Treating the H5N1 Cytokine Storm


This was published on the BMJ on line

The Editor
Tavistock Sq.,
London WC1H 9JR



Since we will have no vaccines for the first 6 months of a H5N1 pandemic 1 , since the effectiveness of the effectiveness of the neuraminidases is in doubt 2 , and since Sang, Hoffmann and Webster 3 show that H5N1 influenza viruses are resistant to the antiviral effects of interferons and tumour necrosis factor alpha, we would do well to look at other approaches to treatment.

When H5N1 avian gains human to human transmissibility, its lethality will probably be related to the ability of the virus to induce a cytokine storm 4 , a positive feedback loop between cytokines and immune cells such as macrophages and T cells. Davy, Lee et al 5 showed that H5N1/97 strongly activates mitogen-activated protein kinase (MAPK) in response to H5N1 Avian.

It is therefore reasonable to look for ways of inhibiting the cytokine storm. Corticosteroids may be effective 6 , but carry the risk of avascular necrosis of bone as well as their usual side effects 7 . Xiaohui Peng et al 8 have shown that naltrexone, a specific inhibitor of classic opioid receptors, reverses the morphine induced enhancement of IL-12 at both the mRNA and protein levels in rats.

Holan et al. 9 showed that production of pro-inflammatory cytokines was enhanced and allotransplantation reactions were accelerated significantly in heroin-treated mice, and that this enhancing effects of heroin on the production of pro-inflammatory cytokines were antagonized by naltrexone.

Lin et al 10 induced sepsis by administration of lipopolysaccaridase (LPS) in anesthetized rats and demonstrated that pre-treatment with naltrexone significantly ameliorated hypotension and bradycardia, reduced the elevation of serum glutamate-oxalacetate transaminase and glutamate-pyruvate transaminase, reduced the infiltration of polymorphonuclear neutrophils into liver after LPS treatment in mice and significantly decreased the levels of plasma TNF-alpha and inhibited overproduction of superoxide anions in aortic rings.

Greeneltch et al 11 find that in mice naltrexone is capable of preventing LPS-induced septic shock mortality by indirect inhibition of TNF-alpha production in vivo.

Apart from corticosteroids, the other available treatment for cytokine storm is OX40-mIgG1 fusion protein 12 which is unlikely to be available and affordable by the time the pandemic reaches us.

Since Naltrexone is a cheap, long established drug and has a low side effect profile, it would be reasonable to conduct trials of Naltrexone treatment in human cases of H5N1 infections, and fulminating viral infections where cytokine storm is suspected and where the patient would otherwise die, in order to gain evidence for its possible usefulness in the expected pandemic of H5N1 influenza.

Yours sincerely,

Richard Lawson MB BS, MRCPsych.
General Practitioner
North Somerset
BS49 5DX

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55 Davy C. W. Lee et al. Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1. Journal of Virology 2005;79:10147-10154
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9 Hola N V, Zaji Cova A, Krulova M, Blahoutova V, Wilczek H. Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clinical & Experimental Immunology 2003;132:40-45.
10 Lin S L, Lee Y M, Chang H Y, Cheng Y W and Yen M H. Effects of naltrexone on lipopolysaccharide-induced sepsis in rats. J Biomed Sci. 2005;12:431-40.
11Greeneltch KM, Haudenschild CC, Keegan AD, Shi Y. The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production. Brain Behav Immun. 2004;18:476-84.
12 Humphreys I R, Walzl G, Edwards L, Rae A, Hill S, Hussell T. A Critical Role for OX40 in T Cell-mediated Immunopathology during Lung Viral Infection. The Journal of Experimental Medicine 2003;198:1237-1242

© 2001 R. Lawson u