British medical journal, 332 (7544): 786-788Analysis and comment An iatrogenic pandemic of panic
Luc Bonneux, Wim Van Damme
Nine decades after the disappearance of the infamous sive food poisoning such as the dioxin crisis. Airborne Spanish flu, its ghost is threatening again. In many transmission of the extremely lethal Ebola Zaire virus countries, panicking citizens are buying drugs from might cause a devastating epidemic and is popular in uncertain sources through the internet for a disease both fiction and (alleged) non-fiction. The HIV super- Department ofPublic Health, that does not yet exist.1 In September 2005, bug appeared in February 2005 in New York as a virus Institute of Tropical Dr Nabarro, the World Health Organization's public with multiple mutations, multiple drug resistance, and Medicine, B-2000, health expert coordinating the response to avian influ- a rapid course of infection, but in only one person. The enza, told the Associated Press that a global avian case served to rekindle the US public's fear after inter- influenza pandemic could kill 150 million people est in AIDS had been waning because of Iraq.
Correspondence to: worldwide.2 What are the risks of a pandemic and is In the Belgian dioxin crisis, dioxins got mixed up stockpiling antiviral drugs the best response? in the food chain, causing levels of exposure to dioxins similar to those in the 1980s.3 The crisis fell conveniently (for the political opposition) just before How real is the risk of pandemic?
an election. Competitors in the highly regulated A new pandemic with a highly pathogenic influenza European food market saw their chance to increase strain is obviously possible. But other infectious agents market shares. Seven million chicken and 60 000 present similar risks—for example, an Ebola epidemic pigs were slaughtered. Not one person has been with airborne transmission, an AIDS epidemic with a detected with any observable consequence of dioxin much more virulent strain of HIV (superbug), or mas- BMJ VOLUME 332 1 APRIL 2006
Analysis and comment heart or lung disease. Among people younger than65, excess mortality was 0 to 1 per million.6 Pandemic of avian flu among birds—Outbreaks of avian flu are frequent.7 The recent outbreak is causedby a virus that can infect humans, as were similar out-breaks since 1997. The virus is highly pathogenic butcannot sustain an epidemic among humans. Since2003, about 60 people have died each year worldwide.8 Influenza A viruses—These viruses also cause pandemics. In the last 1968-9 pandemic excess mortal-ity was 14 per 100 000 person-years, some three timesmore than in annual winter flu. The excess death rateamong people younger than 65 was 6 per 100 000,with most of these deaths in people aged 50-65.6 claimed an estimated 250 000 deaths in the UnitedKingdom alone. It combined the highly unusual char-acteristics of high pathogenicity, the ability to transmitbetween humans, and high mortality among youngpeople.6 The excess death rate was 166 per 100 000among people older than 65 but 546 per 100 000among younger people—a hundred times higher thanthe rate in the 1968-9 pandemic. This is the only cata-strophic flu pandemic with high case fatality among younger people known in all human history.9 Price of control
Getting into a flap about flu The wish to feel in control over the looming pandemic, Perception of risk
accompanied by clever marketing, has caused anuncontrolled scramble for stockpiles of antiviral drugs.
In a global world with global media coverage and com- Two neuraminidase inhibitors are active against flu, zan- petition for sensational news, any hypothetical dooms- amivir and oseltamivir.10 Neuraminidase inhibitors have day scenario that could capture the public imagination been available since the end of the 1990s but have been risks unleashing a media storm. Disease experts are used rarely during winter flu epidemics. The drugs vying for attention and consequent research funding.
inhibit virus spread within the respiratory tract, but viral The perception of risk is then easily distorted from the reproduction largely precedes the symptoms.11 They are actual risk. People intuitively overestimate the risk of rare therefore not very effective in treating clinical flu.12 If events and underestimate the risk of common events.4 taken early after the appearance of symptoms, they People perceive unlikely and uncertain catastro- reduce the duration of disease by one day; the effective- phes as more threatening than frequent and likely ness in true life will be worse than in regularly controlled risks. The risk that next winter you will be killed in a car and motivated clinical trial populations. Case fatality is crash is far higher than that you will killed by highly low in patients under 65, limiting potential cost pathogenic flu, an unusual event. Moreover, you are effectiveness to frail patients at high risk of complica- much more likely to be killed by non-pandemic flu tions, treated within the first 48 hours of symptoms.13 than by pandemic flu.5 Winter flu causes cumulatively A recent Cochrane review of neuraminidase more disease and death than pandemic flu, but as inhibitors concluded against over-reliance on antiviral annual flu occurs annually we are used to it.
drugs.14 It found no credible evidence that neuramini- Perception of risk is linked to the subjective feeling dase inhibitors were effective in avian influenza.
of control: although driving your car is more Oseltamivir resistant viruses have been observed in up dangerous than taking a plane, the risk of driving is to 16% of infected children. Although these drugs may more readily accepted than the risk of flying. The prevent symptoms and complications, they do not threat of a pandemic is particularly scary as we lack prevent infection or suppress viral nasal excretion, control, which in turn tempts us into aimless activity.
which promotes further viral spread. The successfulmarketing of these drugs seems to be more the Confusion about flu
invention of "an ill by a pill."15 The scramble for neuraminidase inhibitors shows In the popular press and citizens' minds, avian the effects of patenting laws. The manufacturer has the influenza, winter flu, pandemic flu, and a catastrophic monopoly and the rational monopolist sets the price pandemic like Spanish flu are confounded, with some based on "what the market will bear." Rich countries help from disease advocates. We should therefore clas- are stockpiling the drugs, at an average of $5 (£3; €4) a sify flu epidemics.5 person, representing less than 1% of their annual Annual winter flu—Since the 1980s winter flu has healthcare budgets.16 But $5 is higher than the annual caused between two and five excess deaths per 100 000 healthcare budget for 300 million poor Africans. The person-years.6 Most of those who die are frail, Asian nations where the avian flu causes most deaths predominantly elderly people and those with chronic and where the risks of recombination of avian and BMJ VOLUME 332 1 APRIL 2006
Analysis and comment generic capacity to deal with all types of emergencies,not just a hypothetical flu pandemic. WHO should advocate the need for expanded capacity to producevaccines and for fairer and more workable health The perceived threat of a hypothetical pandemic of avian flu among exceptions to the international trade agreements.
humans fuels fear Avian flu, winter flu, pandemic flu, and Spanish flu are often confused and mixed up Panic in epidemics is a part of the human condition.19The increase in health scares may reflect the absence of Stockpiling antiviral drugs lacks an evidence base and is costly real attacks, making us over-react to hypothetical dan-gers. We should use panic, with good reason or not, to The energy unleashed by the fear of a pandemic should be directed tackle the larger agenda of preventable and curable at tackling real health problems disease in the world, starting with low vaccination ratesin winter flu. International health policy should stay human flu are highest cannot afford stockpiles of cool and not be distracted by the latest health scare and its industry sponsored quick fix. The humanist road The development of oseltamivir was a final step in a leading to adequate healthcare services for all citizens long history of human discovery, starting in 1942.10 In of the world is still long.
this long walk, funded in large part by taxpayers,16 the Contributors and sources: LB has a longstanding interest in pri- name of Hoffman La Roche appears in 1997, describing ority setting in health care and has published widely on public oseltamivir. The company should be rewarded justly.
health decision making. WVD is an academic specialised in Justly does not mean cashing in all the rewards of five health systems in developing countries. He is working oncontrol of epidemics and on health policies in countries in fast decades of research: innovative drugs are not created in transition. For this article they studied papers and reports from an intellectual vacuum by a lonely genius. Present incen- the scientific literature and authoritative bodies describing the tives direct all pharmaceutical research to the block- history, effectiveness, and cost-effectiveness of neuraminidase buster drugs that target the scares of the ageing rich. If inhibitors in the treatment and prevention of influenza. LB hadthe idea for the article and discussed it with WVD. LB wrote shortage of production capacity for oseltamivir leads to subsequent drafts, which were completed and reviewed by WVD.
patenting laws being revised so that industry incentives Both will act as guarantors.
are redirected to the disease burden of the world, the Competing interests: None declared.
blindly selfish scramble for neuraminidase inhibitorswould turn out to be a blessing.17 Boersema D. Vogelgriep leidt tot run op virusremmer via website [Birdflu causes run for antivirals through website]. Volkskrant 2005 Oct 20.
CNN. Bird flu may kill 150m, warns UN, 30 September 2005.
Managing global pandemics globally
Bernard A, Hermans C, Broeckaert F, De Poorter G, De Cock A, Houins In history, epidemics and the fear they caused were fer- G. Food contamination by PCBs and dioxins. Nature 1999;401:231-2.
tile grounds for public health breakthroughs. The Bellaby P. Communication and miscommunication of risk: understand-ing UK parents' attitudes to combined MMR vaccination. BMJ plague epidemics in the Middle Ages in Europe are at the origin of public health authorities. Flu pandemics Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH,Schonberger LB. The impact of influenza epidemics on mortality: intro- teach us that global health problems need global solu- ducing a severity index. Am J Public Health 1997;87:1944-50.
tions. Can the fear of a catastrophic flu pandemic be Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K.
Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998;178:53-60.
The old medical humanist adage "To cure Centers for Disease Control and Prevention. Spread of avian influenzaviruses sometimes, to relieve often, to comfort always" remains (accessed 13 Mar 2006).
central. There are no magic pills to replace the compe- Macfarlane JT, Lim WS. Bird flu and pandemic flu. BMJ 2005;331:975-6.
tent care of dedicated nurses and doctors. In a Beveridge WI. The chronicle of influenza epidemics. Hist Philos Life Sci1991;13:223-34.
pandemic, maintaining sufficient admission capacity 10 Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase for acute cases will be crucial. Sufficient capacity of inhibitors. Lancet 2000;355:827-35.
11 Dolin R. Influenza. In: Harrison's Principles of Internal Medicine. 15th ed.
acute care beds and strengthened health services can McGraw-Hill, New York, 2001:1125-30.
respond to all types of emergencies, not only a flu pan- 12 Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG.
Effectiveness of neuraminidase inhibitors in treatment and prevention of demic. This holds even more for the weaker healthcare influenza A and B: systematic review and meta-analyses of randomised systems in developing countries.18 controlled trials. BMJ 2003;326:1235.
13 National Institute for Health and Clinical Excellence. Guidance on the use Our annual foe, winter flu, has killed far more peo- of zanamivir, oseltamivir and amantadine for the treatment of influenza. Tech- ple since the second world war than the number who nology appraisal No 58. www.nice.org.uk/pdf/58_Flu_fullguidance.pdf(accessed 13 Mar 2006).
died in the 1918 pandemic. We could turn the panic 14 Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A.
for bird flu to better use by increasing our capacity to Antivirals for influenza in healthy adults: systematic review. Lancet2006;367:303-13.
produce vaccines and increasing vaccination coverage.
15 Moynihan R, Cassels A. Selling sickness: how the world's biggest pharmaceuti- If WHO didn't exist, we would have to invent it. A cal companies are turning us all into patients. Berkley, CA: Greystone Books,2005.
pandemic, even a pandemic of iatrogenic panic, needs 16 Lokuge B, Drahos P, Neville W. Pandemics, antiviral stockpiles and global health governance and an institution with an biosecurity in Australia: what about the generic option? Med J Aust international mandate in health to intervene. However, 17 Barton JH, Emanuel EJ. The patents-based pharmaceutical development rather than increasing the panic, supporting wasteful investments in large stocks of drugs of no clear use, and 18 Van Damme W, Van Lerberghe W. Strengthening health services to con- following mindlessly the advice of disease experts with trol epidemics: empirical evidence from Guinea on its cost-effectiveness.
undeniable interests, WHO should help countries to Trop Med Int Health 2004;9:281-91.
19 Van Damme W, Van Lerberghe W. Epidemics and fear. Trop Med Int strengthen their health systems and improve their BMJ VOLUME 332 1 APRIL 2006
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