehan D, Hill KH. Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918-20 pandemic: a quantitative analysis. Lancet 2006; 368:2211-8; PMID:17189032; http://dx.doi.org/10.1016/S0140-6736(06)69895-4.
31. Robertson JS, Nicolson C, Harvey R, Johnson R, Major D, Guilfoyle K, et al. The development of vaccine viruses against pandemic A(H1N1) influenza. Vaccine 2011; 29:1836-43; PMID:21199698; http://dx.doi.org/10.1016/j.vaccine. 2010.12.044.
32. Partridge J, Kieny MP. World Health Organization H1N1 influenza vaccine Task Force. Global production of seasonal and pandemic (H1N1) influenza vaccines in 2009-2010 and comparison with previous estimates and global action plan targets. Vaccine 2010; 28:4709-12; PMID:20488262; http://dx.doi.org/10.1016/j. vaccine.2010.04.083.
33. Monto AS, Black S, Plotkin SA, Orenstein WA. Response to the 2009 pandemic: effect on influenza control in wealthy and poor countries. Vaccine 2011; 29:6427-31; PMID:21763381; http://dx.doi.org/10.1016/j.vaccine.2011.06. 113.
34. Fisher D, Hui DS, Gao Z, Lee C, Oh MD, Cao B, et al. Pandemic response lessons from influenza H1N1 2009 in Asia. Respirology 2011; 16:876-82; PMID:21627715; http://dx.doi.org/10.1111/j.1440-1843.2011.02003.x.
35. Ropero-Álvarez AM, Whittembury A, Kurtis HJ, dos Santos T, Danovaro-Holliday MC, Ruiz-Matus C. Pandemic influenza vaccination: lessons learned from Latin America and the Caribbean. Vaccine 2012; 30:916-21; PMID:22155136; http://dx.doi.org/10.1016/j.vaccine.2011.11.092.
36. Fedson DS. Confronting the next influenza pandemic with anti-inflammatory and immunomodulatory agents: why they are needed and how they might work. Influenza Other Respi Viruses 2009; 3:129-42; PMID:19627370; http://dx.doi.org/10.1111/j.1750-2659.2009.00090.x.
37. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008; 198:962-70; PMID:18710327; http://dx.doi.org/10.1086/591708.
38. Shanks GD, Brundage JF. Pathogenic responses among young adults during the 1918 influenza pandemic. Emerg Infect Dis 2012; 18:201-7; PMID:22306191; http://dx.doi.org/10.3201/eid1802.102042.
39. Morens DM, Taubenberger JK. 1918 influenza, a puzzle with missing pieces. Emerg Infect Dis 2012; 18:332-5; PMID:22304897; http://dx.doi.org/10.3201/ eid1802.111409.
40. Fedson DS. Was bacterial pneumonia the predominant cause of death in the 1918-1919 influenza pandemic? J Infect Dis 2009; 199:1408-9, author reply 1409-10; PMID:19358675; http://dx.doi.org/10.1086/597621.
41. Ahmed R, Oldstone MBA, Palese P. Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nat Immunol 2007; 8:1188-93; PMID:17952044; http://dx.doi.org/10.1038/ni1530.
42. Espinola-Klein C, Gori T, Blankenberg S, Munzel T. Inflammatory markers and cardiovascular risk in the metabolic syndrome. Front Biosci 2011; 16:1663-74; PMID:21196255; http://dx.doi.org/10.2741/3812.
43. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest 2011; 121:2111-7; PMID:21633179; http://dx.doi.org/10. 1172/JCI57132.
44. Robinson K, Kruger P, Prins J, Venkatesh B. The metabolic syndrome in critically ill patients. Best Pract Res Clin Endocrinol Metab 2011; 25:835-45; PMID:21925082; http://dx.doi.org/10.1016/j.beem.2011.04.008.
45. Pazos M, Sperling RS, Moran TM, Kraus TA. The influence of pregnancy on systemic immunity. Immunol Res 2012; 54:254-61; PMID:22447351; http://dx.doi.org/10.1007/s12026-012-8303-9.
46. Karlsson EA, Marcelin G, Webby RJ, Schultz-Cherry S. Review on the impact of pregnancy and obesity on influenza virus infection. Influenza Other Respi Viruses 2012; 6:449-60; PMID:22335790; http://dx.doi.org/10.1111/j.1750-2659. 2012.00342.x.
47. Hussell T, Cavanagh MM. The innate immune rheostat: influence on lung inflammatory disease and secondary bacterial pneumonia. Biochem Soc Trans 2009; 37:811-3; PMID:19614599; http://dx.doi.org/10.1042/BST0370811.
48. Lee N, Wong CK, Chan PKS, Chan MCW, Wong RYK, Lun SWM, et al. Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults. PLoS One 2011; 6:e26050; PMID:22022504; http://dx.doi.org/10.1371/journal.pone.0026050.
49. Huang Y, Zaas AK, Rao A, Dobigeon N, Woolf PJ, Veldman T, et al. Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection. PLoS Genet 2011; 7:e1002234; PMID:21901105; http://dx.doi.org/10.1371/journal.pgen.1002234.
50. Wang TS, Deng JC. Molecular and cellular aspects of sepsis-induced immunosuppression. J Mol Med (Berl) 2008; 86:495-506; PMID:18259721; http://dx.doi.org/10.1007/s00109-007-0300-4.
51. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012; 76:16-32; PMID:22390970; http://dx.doi.org/10.1128/MMBR.05015-11.
52. Maines TR, Belser JA, Gustin KM, van Hoeven N, Zeng H, Svitek N, et al. Local innate immune responses and influenza virus transmission and virulence in ferrets. J Infect Dis 2012; 205:474-85; PMID:22158704; http://dx.doi.org/10. 1093/infdis/jir768.
53. Shinya K, Gao Y, Cilloniz C, Suzuki Y, Fujie M, Deng G, et al. Integrated clinical, pathologic, virologic, and transcriptomic analysis of H5N1 influenza virus-induced viral pneumonia in the rhesus macaque. J Virol 2012; 86:6055-66; PMID:22491448; http://dx.doi.org/10.1128/JVI.00365-12.
54. Peiris JS, Hui KP, Yen HL. Host response to influenza virus: protection versus immunopathology. Curr Opin Immunol 2010; 22:475-81; PMID:20594815; http://dx.doi.org/10.1016/j.coi.2010.06.003.
55. O'Donnell CD, Subbarao K. The contribution of animal models to the understanding of the host range and virulence of influenza A viruses. Microbes Infect 2011; 13:502-15; PMID:21276869; http://dx.doi.org/10.1016/j.micinf.2011. 01.014.
56. Fukuyama S, Kawaoka Y. The pathogenesis of influenza virus infections: the contributions of virus and host factors. Curr Opin Immunol 2011; 23:481-6; PMID:21840185; http://dx.doi.org/10.1016/j.coi.2011.07.016.
57. Korth MJ, Tchitchek N, Benecke AG, Katze MG. Systems approaches to influenza-virus host interactions and the pathogenesis of highly virulent and pandemic viruses. Sem Immunol 2012; http://dx.doi.org/10.1016/j.smim.2012.11. 001.
58. Hatta Y, Hershberger K, Shinya K, Proll SC, Dubielzig RR, Hatta M, et al. Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 influenza virus infection in mice. PLoS Pathog 2010; 6:e1001139; PMID:20949022; http://dx.doi.org/10.1371/journal.ppat.1001139.
59. Boon ACM, Finkelstein D, Zheng M, Liao G, Allard J, Klumpp K, et al. H5N1 influenza virus pathogenesis in genetically diverse mice is mediated at the level of viral load. MBio 2011; 2:e00171-11; PMID:21896679; http://dx.doi.org/ 10.1128/mBio.00171-11.
60. Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 2008; 133:235-49; PMID:18423196; http://dx.doi.org/10.1016/j.cell.2008.02.043.
61. Serhan CN. The resolution of inflammation: the devil in the flask and in the details. FASEB J 2011; 25:1441-8; PMID:21532053; http://dx.doi.org/10.1096/ fj.11-0502ufm.
62. Marcelin G, Aldridge JR, Duan S, Ghoneim HE, Rehg J, Marjuki H, et al. Fatal outcome of pandemic H1N1 2009 influenza virus infection is associated with immunopathology and impaired lung repair, not enhanced viral burden, in pregnant mice. J Virol 2011; 85:11208-19; PMID:21865394; http://dx.doi.org/10. 1128/JVI.00654-11.
63. Armstrong SM, Wang C, Tigdi J, Si X, Dumpit C, Charles S, et al. Influenza infects lung microvascular endothelium leading to microvascular leak: role of apoptosis and claudin-5. PLoS One 2012; 7:e47323; PMID:23115643; http://dx.doi.org/10.1371/journal.pone.0047323.
64. Carré JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med 2010; 182:745-51; PMID:20538956; http://dx.doi.org/10.1164/rccm.201003-0326OC.
65. Piantadosi CA, Withers CM, Bartz RR, MacGarvey NC, Fu P, Sweeney TE, et al. Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J Biol Chem 2011; 286:16374-85; PMID:21454555; http://dx.doi.org/10.1074/jbc.M110.207738.
66. Piantadosi CA, Suliman HB. Redox regulation of mitochondrial biogenesis. Free Radic Biol Med 2012; 53:2043-53; PMID:23000245; http://dx.doi.org/10.1016/ j.freeradbiomed.2012.09.014.
67. McCall CE, El Gazzar M, Liu T, Vachharajani V, Yoza B. Epigenetics, bioenergetics, and microRNA coordinate gene-specific reprogramming during acute systemic inflammation. J Leukoc Biol 2011; 90:439-46; PMID:21610199; http://dx.doi.org/10.1189/jlb.0211075.
68. Liu TF, Brown CM, El Gazzar M, McPhail L, Millet P, Rao A, et al. Fueling the flame: bioenergy couples metabolism and inflammation. J Leukoc Biol 2012; 92:499-507; PMID:22571857; http://dx.doi.org/10.1189/jlb.0212078.
69. Fedson DS. Influenza vaccination or treatment for influenza-associated myocardial infarction. J Infect Dis 2012; 205:1618-9; PMID:22474032; http://dx.doi.org/10.1093/infdis/jis245.
70. Kwong JC, Li P, Redelmeier DA. Influenza morbidity and mortality in elderly patients receiving statins: a cohort study. PLoS One 2009; 4:e8087; PMID:19956645; http://dx.doi.org/10.1371/journal.pone.0008087.
71. O'Neal HR Jr., Koyama T, Koehler EAS, Siew E, Curtis BR, Fremont RD, et al. Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome. Crit Care Med 2011; 39:1343-50; PMID:21336116; http://dx.doi.org/10.1097/CCM.0b013e3182120992.
72. Vinogradova Y, Coupland C, Hippisley-Cox J. Risk of pneumonia in patients taking statins: population-based nested case-control study. Br J Gen Pract 2011; 61:e742-8; PMID:22054338; http://dx.doi.org/10.3399/bjgp11X606654.
73. Novack V, MacFadyen J, Malhotra A, Almog Y, Glynn RJ, Ridker PM. The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial. CMAJ 2012; 184:E367-72; PMID:22431901; http://dx.doi.org/10.1503/cmaj.111017.
74. Nielsen AG, Nielsen RB, Riis AH, Johnsen SP, Sørensen HT, Thomsen RW. The impact of statin use on pneumonia risk and outcome: a combined population-based case-control and cohort study. Crit Care 2012; 16:R122; PMID:22789037; http://dx.doi.org/10.1186/cc11418.
75. Chopra V, Rogers MAM, Buist M, Govindan S, Lindenauer PK, Saint S, et al. Is statin use associated with reduced mortality after pneumonia? A systematic review and meta-analysis. Am J Med 2012; 125:1111-23; PMID:22835463; http://dx.doi.org/10.1016/j.amjmed.2012.04.011.
76. Yende S, Milbrandt EB, Kellum JA, Kong L, Delude RL, Weissfeld LA, et al. Understanding the potential role of statins in pneumonia and sepsis. Crit Care Med 2011; 39:1871-8; PMID:21516038; http://dx.doi.org/10.1097/CCM. 0b013e31821b8290.
77. Rothberg MB, Bigelow C, Pekow PS, Lindenauer PK. Association between statins given in hospital and mortality in pneumonia patients. J Gen Intern Med 2012; 27:280-6; PMID:21842322; http://dx.doi.org/10.1007/s11606-011-1826-2.
78. Mortensen EM, Nakashima B, Cornell J, Copeland LA, Pugh MJ, Anzueto A, et al. Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes. Clin Infect Dis 2012; 55:1466-73; PMID:22918991; http://dx.doi.org/10.1093/cid/ cis733.
79. Patel JM, Snaith C, Thickett DR, Linhartova L, Melody T, Hawkey P, et al. Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial). Crit Care 2012; 16:R231; PMID:23232151; http://dx.doi.org/10.1186/cc11895.
80. Fedson DS. Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin Infect Dis 2006; 43:199-205; PMID:16779747; http://dx.doi.org/10.1086/505116.
81. Radigan KA, Urich D, Misharin AV, Chiarella SE, Soberanes S, Gonzalez A, et al. The effect of rosuvastatin in a murine model of influenza A infection. PLoS One 2012; 7:e35788; PMID:22536437; http://dx.doi.org/10.1371/journal.pone. 0035788.
82. Kumaki Y, Morrey JD, Barnard DL. Effect of statin treatments on highly pathogenic avian influenza H5N1, seasonal and H1N1pdm09 virus infections in BALB/c mice. Future Virol 2012; In Press; http://dx.doi.org/10.2217/fvl.12.71.
83. Sposito AC, Carvalho LSF, Cintra RMR, Araújo ALR, Ono AH, Andrade JM, et al.; Brasilia Heart Study Group. Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal. Atherosclerosis 2009; 207:191-4; PMID:19464010; http://dx.doi.org/10.1016/j. atherosclerosis.2009.04.008.
84. Palamara AT, Nencioni L, Aquilano K, De Chiara G, Hernandez L, Cozzolino F, et al. Inhibition of influenza A virus replication by resveratrol. J Infect Dis 2005; 191:1719-29; PMID:15838800; http://dx.doi.org/10.1086/429694.
85. Budd A, Alleva L, Alsharifi M, Koskinen A, Smythe V, Müllbacher A, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother 2007; 51:2965-8; PMID:17562808; http://dx.doi.org/10.1128/AAC.00219-07.
86. Aldridge JR Jr., Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci U S A 2009; 106:5306-11; PMID:19279209; http://dx.doi.org/10.1073/pnas.0900655106.
87. Moseley CE, Webster RG, Aldridge JR. Peroxisome proliferator-activated receptor and AMP-activated protein kinase agonists protect against lethal influenza virus challenge in mice. Influenza Other Respi Viruses 2010; 4:307-11; PMID:20716159; http://dx.doi.org/10.1111/j.1750-2659.2010.00155.x.
88. 2 reduces lung inflammation and protects mice against lethal influenza infection. J Infect Dis 2012; 205:621-30; PMID:22219346; http://dx.doi.org/10.1093/infdis/ jir804.
89. Sgarbanti R, Nencioni L, Amatore D, Coluccio P, Fraternale A, Sale P, et al. Redox regulation of the influenza hemagglutinin maturation process: a new cellmediated strategy for anti-influenza therapy. Antioxid Redox Signal 2011; 15:593-606; PMID:21366409; http://dx.doi.org/10.1089/ars.2010.3512.
90. Singhal J, Nagaprashantha L, Vatsyayan R, Awasthi S, Singhal SS. RLIP76, a glutathione-conjugate transporter, plays a major role in the pathogenesis of metabolic syndrome. PLoS One 2011; 6:e24688; PMID:21931813; http://dx.doi.org/ 10.1371/journal.pone.0024688.
91. Brett SJ, Myles P, Lim WS, Enstone JE, Bannister B, Semple MG, et al.; Influenza Clinical Information Network (FLU-CIN). Pre-admission statin use and inhospital severity of 2009 pandemic influenza A(H1N1) disease. PLoS One 2011; 6:e18120; PMID:21541017; http://dx.doi.org/10.1371/journal.pone.0018120.
92. Vandermeer ML, Thomas AR, Kamimoto L, Reingold A, Gershman K, Meek J, et al. Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study. J Infect Dis 2012; 205:13-9; PMID:22170954; http://dx.doi.org/10.1093/infdis/ jir695.
93. Jackson LA, Nelson JC. Association between statins and mortality. J Infect Dis 2012; 206:303-4, author reply 304-5; PMID:22569852; http://dx.doi.org/10.1093/infdis/jis344.
94. Jackson LA, Jackson ML, Nelson JC, Neuzil KM, Weiss NS. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J Epidemiol 2006; 35:337-44; PMID:16368725; http://dx.doi.org/10.1093/ije/dyi274.
95. Thomas A. Reply to Jackson. J Infect Dis 2012; 206:304-5; http://dx.doi.org/10.1093/infdis/jis345.
96. Fedson DS. Treatment of severe influenza with immunomodulatory agents. Influenza Other Respir Viruses 2011; 5(Suppl 1):246-9.
97. Howard WA, Peiris M, Hayden FG. Report of the 'mechanisms of lung injury and immunomodulator interventions in influenza' workshop, 21 March 2010, Ventura, California, USA. Influenza Other Respi Viruses 2011; 5:453-4, e458-75; PMID:21810053; http://dx.doi.org/10.1111/j.1750-2659.2011.00278.x; http://dx.doi.org/10.1586/eri.11.56.
98. Shin T, Kuboki S, Huber N, Eismann T, Galloway E, Schuster R, et al. Activation of peroxisome proliferator-activated receptor-gamma during hepatic ischemia is age-dependent. J Surg Res 2008; 147:200-5; PMID:18498870; http://dx.doi.org/10.1016/j.jss.2008.02.004.
99. Huang SSH, Banner D, Degousee N, Leon AJ, Xu L, Paquette SG, et al. Differential pathological and immune responses in newly weaned ferrets are associated with a mild clinical outcome of pandemic 2009 H1N1 infection. J Virol 2012; 86:13187-201; PMID:23055557; http://dx.doi.org/10.1128/JVI.01456-12.
100. Patel GP, Balk RA. Systemic steroids in severe sepsis and septic shock. Am J Respir Crit Care Med 2012; 185:133-9; PMID:21680949; http://dx.doi.org/10. 1164/rccm.201011-1897CI.
101. Confalonieri M, Kodric M, Santagiuliana M, Longo C, Biolo M, Cifaldi R, et al. To use or not to use corticosteroids for pneumonia? A clinician's perspective. Monaldi Arch Chest Dis 2012; 77:94-101; PMID:23193846.
102. Brun-Buisson C, Richard JCM, Mercat A, Thiébaut ACM, Brochard L; REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am J Respir Crit Care Med 2011; 183:1200-6; PMID:21471082; http://dx.doi.org/10.1164/rccm.201101- 0135OC.
103. Lim SH, Hong SB, Yun SC, Choi WI, Ahn JJ, Lee YJ, et al. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection. Am J Respir Crit Care Med 2012; 183:1207-14.
104. Matthay MA, Liu KD. Con: corticosteroids are not indicated for treatment of acute lung injury from H1N1 viral pneumonia. Am J Respir Crit Care Med 2011; 183:1127-8; PMID:21531953; http://dx.doi.org/10.1164/rccm.201103-0395ED.
105. Annane D. Pro: the illegitimate crusade against corticosteroids for severe H1N1 pneumonia. Am J Respir Crit Care Med 2011; 183:1125-6; PMID:21531952; http://dx.doi.org/10.1164/rccm.201102-0345ED.
106. Matthews L, Berry A, Tersigni M, D'Acquisto F, Ianaro A, Ray D. Thiazolidinediones are partial agonists for the glucocorticoid receptor. Endocrinology 2009; 150:75-86; PMID:18801908; http://dx.doi.org/10.1210/en.2008- 0196.
107. Bougarne N, Paumelle R, Caron S, Hennuyer N, Mansouri R, Gervois P, et al. PPARalpha blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-kappaB. Proc Natl Acad Sci U S A 2009; 106:7397-402; PMID:19376972; http://dx.doi.org/10.1073/pnas.0806742106.
108. Maneechotesuwan K, Kasetsinsombat K, Wamanuttajinda V, Wongkajornsilp A, Barnes PJ. Statins enhance the effects of corticoids on the balance between regulatory T cells and Th17 cells. J Allergy Clin Immunol 2012; In Press.
109. Bauer CMT, Zavitz CCJ, Botelho FM, Lambert KN, Brown EG, Mossman KL, et al. Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. PLoS One 2010; 5:e13251; PMID:20967263; http://dx.doi.org/10.1371/journal.pone. 0013251.
110. STIP. Statins Trial for Influenza Patients. NCT00970606. Available at
111. InFACT Global H1N1 Collaboration. InFACT: a global critical care research response to H1N1. Lancet 2010; 375:11-3; PMID:19906418; http://dx.doi.org/10. 1016/S0140-6736(09)61792-X.
112. Terblanche MJ, Pinto R, Whiteley C, Brett S, Beale R, Adhikari NKJ. Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study. Crit Care 2011; 15:R74; PMID:21356051; http://dx.doi.org/10.1186/cc10063.
113. Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, et al. Resilience to bacterial infection: difference between species could be due to proteins in serum. J Infect Dis 2010; 201:223-32; PMID:20001600; http://dx.doi.org/10.1086/649557.
114. Barnard DL. Animal models for the study of influenza pathogenesis and therapy. Antiviral Res 2009; 82:A110-22; PMID:19176218; http://dx.doi.org/10. 1016/j.antiviral.2008.12.014.
115. Otte A, Sauter M, Alleva L, Baumgarte S, Klingel K, Gabriel G. Differential host determinants contribute to the pathogenesis of 2009 pandemic H1N1 and human H5N1 influenza A viruses in experimental mouse models. Am J Pathol 2011; 179:230-9; PMID:21703405; http://dx.doi.org/10.1016/j.ajpath.2011. 03.041.
116. Alberts R, Srivastava B, Wu H, Viegas N, Geffers R, Klawonn F, et al. Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection. Microbes Infect 2010; 12:309-18; PMID:20114087; http://dx.doi.org/10.1016/j.micinf.2010.01.008.
117. Pica N, Iyer A, Ramos I, Bouvier NM, Fernandez- Sesma A, García-Sastre A, et al. The DBA.2 mouse is susceptible to disease following infection with a broad, but limited, range of influenza A and B viruses. J Virol 2011; 85:12825-9; PMID:21917963; http://dx.doi.org/10.1128/JVI. 05930-11.
118. Trammell RA, Liberati TA, Toth LA. Host genetic background and the innate inflammatory response of lung to influenza virus. Microbes Infect 2012; 14:50-8; PMID:21920449; http://dx.doi.org/10.1016/j.micinf.2011.08.008.
119. Easterbrook JD, Dunfee RL, Schwartzman LM, Jagger BW, Sandouk A, Kash JC, et al. Obese mice have increased morbidity and mortality compared to non-obese mice during infection with the 2009 pandemic H1N1 influenza virus. Influenza Other Respi Viruses 2011; 5:418-25; PMID:21668672; http://dx.doi.org/10.1111/j. 1750-2659.2011.00254.x.
120. Naghavi M, Wyde P, Litovsky S, Madjid M, Akhtar A, Naguib S, et al. Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation 2003; 107:762-8; PMID:12578882; http://dx.doi.org/10.1161/01.CIR.0000048190.68071.2B.
121. Doshi SM, Kulkarni PA, Liao JM, Rueda AM, Musher DM. The impact of statin and macrolide use on early survival in patients with pneumococcal pneumonia. Am J Med Sci 2012; In press; PMID:23111390; http://dx.doi.org/10.1097/MAJ. 0b013e3182639c26.
122. Boggild AK, Krudsood S, Patel SN, Serghides L, Tangpukdee N, Katz K, et al. Use of peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for Plasmodium falciparum malaria: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2009; 49:841-9; PMID:19673614; http://dx.doi.org/10.1086/605431.
123. Whitehorn J, Van Vinh Chau N, Truong NT, Tai LTH, Van Hao N, Hien TT, et al. Lovastatin for adult patients with dengue: protocol for a randomised controlled trial. Trials 2012; 13:203; PMID:23114081; http://dx.doi.org/10.1186/ 1745-6215-13-203.
124. Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, et al.; Inflammation and Host Response to Injury Large-Scale Collaborative Research Program. A genomic storm in critically injured humans. J Exp Med 2011; 208:2581-90; PMID:22110166; http://dx.doi.org/10.1084/jem.20111354.
125. Sauerbeck A, Gao J, Readnower R, Liu M, Pauly JR, Bing G, et al. Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. Exp Neurol 2011; 227:128-35; PMID:20965168; http://dx.doi.org/10.1016/j.expneurol. 2010.10.003.
126. Tzika AA, Mintzopoulos D, Mindrinos M, Zhang J, Rahme LG, Tompkins RG. Microarray analysis suggests that burn injury results in mitochondrial dysfunction in human skeletal muscle. Int J Mol Med 2009; 24:387-92; PMID:19639232; http://dx.doi.org/10.3892/ijmm-00000244.
127. Elijah IE, Børsheim E, Maybauer DM, Finnerty CC, Herndon DN, Maybauer MO. Role of the PPAR-α agonist fenofibrate in severe pediatric burn. Burns 2012; 38:481-6; PMID:22226866; http://dx.doi.org/10.1016/j.burns. 2011.12.004.
128. Santosham M, Chandran A, Fitzwater S, Fischer-Walker C, Baqui AH, Black R. Progress and barriers for the control of diarrhoeal disease. Lancet 2010; 376:63-7; PMID:20609988; http://dx.doi.org/10.1016/S0140-6736(10)60356-X.
129. Walsh EE. Statins and influenza: can we move forward? J Infect Dis 2012; 205:1-3; PMID:22170953; http://dx.doi.org/10.1093/infdis/jir693.