This was published on the BMJ on line
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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
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.
Richard Lawson MB BS, MRCPsych.
1 Pennington TH, A slippery disease: a microbiologists's view.
2 Bonneux L Van Damme W, An iatrogenic pandemic of panic. BMJ
3 Sang HS, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses
escape host anti-viral cytokine responses. Nature Medicine 2002;8:950
4Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan
Y, Peiris JS. Induction of proinflammatory cytokines in human
macrophages by influenza A (H5N1) viruses: a mechanism for the
unusual severity of human disease? Lancet 2002; 360: 1831-7
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
6 Lee N , Sung J. The use of corticosteroids in SARS. N Engl J
7 Yu W C, Hui D S C and Chan-Yeung M. Antiviral agents and corticosteroids
in the treatment of severe acute respiratory syndrome (SARS).
8 Peng X, Mosser DM, Adler M, et al. Morphine enhances interleukin-12
and the production of other pro-inflammatory cytokines in mouse
peritoneal macrophages, Journal of Leukocyte Biology. 2000;68:723-728.
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
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