On 12 March 2003 the World Health Organisation (WHO) issued a global alert entitled 'Cases of atypical pneumonia'. The events that led to this probably started in early November 2002 in China's Guangdong province, although there is considerable uncertainty surrounding events up to mid-February. We do know that there was severe illness, including deaths, in Guangdong from November onwards. Unfortunately this was not immediately recognised as new or alarming, and there remained a paucity of information. However, by mid-February, the Chinese government had reported 305 cases of the atypical pneumonia, with five deaths.
Countdown to an epidemic
The trigger for a global alert came on 26 February 2003, when a businessman was admitted to hospital in Hanoi, Vietnam, with an illness initially resembling influenza but which later developed into Adult Respiratory Distress Syndrome. He died after transfer to Hong Kong on 13 March. Outbreaks then followed in Vietnam, Hong Kong, and subsequently Toronto and Singapore. Smaller outbreaks were reported elsewhere in the world. There has been only a handful of suspected cases in the UK, some of which may not be SARS.
As of 5 June 2003, the WHO reported 8,403 probable cases, with 6 recent cases since the last update and a cumulative 775 deaths. However, these figures may be distorted due to under-reporting of cases from China, and over-reporting (the inclusion of non-SARS cases) from other countries such as the US.
The disease appears to spread by respiratory secretions, either directly through aerosol transmission or through contact. There are reports that the infectious agent also appears in faeces, though there is little to indicate that this is an important route of spread.
Determining the cause
The speed with which the WHO recognised the significance of the emerging epidemic, and engaged a network of clinical expertise and laboratories, can be attributed to the pre-existence of a global response network for new influenza epidemics. As a result, less than a month elapsed from the time a global alert was issued to the identification of the probable cause of the illness.
Attention had been focused initially on a new (possibly avian) influenza virus. Such a virus (known as the Hong Kong H5 influenza) had appeared in 1997/8, causing six deaths, and again in Hong Kong in February 2003, as the cause of two further deaths. The latter occurrence was particularly unfortunate, coinciding as it did with the appearance of SARS in Vietnam. However, no evidence of influenza infection was found for cases of SARS, and a search began for other causes.
Two pivotal studies have demonstrated that a new coronavirus is the cause of SARS. In the first, Peiris et al. (Hong Kong)1, have found evidence of coronavirus infection in 45 out of 50 SARS cases, but in none of a panel of controls. In the second study, the Rotterdam-based Erasmus Medical Centre took an isolate of the virus and reproduced the disease in an animal model2. The consensus of scientific opinion is that a new coronavirus is the cause of SARS.
Coronaviruses are well known to scientists. Viruses from this group are known to be the cause of several serious animal diseases, including a respiratory disease in birds (avian infectious bronchitis), gastroenteritis in pigs, and diseases in cattle, cats and dogs. Infection in humans has, until now, only been associated with very mild illness - usually the common cold or diarrhoea.
In another remarkable feat of scientific endeavour and co-operation, two laboratories have determined the complete genetic sequence of the coronavirus causing SARS3. From this information we can conclude that this SARS virus does not match closely any of the other coronaviruses that have been similarly characterised. This leads to several possible theories for the emergence of an apparently new human pathogen:
- The virus may have existed in the human population for a long time but without causing disease. Changes (mutations) have led to the evolution of a more pathogenic strain that has now come to our attention;
- The virus has existed in some other animal species but has undergone genetic change so that it can now infect humans. This is analogous to the mechanism whereby new influenza strains emerge infrequently; or
- The virus may persist in another species but occasionally spread to humans (analogous to plague or Ebola, for example).
At present any of these is a possibility. Understanding how this has occurred is, however, vital to any strategy for the future eradication and control of SARS.
There has been some suggestion that the virus may have emerged from a covert biological weapons programme. This seems an extremely implausible and distracting speculation. Since coronaviruses have never been associated with serious human infection, there would be no reason for their inclusion in any such programme. However, now that the virus has emerged, we would be prudent to include it among those organisms for which good guardianship is appropriate.
Controlling the disease and its spread
Only traditional countermeasures - of good hygiene, barrier protection and prevention of spread through reducing contact with infected persons - are available for the foreseeable future to prevent the spread of SARS. These in turn rely on good early identification of cases and the tracing of contacts. National and international authorities have issued guidance on such matters as case identification, precautions in providing medical and nursing care and travel (see the WHO, US Centers for Disease Control and the UK Health Protection Agency websites). So far these strategies seem to be working, as the spread of infection has peaked in most affected areas and the global incidence of SARS is steady, if not declining.
Although vaccines are available for prevention of some of the animal coronavirus infections, these are licensed only for animal use, and have no record of safety or benefit in humans. Furthermore, given that the SARS virus is different from previously known coronaviruses, it is unlikely that the same vaccines will work. The development of a new vaccine for the human SARS coronavirus will take research, testing and regulatory approval: this would normally take several years with no ultimate guarantee of success. Faced with a global emergency a faster process may be possible, although this would carry some risk.
Viruses, unlike many bacteria, are not amenable to the development of so-called 'broad-spectrum' medicines. Whereas antibiotics will usually be effective in the treatment of a range of different bacterial infections, antivirals are usually specific for a particular virus type. Therefore antiviral medicines for AIDS, hepatitis, influenza or herpes infections (cold sores, chicken pox, shingles), will not work against coronaviruses. The only broad-spectrum antiviral drug available (ribavirin) has been shown not to stop the virus in laboratory studies - it is no longer recommended for use in SARS.
Short-term prospects may appear bleak, but if the epidemic continues there will no doubt be significant investment in a search for new vaccines and treatments.
Prospects for the future
It is difficult (if not impossible) to predict the future course of this epidemic. The rate of spread appears low - certainly lower than influenza, for example. With good public health control measures locally, nationally and internationally, SARS may be controlled or even eliminated. By early May 2003, signs of progress were evident in many of the affected areas. Should SARS be beaten, vigilance must be maintained because the virus may re-emerge from an as yet unidentified animal source, or linger in the human population at a low level of incidence.
An alternative scenario is much more alarming. The disease has a fatality rate of approximately 10% (the most recent analyses suggest an even higher rate, especially among older patients where a case fatality rate of up to 50% is reported4). Should the spread of infection become unfettered, or the virus change to a faster rate of spread, an epidemic may result that will be remembered as one of the world's great plagues.
The UK is particularly well placed to respond to both health needs and public concern. The creation of the Health Protection Agency in April 2003, from the Public Health Laboratory Service, Centre for Applied Microbiology & Research and other units and health professionals, has provided an integrated response to both UK needs and to the international efforts. This includes one of the 13 WHO Influenza Reference Laboratories that has been engaged from the start of this epidemic. The Health Protection Agency is providing the resource and expertise for diagnosis, surveillance, advice to health services, public and other government services, and is prepared to support the health response to any significant UK outbreak for the development of vaccines and other countermeasures.
SARS has rapidly commanded world attention as a new human infectious disease with a significant mortality rate. There has been a dramatic public and medical response in affected areas, and a measurable one on a worldwide basis. Although the potential for global spread should not be underestimated, the incidence of infection and death is still well below those for other established infections such as tuberculosis, malaria and Advanced Immune Deficiency Syndrome.
In the context of bioterrorism, SARS has provided a real illustration of the impact of the unexpected spread of a new organism. This impact goes well beyond the immediate and local effects of health and health services. It also provides a timely reminder that our investment in resilience to bioterrorism should serve to strengthen, not distract from, our resilience to natural disease.
Information on SARS is emerging on a daily basis, and little has yet appeared in the peer-reviewed scientific or medical journals. The following websites provide a regular source of scientific information, epidemiological data and guidance:
World Health Organisation
UK Health Protection Agency
US Centers for Disease Control
Dr Charles R Penn is director of research and development at the UK Health Protection Agency
1 Peiris et al., 'Coronavirus as a possible cause of severe acute respiratory syndrome', Lancet 19 April 2003.
2 See www.who.int/mediacentre/ releases/2003/pr31/en/
3 Rota et al. And Marra et al. Published in Science May 2003
4 Donnelly et al. Published in Lancet May 2003