Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus.
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 LD50 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.
State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Pok Fu Lam, Hong Kong.
Bo-Jian
BJ
Zheng
Kwok-Wah
KW
Chan
Yong-Ping
YP
Lin
Guang-Yu
GY
Zhao
Chris
C
Chan
Hao-Jie
HJ
Zhang
Hong-Lin
HL
Chen
Samson S Y
SS
Wong
Susanna K P
SK
Lau
Patrick C Y
PC
Woo
Kwok-Hung
KH
Chan
Dong-Yan
DY
Jin
Kwok-Yung
KY
Yuen
D000418:Albumins / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D005260:Female; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000821:virology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D011453:Prostaglandins / Q000378:metabolism; D016019:Survival Analysis; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D013997:Time Factors; D019562:Viral Load
D000418:Albumins; D000998:Antiviral Agents; D018925:Chemokines; D007155:Immunologic Factors; D011453:Prostaglandins