Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus
Open accessAbstract
The mortality of human infection by influenza A/H5N1 virus can exceed 80%. The high mortality and its poor response to the neuraminidase inhibitor oseltamivir have been attributed to uncontrolled virus-induced cytokine storm. We challenged BALB/c mice with 1,000 LD 50 of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamvir, celecoxib, gemfibrozil, and mesalazine. To imitate the real-life scenario, treatment was initiated at 48 h after viral challenge. There were significant improvements in survival rate ( P = 0.02), survival time ( P < 0.02), and inflammatory markers ( P < 0.01) in the group treated with a triple combination of zanamivir, celecoxib, and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4 + and CD8 + T lymphocytes and less pulmonary inflammation were also found in the group receiving triple therapy. Zanamivir alone reduced viral load but not inflammation and mortality. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing apoptosis. Combinations of a neuraminidase inhibitor with these immunomodulators should be considered in randomized controlled treatment trials of patients suffering from H5N1 infection.
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Combination therapy consisting of zanamvir, an inhibitor of the influenza virus neuraminidase, and celecoxib and mesalazine, inhibitors of inflammation, increased the survival of mice infected with a highly pathogenic strain of H5N1 influenza virus.
“Combination therapy consisting of zanamvir, an inhibitor of the influenza virus neuraminidase, and celecoxib and mesalazine, inhibitors of inflammation, increased the survival of mice infected with a highly pathogenic strain of H5N1 influenza virus (157).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [157]
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Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.
de Jong, M. D., Simmons, C. P., Thanh, T. T., Hien, V. M., Smith, G. J. D., Chau, T. N. B., Hoang, D. M., Van Vinh Chau, N., Khanh, T. H., Dong, V. C., et al. (2006) · Nature Medicine · doi:10.1038/nm1477 · Cited by 1,858 · see citing works
Avian Influenza A (H5N1) Infection in Humans
The Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5 (2005) · New England Journal of Medicine · doi:10.1056/nejmra052211 · Cited by 1,280 · see citing works
Yuen, K., Chan, P., Peiris, M. J. S., Tsang, D., Que, T., Shortridge, K. F., Cheung, P., To, W., Ho, E., Sung, R. Y. T., et al. (1998) · The Lancet · doi:10.1016/s0140-6736(98)01182-9 · Cited by 1,049 · see citing works
Self-citationChinetti, G., Fruchart, J.-C., & Staels, B. (2000) · Inflammation Research · doi:10.1007/s000110050622 · Cited by 954 · see citing works
Re-emergence of fatal human influenza A subtype H5N1 disease
Peiris, J., Yu, W., Leung, C., Cheung, C., Ng, W., Nicholls, J., Ng, T., Chan, K., Lai, S., Lim, W., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15595-5 · Cited by 812 · see citing works
Self-citationA question of self‐preservation: immunopathology in influenza virus infection
Gruta, N. L. L., Kedzierska, K., Stambas, J., & Doherty, P. C. (2007) · Immunology and Cell Biology · doi:10.1038/sj.icb.7100026 · Cited by 454 · see citing works
Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque
Li, B.-J., Tang, Q., Cheng, D., Qin, C., Xie, F. Y., Wei, Q., Xu, J., Liu, Y., Zheng, B.-J., Woodle, M. C., et al. (2005) · Nature Medicine · doi:10.1038/nm1280 · Cited by 433 · see citing works
Self-citationRole of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice
Szretter, K. J., Gangappa, S., Lu, X., Smith, C. S., Shieh, W., Zaki, S. R., Sambhara, S. R., Tumpey, T. M., & Katz, J. M. (2006) · Journal of Virology · doi:10.1128/jvi.02336-06 · Cited by 373 · see citing works
Smith, P. W., Sollis, S. L., Howes, P. D., Cherry, P. C., Starkey, I. D., Cobley, K. N., Weston, H. E., Scicinski, J. J., Merritt, A., Whittington, A. R., et al. (1998) · Journal of Medicinal Chemistry · doi:10.1021/jm970374b · Cited by 342 · see citing works
Avian Influenza Virus Infections in Humans
Wong, S. S. Y., & Yuen, K. (2006) · CHEST Journal · doi:10.1378/chest.129.1.156 · Cited by 340 · see citing works
Self-citationInhibition of the cytokine response does not protect against lethal H5N1 influenza infection
Salomon, R., Hoffmann, E., & Webster, R. G. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705289104 · Cited by 265 · see citing works
Beigel, J. H., Farrar, J., Han, A. M., Hayden, F. G., Hyer, R. N., & Jong, D. (2005) · Cited by 260 · see citing works
Govorkova, E. A., Ленева, И. А., Goloubeva, O. G., Bush, K., & Webster, R. G. (2001) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.45.10.2723-2732.2001 · Cited by 241 · see citing works
Prophylactic and Therapeutic Efficacy of Human Monoclonal Antibodies against H5N1 Influenza
Simmons, C. P., Bernasconi, N. L., Suguitan, A. L., Mills, K., Ward, J. M., Châu, N. V. V., Hien, T. T., Sallusto, F., Ha, D. Q., Farrar, J., et al. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040178 · Cited by 208 · see citing works
Apoptosis and Pathogenesis of Avian Influenza A (H5N1) Virus in Humans
Uiprasertkul, M., Kitphati, R., Puthavathana, P., Kriwong, R., Kongchanagul, A., Ungchusak, K., Angkasekwinai, S., Chokephaibulkit, K., Srisook, K., Vanprapar, N., et al. (2007) · Emerging infectious diseases · doi:10.3201/eid1305.060572 · Cited by 170 · see citing works
Yen, H., Monto, A. S., Webster, R. G., & Govorkova, E. A. (2005) · The Journal of Infectious Diseases · doi:10.1086/432008 · Cited by 170 · see citing works
Ленева, И. А., Roberts, N. A., Govorkova, E. A., Goloubeva, O. G., & Webster, R. G. (2000) · Antiviral Research · doi:10.1016/s0166-3542(00)00123-6 · Cited by 167 · see citing works
Drug Insight: aminosalicylates for the treatment of IBD
Nielsen, O. H., & Munck, L. K. (2007) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep0696 · Cited by 158 · see citing works
Efficacy of Orally Administered T-705 on Lethal Avian Influenza A (H5N1) Virus Infections in Mice
Sidwell, R. W., Barnard, D. L., Day, C. W., et al. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01051-06 · Cited by 154 · see citing works
Ryan, D., Ticehurst, J. R., Dempsey, M. H., & Penn, C. R. (1994) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.38.10.2270 · Cited by 144 · see citing works
Du, L., Zhao, G., Lin, Y., Sui, H., Chan, C. C. S., Ma, S., He, Y., Jiang, S., Wu, C. Y., Yuen, K., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.2.948 · Cited by 136 · see citing works
Self-citationCarey, M. A., Bradbury, J. A., Seubert, J. M., Langenbach, R. J., Zeldin, D. C., & Germolec, D. R. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.10.6878 · Cited by 121 · see citing works
Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza
Budd, A. C., Alleva, L. M., Alsharifi, M., Koskinen, A. M. L., Smythe, V., Müllbacher, A., Wood, J. T., & Clark, I. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00219-07 · Cited by 101 · see citing works
A rationale for using steroids in the treatment of severe cases of H5N1 avian influenza
Carter, M. J. (2007) · Journal of Medical Microbiology · doi:10.1099/jmm.0.47124-0 · Cited by 71 · see citing works
Zheng, B., Guan, Y., He, M., et al. (2005) · Antiviral Therapy · doi:10.1177/135965350501000301 · Cited by 70 · see citing works
Self-citationCatalano, A., Graciotti, L., Rinaldi, L., et al. (2004) · International Journal of Cancer · doi:10.1002/ijc.11710 · Cited by 46 · see citing works
Effect of 5-aminosalicylic acid on radiation-induced micronuclei in mouse bone marrow
Kumar, M. S., Unnikrishnan, M. K., & Devi, P. U. (2003) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(03)00052-6 · Cited by 30 · see citing works
5-Aminosalicylate stimulates phospholipase D activity in macrophages
Gómez‐Muñoz, A., O’Brien, L., Salh, B. S., & Steinbrecher, U. P. (2001) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(01)00149-4 · Cited by 12 · see citing works
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Tisoncik, J. R., Korth, M. J., Simmons, C. P., Farrar, J., Martin, T. R., & Katze, M. G. (2012) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.05015-11 · Cited by 1,940 · see citing works
Innate immune responses to influenza A H5N1: friend or foe?
Peiris, J. S. M., Cheung, C. Y., Leung, C. Y. H., & Nicholls, J. M. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.09.004 · Cited by 232 · see citing works
Chen, Y.-H., Chang, G.-K., Kuo, S.-M., Huang, S.-Y., Hu, I.-C., Lo, Y.-L., & Shih, S.-R. (2016) · Scientific Reports · doi:10.1038/srep24253 · Cited by 112 · see citing works
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Bassaganya-Riera, J., Song, R., Roberts, P. C., & Hontecillas, R. (2010) · Viral Immunology · doi:10.1089/vim.2010.0016 · Cited by 83 · see citing works
Kash, J. C., Xiao, Y., Davis, A. S., Walters, K.-A., Chertow, D. S., Easterbrook, J. D., Dunfee, R. L., Sandouk, A., Jagger, B. W., Schwartzman, L. M., et al. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.10.014 · Cited by 43 · see citing works
Li, T., Liu, Y., Di, B., Wang, M., Shen, J., Zhang, Y., Chen, X., Yuan, J., Wu, J., & Li, K. (2011) · Journal of Clinical Virology · doi:10.1016/j.jcv.2010.11.012 · Cited by 25 · see citing works
- Authors
- Zheng, B.-J., Chan, K.-W., Lin, Y.-P., Zhao, G.-Y., Chan, C., Zhang, H.-J., Chen, H.-L., Wong, S. S. Y., Lau, S. K. P., Woo, P. C. Y., Chan, K.-H., Jin, D.-Y., & Yuen, K.-Y.
- Affiliations
- *State Key Laboratory of Emerging Infectious Diseases,
- Departments of §Pathology and
- Department of Microbiology,
- University of Hong Kong (HK)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-06-10
- Volume
- 105
- Issue
- 23
- Pages
- 8091-8096
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2430364
- OpenAlex
- W2113038532
- Cited by
- 302
- References
- 28
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 13 · 2021: 15 · 2020: 27 · 2019: 8 · 2018: 14 · 2017: 19 · 2016: 27 · 2015: 19 · 2014: 16 · 2013: 31 · 2012: 15
- FWCI
- 19.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Outbreaks Research
- Keywords
- H5N1 avian influenza, avian influenza, treatment delay, zanamivir, oseltamivir, celecoxib, 5-aminosalicylic acid, gemfibrozil, immunomodulators, cytokine storm, viral load, T cells, lung inflammation, survival, combination therapy
- MeSH terms
- Albumins, Animals, Antiviral Agents, Body Weight, Female, Immunologic Factors, Lung, Mice, Inbred BALB C, Orthomyxoviridae Infections, Prostaglandins, T-Lymphocytes, Time Factors, Survival Rate, Survival Analysis, Lymphocyte Count, Chemokines, Viral Load, Mice, Influenza A Virus, H5N1 Subtype
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