Too much fuss?
Hugh Pennington on the infirmity coming out of China
On 24 April 1497 there was a meeting of the Aberdeen town council. Controlling the ‘infirmity coming out of France’ was one item on the agenda. This ‘infirmity’ was malignant syphilis, a new disease which had been sweeping northwards across Europe since 1493. The council decided (I’m translating from braid Scots) ‘that all loose women be charged and ordained to desist from their vice and sin of venery and all their booths and houses closed; and they should work honestly for their bread under the pain of a brand of the iron on their cheeks and banishment from the town.’ More than five hundred years later, sex-workers still trade in Aberdeen’s red-light district. Syphilis became less virulent as the years went by, although this had nothing to do with the efforts of the council; it was simply that the organism was evolving. Real control of syphilis didn’t come until the discovery of penicillin in the 1940s.
So where do we stand with Severe Acute Respiratory Syndrome (Sars), the new ‘infirmity’ coming out of China? Are attempts to control it going to work any better than in the case of syphilis? Mercury seems to have been used therapeutically in the 1490s; it benefited some and probably saved lives. When will we have remedies for Sars? (Because it is caused by a virus we can be certain that it will not fall to penicillin.) Is the virus evolving? How malignant is it? Is it possible that too much fuss is being made about it and that our response to Sars points to a defining feature of modernity – that we are afraid?
The most unremarkable thing about Sars is its novelty. Infectious agents evolve so quickly that new ones – or ones related to but very different from their immediate ancestors – appear often enough to justify the monthly publication of a peer-reviewed journal, Emerging Infectious Diseases. Recent British experience of these diseases has been especially bitter. The most optimistic estimate for BSE predicts that it will kill at least two hundred people, most of them young. After a decade of reassurance, the announcement in Parliament in 1996 that it probably caused variant CJD resulted in a catastrophic loss of trust in government ministers, experts and British beef. Current control measures are costing the taxpayer more than £400 million a year.
The BSE agent was brand new. It is also a very unconventional pathogen and understanding it scientifically has been slow, hard work; policy-making has therefore been particularly difficult. But even a conventional virus – foot and mouth, discovered in 1897 and studied intensively for a century – was still capable of throwing off a variant that penetrated long-standing defences, and made official contingency plans look like hasty scribbles on the back of an envelope. The new pan-Asia strain of the foot and mouth virus first appeared in India in 1990. On its way to causing the 2001 outbreak in Britain, in 2000 it infected animals in Japan and South Korea (the first outbreaks of the disease in those countries for many, many decades) and South Africa. The National Audit Office estimated that the British outbreak cost the public sector more than £3 billion and the private sector more than £5 billion.
Whether or not the coronavirus isolated in March from Sars patients in Hong Kong, Singapore, Vietnam and Canada is the sole cause of the disease – and the consensus that it is is already very strong – there are no doubts about its novelty. The first human coronaviruses were isolated by scientists researching the common cold in the mid-1960s. The viruses were defined as a group because of their shape: under the electron microscope, virus particles appear as roughly spherical bags studded with long, clubbed, petal-shaped spikes, an appearance reminiscent of the solar corona. The Sars virus has this shape, and a crown-like fringe of spikes, but unlike the common-cold coronaviruses, it grows easily in tissue culture. Within days of their first culture, laboratories in Canada, the US and Germany had confirmed by gene sequencing that the new isolates were all the same, and that they were different from other coronaviruses, but sufficiently related to sit easily in the group.
Coronaviruses use efficient and economical mechanisms to reproduce themselves in animal cells. Their genomes – chromosomes – are made of ribonucleic acid, RNA. Each virus particle contains a single molecule, infectious by itself. The RNA codes for about twenty different proteins: one, for example, is able to cut protein chains at particular points and uses this facility to chop itself into several molecules with different functions. This demonstrates the power of evolution to generate an unexpected degree of complexity in biological processes, but tells us nothing in particular about Sars. One set of molecular properties of coronaviruses might, however. Like most RNA viruses they accumulate mutations very fast, and the way the virus RNA replicates itself facilitates frequent recombination. This is sex without copulation: it generates virus strains with composite RNA genomes derived from two different progenitor coronaviruses. It happens when different viruses simultaneously infect a single cell. It has even been suggested that new coronavirus strains may have arisen by incorporating RNA from their animal hosts or from other RNA viruses such as influenza.
High levels of recombination and mutation are both good news and bad. They help the virus to evolve fast. Pessimists say, therefore, that Sars could rapidly become more virulent. Optimists claim the opposite. And while, on the one hand, vaccinologists should in principle find it easier to construct candidate vaccine strains, on the other, Sars may rapidly evolve its way round the immune status they induce.
There are many different animal coronaviruses. So far they have been found in chickens, turkeys, rats, mice, pigs, cattle, dogs and cats. Some have been studied in detail because they are economically important, such as avian infectious bronchitis and porcine transmissible gastroenteritis viruses; others, such as mouse hepatitis virus, have been investigated because it is hoped that they will yield useful information about infections in general. As a group, these viruses are versatile. Different strains infect different tissues and organs – lungs, guts, kidneys, livers, brains or reproductive systems. A single mutation can have a large effect. In 1984 a new virus emerged in Europe that caused widespread, devastating outbreaks of respiratory disease in pigs. Gene sequencing showed that it was derived from the porcine transmissible gastroenteritis virus by the loss of a sizeable chunk of RNA from one of its genes. It is very possible that Sars could have evolved in this simple way, not from any of the intensively studied human and animal viruses (their genome sequences are too different), but from an as yet unsequenced one. They certainly exist: they are seen from time to time, for example, by enthusiastic electron microscopists in loose human stools. Knowledge of them is still very limited; scanning diarrhoea for coronaviruses is not to everybody’s taste, and virus particles are not only rare, but their shape makes it difficult to distinguish them from the cellular debris that is the dominant component of crap.
Whatever the origin of Sars, its effects mirror the behaviour of coronaviruses as a group, in that it affects more than one organ system. The main impact is on the lungs: the virus kills by setting mechanisms in train that cause their function to fail. But it can also cause diarrhoea, and upsets liver function in a significant minority of victims. In China it has given those carrying hepatitis B virus an especially hard time. Some animal coronaviruses have additional properties: unapparent infections are common, and under certain circumstances a virus can persist and set up a carrier state after recovery. The first of these might seem to be good news, but together with the second it could create serious problems for public health authorities trying to control an outbreak; isolating the sick and quarantining them in convalescence is difficult enough. Whether Sars has either of these properties is not yet known.
Drawing up rational outbreak-control plans requires knowledge about how an infection spreads. A striking feature of Sars is its predilection for health workers and family contacts. This pattern of spread has been described as unusual, but it is not new: it is remarkably similar to that of smallpox. In Europe between 1950 and 1971 there were 45 well-defined outbreaks and a total of 680 cases; 339 of them were contracted in hospital and 147 in the home. The comparison with Sars might seem alarmist – it reminds us that despite the best that doctors can do, both illnesses have unacceptable mortality rates (25 per cent among the unvaccinated for smallpox, and 15 per cent for Sars, according to the WHO estimate of 7 May) – but, on balance, the similarity is not all bad news. The epidemiologist Thomas Mack concluded a review of post-1949 smallpox in Europe by saying that the virus ‘cannot be said to live up to its reputation. Far from being a quick-footed menace, it has appeared as a plodding nuisance with more bark than bite.’ The successful control of outbreaks of Sars in Toronto, Singapore, Hong Kong and Vietnam by isolating cases and quarantining contacts suggests that these traditional methods might be the most effective, especially since there is no rash by which to identify cases and no vaccine to reinforce the barrier between virus producers and the public. It is easy to forget how important and effective the isolation of cases was in smallpox control. Vaccination was made compulsory in Scotland in 1863 but indigenous smallpox was not eradicated until 1904, after the Public Health (Scotland) Act of 1897 facilitated the building of isolation hospitals.[*]
The Sars coronavirus is very different from the smallpox virus: smallpox has a DNA genome; Sars mortality rates are highest in the elderly, smallpox in young children; in the 1970s, the decade of its eradication, smallpox victims died from a disease unchanged since it was described by Kung Ho in China in 340 and Al-Razi in Baghdad in 910, whereas there have been rumours that Sars has already evolved since its first appearance in Guangdong Province in November 2002. By early May 2003, the genomes of nine Sars virus strains had been sequenced. Computer programs have been used to order and join the short runs of overlapping sequences obtained in the first steps of the analytical process, and to compare sequences and construct family trees. So far there have been no big genetic changes, but quite a few mutations. Identical patterns have been found in several strains, and amount to what the Singapore sequencers call a genetic signature. Strains with the nucleotide T at genome position 9404, 17,564, 22,222 and 27,827 all come from cases with links to the Metropol Hotel, Hong Kong. Beijing strains have a characteristic sequence at positions 9854, 19,838 and 27,243, and four out of five Singaporean strains have T rather than C at 19,084.
Those who expect Sars to become less virulent believe that it is to the advantage of a disease-causing organism not to kill its host. But this is an oversimplification. The forces driving the evolutionary selection of microbes are their successful reproduction and spread. For most viruses our ignorance of the factors controlling these processes is such that nothing worthwhile can be said about whether an increase or a decrease in virulence would affect them. With Sars we cannot even be certain that our current picture of its natural history is anywhere near complete. For example, attention has focused on short-distance spread of the virus by droplets coughed or breathed out by patients, but the enormous outbreak of more than three hundred cases among residents of the Amoy Gardens tower blocks in Kowloon Bay has been explained by the Hong Kong Department of Health as being caused at least in part by droplets of contaminated sewage which were sucked into the tiny bathrooms of the flats through floor drains with dried-up U-bends when extractor fans were used with the bathroom door closed. Two-thirds of the Amoy Gardens patients had diarrhoea, so the explanation is very plausible. The virus was even found on the inner rim of a toilet in a patient’s flat in Block E, home of 41 per cent of the cases.
Progress in understanding Sars has been rapid. In the less than five months since its first appearance, an organism has been identified and characterised, and tests worked out. In ‘Faster . . . but Fast Enough?’, published electronically on 2 April by the New England Journal of Medicine, Julie Gerberding, the director of the US Centers for Disease Control and Prevention – by far the biggest and best-funded organisation of its kind in the world – emphasised the collaborative efforts of the WHO and CDC, and the speed and scale of information exchange (though her statement in the New York Times of 8 May that the US Government had begun the process of patenting the Sars virus and its genes, because the US could be prevented from developing vaccines and diagnostic tests and putting them into the public domain if others patented them, showed that not everything is sweetness and light). There have been videoconferences, webcasts, satellite broadcasts and exchanges between scientists on a secure website. Many peer-reviewed papers have been fast-tracked and put on the Internet many days before hard-copy publication by the world’s leading medical weeklies, the Lancet and the New England Journal of Medicine. All these things should be applauded. But rapid progress has been due to other things as well. Luck ordained that the Sars coronavirus grew fast with visible effects in tissue culture and had a characteristic shape in the electron microscope, identifying its family group and thereby proving a great help to the nucleic acid sequencers.
Comparing these timelines with those of the science of syphilis is instructive. It emerged around 1493, perhaps after a transatlantic passage among Columbus’s crew. More than four hundred years elapsed before its cause was identified. But progress was then very rapid. A.K., a 25-year-old woman from Berlin, fell ill on 20 January 1905. On 3 March the protozoologist Fritz Schaudinn saw the thin, pale, corkscrew-shaped spirochaetes of syphilis in samples from the surface of her genital ulcer. At a stroke a simple test for early disease had been discovered (it is still in use). Within a year a blood test was developed and introduced by August von Wasserman, Albert Neisser and Carl Bruck, who published their results in May 1906. Paul Ehrlich at Frankfurt started his studies on the therapeutic value of organic arsenic compounds in September 1906. Animal tests on the 606th preparation, dihydroxy-diamino-arsenobenzene, by Ehrlich’s assistant from Tokyo, Sahachiro Hata, began to give promising results 21 months later, in June 1909, and the first patients started treatment on 31 January 1910. After tests on thirty thousand subjects, it was released to the market as Salvarsan in December 1910. The search for antiviral drugs to treat Sars has already begun. I would be surprised if a drug as effective as Salvarsan, which cured many, were in clinical use as quickly, but not surprised if it shared Salvarsan’s defects – substantial side effects and expense.
It would have been reasonable to predict the rapidity of the scientific progress that has been made with Sars. Even the co-ordinating role played by the WHO is not new: its direct predecessor, the League of Nations Health Organisation, drove the development and standardisation of syphilis tests in the 1920s. But it is comforting to know that virological research and international public health is in such good hands. Sars has also demonstrated the strength of science in Hong Kong and Singapore, and sequencers in Beijing have also shown their mettle. In Britain plans are being made in the light of experiences such as that of the Prince of Wales Hospital, Hong Kong, where within three weeks of the admission of a patient with Sars, who was treated with a nebuliser which probably optimised the spread of the virus, 20 doctors, 34 nurses, 15 allied health workers, 16 medical students and 53 patients in and visitors to his ward had been infected. Having good researchers has never been the problem in this country; translating science quickly and effectively into policy and practice has. The experience of a Derbyshire GP quoted in the 10 May issue of BMA News suggests that the lessons of BSE and foot and mouth are taking a long time to be learned: ‘When was the last time your average GP even saw a mask, let alone put it on? I rang our local public health people and asked where I could get a mask from. They sent two: one for me and one for the rest of the practice to fight over.’ We have contingency plans, but it looks as though they are in the same class as those we had for foot and mouth disease. Those were thought comprehensive, and had been prepared in accordance with Article 5 of EU Directive 90/423 and updated in July 2000. The plans were designed to cope immediately with up to ten cases, but in the event, by the time the first cases were confirmed, at least 57 farms had been infected. The current consensus view is that the Sars virus will probably settle down in China as a permanent resident, its incidence perhaps rising and falling with the seasons. It would be wise to plan for its occasional export, as for smallpox from the Indian Subcontinent in the 1960s. It is unlikely that Sars will pass us by.