A serial killer still lurking in shadows

Luckily, last year's Sars epidemic was brought under control quickly and efficiently. But, warns Roy Anderson, we may not be so fortunate next time round.

On December 26 the Chinese ministry of health informed the World Health Organisation about a suspect case of severe acute respiratory syndrome in a hospital in Guangzhou, the city where this new infectious disease is believed to have first emerged in November 2002. This rapid and open response by the Chinese government contrasts sharply with its reaction when it first became aware of Sars late in 2002. Lessons have been learnt quickly - and applied effectively. This time round, public health authorities in Quangdong have rapidly identified all close contacts of the patient and provided advice on symptoms and actions to be taken if they feel unwell. Ever since December 26, the ministry of health and the Chinese Centre for Disease Control and Prevention have met daily with WHO officials, and provided them with a comprehensive list of information, including the patient's clinical history and test results. It is the first case to be confirmed for six months.

The alarm raised by China reminds us that the resurgence of Sars as a global epidemic remains a distinct possibility, given its uncertain origins and the possible existence of animal or bird reservoirs of the virus or its close relatives. In the coming year, all countries have been requested by the WHO to remain vigilant for a recurrence of Sars and to maintain their capacity to detect and respond to the re-emergence of the disease should it occur. This will be made difficult by a number of factors. These include the fact that there are no specific clinical features of Sars, the lack of a rapid diagnostic test that can reliably detect Sars-CoV (the virus that leads to Sars) in the first few days after the onset of clinical symptoms, and the seasonal occurrence of other respiratory diseases, including influenza. The major problem in the coming year will be the management of false alarms triggered by suspect clinical cases.

Great progress has been made in understanding the biology, pathogenesis and epidemiology of both the virus and the disease it induces since the first emergence and rapid spread of Sars in late 2002-early 2003. Much remains to be done, however, including the development of effective therapeutic interventions and the creation of sensitive diagnostic tools. Vaccine and chemotherapeutic agent development, plus greater understanding of the origins of the virus and the identification of wildlife reservoirs, are the major priorities.

The origins of the virus remain uncertain, although closely related strains have been isolated in China in Himalayan palm civets and raccoon-dogs. The jump from animal to human host seems to have involved a major deletion in the genetic code of the virus since its make-up is different in humans and animals. Other studies suggest a part-bird and part-mammal origin of the virus. Further surveillance of animals and birds in settings where the human virus has spread extensively is clearly necessary.

In the global response to Sars, orchestrated by WHO, there were five priority tasks at the start of the outbreak. Most of these were completed rapidly, but detection of the presence of the virus soon after the onset of clinical symptoms remains difficult, with the most sophisticated tests still only providing a sensitivity of 60 to 70 per cent in samples taken at mixed times post onset of fever. Sensitivity can be improved if samples from the lower respiratory tract can be obtained in the second week after the clinical symptoms have appeared, but the procedures to obtain material for analysis are invasive and not without risk to the patient. Tests based on the detection of immune system markers of past infection in blood are highly sensitive, but only at least 21 days after the onset of illness. Too little has been done to date to analyse clinical data on the effectiveness of efforts to reduce illness and death. This task is urgent since uncertainties persist over the effectiveness of some treatments used.

Despite these problems, simple public health interventions, such as the isolation of sick patients suspected of having Sars, contact tracing and quarantining of contacts, restrictions on travel and behavioural change within communities, brought the first global epidemic under control by mid-summer of 2003. Following its recognition as a global threat in mid-March 2003, Sars was successfully contained in less than four months.

During the four-month period of the major epidemic, 8,098 cases were reported, with more than 800 deaths in 26 countries.

Most countries had no or a few cases, while one country had over 1,000 cases. The epidemic was largely in China and surrounding countries or administrative regions such as Taiwan, Singapore and Hong Kong. Although the total number of cases is small by comparison with other major infections such as influenza, malaria, Aids and tuberculosis, the case fatality rate was high and the economic impact in the Asian region and in Canada was great, involving losses to various economies of many billions of dollars. A detailed study of the epidemic in Hong Kong, for example, revealed 6.8 per cent mortality for patients under 60 years and 55 per cent for those over 60. Overall, a WHO summary suggests a global average mortality rate of about 15 per cent. However, this figure hides much variation linked to patients' age and the presence of conditions such as pre-existing heart or respiratory tract disease. The transmissibility of the virus was fortunately low, with each primary case typically generating about two to three secondary cases. But some mild cases may not have been recorded as Sars. However, in Hong Kong a study of more than 1,000 individuals who had been in contact with a confirmed Sars case revealed very few infections. It seems that the most effective way of limiting Sars'

spread is the use of conventional public health measures (such as isolation and quarantine) before viral load and infectiousness peak in the patient.

Unfortunately, though, some 21 per cent of the global total of cases occurred in healthcare settings among staff who were caring for Sars patients. Improvements in infection-control procedures for respiratory tract viruses within hospitals is a clear priority in the management of any future outbreak.

What lessons can be learnt from Sars? First, for effective ongoing public health policy formulation, information must be captured countrywide on a daily basis. Unique patient identifiers should be used to record all sociodemographic, clinical, treatment and epidemiological information (for example, who got infected by whom). Web-based, password-protected systems need to be ready to be put into action, with information fed daily to one centralised database for analysis and interpretation. No one country or region had such a system in place before the emergence of Sars. Ideally, some common database/software structure should be used across all countries and regions.

Second, statistical projections that estimate the pattern of the epidemic need to be used appropriately. Of particular note in the Sars outbreak were inaccurate reports of case fatality rates. Third, there are lessons for clinical epidemiology. If infectiousness peaks well after the onset of clinical symptoms, isolation of suspect cases is very effective in limiting onward transmission. In the early stages of the epidemic not enough attention was paid to quantifying the typical course of infection, day by day, for large samples of patients. Fourth, we urgently need epidemiological analyses and different mathematical models that chart viral spread in place before an outbreak. We have to understand much better the impact of different interventions and their cost-effectiveness - travel directives and airport screening for fever immediately come to mind. We understand very little about how effective these actions were in limiting the spread of Sars.

Finally, we need to calculate how best to trace individuals who had contact with cases of Sars and how to analyse and interpret data on this. This is important in terms of limiting the spread of disease and in calculating the path of transmission.

In seriously affected regions, the Sars epidemic caused much suffering, significant mortality, great disruption to social and work activities and considerable economic losses. However, it was brought under control - and relatively quickly - with the WHO playing a vital role in coordinating the international response.

But it is difficult to escape the conclusion that the world community was very lucky this time round, given the low transmissibility of the agent and its biology where clinical symptoms appear well before peak infectiousness, plus the fact that fairly draconian public health measures could be put in place with great efficiency in Asian regions where the epidemic originated.

Next time we may not be so lucky, in terms of either the biology of the agent or the region of its origin. Thus one of the major dangers arising from the effective control of Sars is complacency. The frequency of the emergence of new pathogens will increase over the coming decades. The evolution, spread and persistence of infectious diseases are facilitated by the mobility of contemporary society, its high degree of connectedness through air travel, the continued growth in world population and the steady rise in the number of densely populated urban areas, which are particularly common in Asia.

Roy Anderson is professor of infectious disease epidemiology in the faculty of medicine, Imperial College, London. He is speaking at a Royal Society debate on Sars on January 13.