Using lessons from the past to plan for pandemic flu
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7544.783 (Published 30 March 2006) Cite this as: BMJ 2006;332:783All rapid responses
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The announcement of the UK’s first confirmed case of H5N1 Avian
Influenza in a swan found in Cellardyke Harbour has once again focused
attention on the level of preparedness of NHS organisations to manage the
effects of a possible pandemic influenza outbreak.
I therefore welcome Hilary Pickles’ article (BMJ 2006;332:783-6),
which echoes many of the concerns of those involved in the production of
local pandemic influenza plans.
Firstly, it was with interest that I read the UK government’s
response to the issues raised in the article. The suggestion that a recent
audit confirmed that “most primary care and NHS trusts reported that they
now consider they have resilient and sustainable contingency measures in
place”, does not mirror the views which I have been party to at a local
(county) level. The sharing of the results of the audit “through Strategic
Health Authorities” will therefore be welcome.
Secondly, there are real local concerns that the production of
workable plans at primary care level are being hampered by information
gaps within the national plan (1), a situation which is being compounded
by the lack of a clear steer from the centre when local planners seek
clarification regarding certain key issues.
For example, there still remains no clear national statement on the
triggers for the suspension of current NHS “productivity targets” for
primary and secondary care during a national pandemic. This makes the
identification and prior re-allocation of the resources that may be
available at such time very problematic.
Furthermore, suggestions that local agreement should determine these
triggers are impracticable and could well lead to delay and widespread
inconsistency in response to what is, in reality, a national emergency.
This will only result in further confusion and an erosion of public
confidence in the overall planning process.
Thirdly, the apparent ‘over’ reliance upon antiviral drugs to
initially contain an outbreak may prove costly (2). The local delivery of
this policy has required planners to focus much of their attention upon
developing safe and efficient dispensing arrangements to all patients with
probable pandemic influenza, although in a large proportion of these
individuals the disease will likely be self-limiting. Should these drugs
prove of limited benefit in a pandemic situation, as considered probable
by an increasing number of experts (3), current national imperatives will
have served to distract attention away from those patients who are in real
need of health service intervention.
The Government needs to be open with the public, outlining the scope
of protection realistically available during a pandemic. Additionally, we
need to encourage the exploration and development of initial control and
management measures outside of antivirals at both national and local
level.
Ivan Browne
(1) Department of health. UK health departments’ influenza pandemic
contingency plan. October 2005
(2) Yi Guan. Resistance to antiviral agents. Lancet October 1,
2005;366: 1139-1140
(3) Andrew Cole. Experts question wisdom of stockpiling oseltamivir,
BMJ November 5, 2005;331:1041
Competing interests:
None declared
Competing interests: No competing interests
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.
1 Pennington TH, A slippery disease: a microbiologists’s view. BMJ 2006;332:789-90
2 Bonneux L Van Damme W, An iatrogenic pandemic of panic. BMJ 2006;332: 786-8
3 Sang HS, Hoffmann E, Webster RG. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nature Medicine 2002;8:950 – 954.
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
5 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 Med 2003;348:2034–5.
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). Thorax 2004;59:643-645.
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 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.
11 Greeneltch 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
Competing interests:
None declared
Competing interests: No competing interests
Current global battle plans against pandemic flu appear to be
ignoring one clear lesson of SARS: that international air travel is the
one feature that most differentiates present day transmission scenarios
from those in 1918. The novel coronavirus arrived in Hong Kong SAR from
China on a jet plane, and from that efficient air hub, quickly spread to
Vietnam, Singapore, and Canada, eventually engulfing 27 countries around
the globe.
Whether H5N1 avian is destined to become the next pandemic or a mere
footnote in the archives of infectious diseases
- like its predecessor H1N1 swine 30 years ago(1) – is anybody’s guess;
but one thing is certain: If and when sustained human-to-human
transmission of H5N1 becomes reality, the world will no longer be dealing
with sporadic avian flu borne along migratory flight paths of birds(2),
but aviation flu - winged at subsonic speed along commercial air conduits
to every corner of planet Earth.
One hopes that appropriate preventive measures are being put into
place by the airlines and airports of the world, but that may be just the
problem: What is the evidential base for effective interventions, and how
rigorously have the aviation policy options been evaluated? Three years
after the SARS episode, we still do not understand the dynamics of
microbial transmission in aircraft cabins, toilets and airport transit
lounges; neither are we clearer regarding the complex spatial interactions
of travelers converging on busy air terminals, nor how best such human
traffic may be channeled to minimize the risk of viral transmission.
Against a conservatively estimated US$800 billion a year that a human
pandemic of avian influenza could cost the global economy(3), not to
mention the incalculable cost in terms of human lives, it seems incredible
that the SARS scare did not spur significant scientific activity to
strengthen public health on the air transportation front. Should not the
technology for picking out passengers capable of transmitting deadly
pathogens and setting off epidemics be pursued as energetically as the
technology for stopping terrorists from boarding a plane?
1. Fineberg HV, Neustadt RE. The Epidemic That Never Was: Policy-
Making and the Swine Flu Scare Vintage Books USA 1983
2. Liu J, Xiao H, Lei F et al. Highly pathogenic H5N1 influenza virus
infection in migratory birds. Science 2005;309(5738):1206
3. The World Bank. Avian Flu: Economic Losses Could Top US$800
Billion. The World Bank News and Broadcast. November 8, 2005. Available
at:
http://web.worldbank.org/WBSITE/EXTERNAL/NEWS/
0,,contentMDK:20715408~pagePK:64257043~piPK:
437376~theSitePK:4607,00.html
(accessed 2 April 2006)
Competing interests:
None declared
Competing interests: No competing interests
Any criticism of vaccination is now regarded as heresy and deserving
the extreme penalty. There are a few voices heard however that express
some scepticism about the inflated claims of benefit of influenza
vaccination (1). Most of the evidence for benefit is based on
observational studies with their liability to bias (2). Pleas have been
made to perform convincing randomised controlled trials on the existing
vaccines. It is even more important to use these techniques when assessing
putative H5N1 vaccines. Surrogate measurements of antibody stimulation
will not do. The panic response that ”Something must be done” will result
in the wrong thing being done. The same question arises about the efficacy
of antiviral drugs. Here at least the definitive therapeutic measures are
available and could be tested shortly after the start of an epidemic. By
the time relevant vaccines have been developed the epidemic will have
passed and the virus mutated. However, the public- even if it consists of
what is called contemptuously the “aged rich”- will have opted for
possible remedies and stockpiled them. It knows that triage means denial
on spurious grounds of social worth.
Doomsday predictions are certain to be wrong- either by overestimating or
underestimating the disaster. It might be best to postpone planning until
the last moment rather than commit to a rigid inappropriate schedule.
1. van der Wouden et al. Resp. Med 2005, 99, 1341-1349. Evidence based
review. Preventing Influenza
2. Simonsen l. Arch.Int Med. 2005, 165, 265-272 Impact of Influenza
vaccination on seasonal mortality in the US elderly population.
Competing interests:
None declared
Competing interests: No competing interests
Setting standards for the pandemic flu response
Hilary Pickles argues that the preparations for an influenza pandemic
could be improved by learning important lessons from the past(1). We
would like to highlight an additional lesson which should be learnt.
In 2004/5 there was an outbreak of mumps among teenagers in the
greater Bristol area. Our audit of the response to the outbreak identified
that there were no comprehensive audit standards for outbreaks of
communicable diseases(2). Whilst the United Kingdom is preparing its
response to a pandemic(3), attention should also be given to how the
response will be audited, in order to identify lessons for the future.
As part of the preparation for an influenza pandemic, the World
Health Organisation, Department of Health, Health Protection Agency, or
Faculty of Public Health should develop audit standards for outbreaks of
communicable disease. The standards should address a range of issues key
to effective outbreak management including strategic leadership;
appropriate communication; surveillance; safety precautions; staff
training; and outcome measures such as impact on spread of disease, cost-
effectiveness and equity.
References
(1) Pickles H. Using lessons from the past to plan for pandemic flu
BMJ 2006;332:783-786.
(2) Hamilton S, Kipping RR, Roderick M, Alexander K, Reid K. Audit
of the Avon MMR Vaccination Campaign for Mumps 2004/5. 2005. Bristol:
Bristol North PCT.
(3) Department of Heath. UK Health Departments’ Influenza Pandemic
Contingency Plan. March 2005. London: Department of Health.
Competing interests:
None declared
Competing interests: No competing interests