Author: David Bradley

David Bradley reporting from the Royal Society of London in January 2004

Despite intense investigation and the development of vaccine, influenza virus remains a major threat to public health, said Professor Robin Bush of the University of California, Irvine. But, do influenza’s lessons apply to SARS?

Influenza and SARS are both RNA viruses with many similarities and many major differences. But, the emergence of new strains of influenza throughout human history can help us understand SARS.

Killer strains of influenza type A are thought to begin in the intestines of waterfowl, such as ducks. The intestine harbours the viral components that, under the right conditions, allow the virus to jump to another species, such as a chicken, and then to people. The leap from symptom-free ducks to the Spanish influenza epidemic of 1918 remains a mystery. Where exactly did this killer come from and why did it become so virulent?

Research on genetic material extracted from frozen samples has taken us tantalizingly close to an answer. We have no genetic records of the strains just prior to their emergence in people so stepping back to the source is currently impossible. We must answer why these viruses that have infected only birds for decades suddenly become infectious to humans and why is such emergence quite rare? Bush suggested that if we continue to keep company with our animals and provide them with over-crowded living conditions then the frequency of emerging epidemics will inevitably increase.

Clues may lie in the places where these viruses appear to originate – the farms and markets of Southeast Asia, for instance. We must understand the factors involved in an emerging virus appearing and learn the lessons of diseases such as influenza if we hope to come quickly to grips with SARS and its ilk.

Read more in Session 2: SARS – a new disease

David Bradley reporting from the Royal Society meeting January 2004

An unusual type of pneumonia emerged in Guangdong in November 2002, said Professor Malik Peiris of the Department of Microbiology, Faculty of Medicine, University of Hong Kong. It caused a significant outbreak in the provincial capital Guangzhou in January 2003 and left the authorities and hospitals in nearby Hong Kong with a serious cause for concern. After all, how could any hospital spot a case of this new atypical pneumonia when around 100 patients each month enter hospital intensive care wards with severe pneumonia?

Information from clinicians in Guangdong suggested that one unusual feature of the disease was its propensity to give rise to clusters of cases with pneumonia, particularly in health care workers. By February and March, outbreaks of pneumonia were reported from Hanoi and Hong Kong, and medical scientists recognized they were dealing with an entirely new disease, subsequently called Severe Acute Respiratory Syndrome, SARS.

The World Health Organization announced that we were facing a major disease threat and significant numbers of cases were observed in Singapore, Canada and with individual cases also been reported in Germany. Peiris was among those who recognized the SARS coronavirus.

The SARS virus was detectable in the respiratory tract, faeces and urine of sufferers indicating that infection was not confined to the respiratory tract. In contrast with other respiratory viral infections, SARS CoV was relatively stable in the environment and in faeces. Respiratory droplets were likely to be a primary source of transmission, but detection of high concentrations of virus in faeces and its environmental stability suggested that faecal contamination may be relevant in explaining large community outbreaks such as that in Amoy Gardens, Hong Kong.

One question that plagued doctors during the outbreak was how to identify patients with the new disease. SARS remains an enigmatic disease, said Peiris. Symptoms look very much like pneumonia. The disease differs in many respects from other respiratory viral infections. Infection seems to be associated with the severe pneumonic spectrum of the illness and asymptomatic infection seems uncommon. In contrast to other respiratory viral infections, the viral load of SARS CoV in the upper respiratory tract and faeces is low in the first few days of illness and peaks around day 10 of illness. This may explain why transmission is less common early in the disease.

A virus similar to SARS CoV has been identified in palm civets, a tree-dwelling mongoose eaten as a delicacy in China, and other small mammals in wild game animal markets in Guangdong. These popular markets, Peiris explained, may be the interfaces where species to species transmission occurs. People working in these markets and handling these animals often show antibodies to the virus in their blood.

SARS was a pandemic whose control required a coordinated global response, said Peiris, the World Health Organization provided leadership in this regard by coordinating a series of virtual research networks who shared information on the causes, diagnosis, disease spread, and clinical management. He pointed out that SARS is but one emerging virus and that medical science should not focus purely on this disease. At the time of the meeting, there was already major concern about an outbreak among people in Vietnam of a strain of bird influenza known as H5N1.

Proof positive

Dutch virologist Professor Albert Osterhaus of Erasmus University, Rotterdam, The Netherlands outlined the scientific proof that led to a novel coronavirus being identified as the primary cause of SARS. The laboratory network for SARS that was established by the World Health Organization was quite instrumental in allowing scientists to make this discovery, said Osterhaus.

At first, this unusual pneumonia baffled scientists. The SARS coronavirus had already been implicated and Osterhaus and his colleagues began performing clinical and experimental test to determine the virus’ precise role in causing SARS.

As part of the network trying to prove whether SARS-CoV was the primary cause, they had access to clinical and post-mortem specimens from 436 SARS patients from six countries. They began testing these samples for infection with SARS-CoV and also for human Metapneumovirus, a well-known childhood infection. Its presence in so many of the SARS cases seemed to suggest it had a primary role in the disease. Indeed, both the newly discovered coronavirus and the well-known metapneumovirus were common factors in SARS.

To prove one way or another which virus was causing SARS, the researchers had to prove three things. First, they had to show that the suspect is present in all known cases. Secondly, they have to isolate it from samples and grow it in the laboratory. And, finally, isolated cultures must be capable of causing the disease in newly infected individuals. The first two are relatively straightforward, it is the latter that involves the most difficult step.

The researchers had to infect related species with SARS-CoV in an attempt to replicate the symptoms of SARS. Animals infected animals were found to exude SARS-CoV from the nose, mouth, and pharynx just two days after infection. Two of the four animals tested also had the same lung damage seen in SARS patients. Those infected with just the metapneuomovirus did not display SARS symptoms. It became clear that the coronavirus was the likely primary cause of SARS itself.

Indeed, reported Osterhaus, SARS-CoV infection was diagnosed in about three quarters of patients diagnosed as having SARS, while metapneumovirus was ultimately diagnosed only in about 12% of patients. This Osterhaus said, suggested that SARS-CoV was the most likely cause of SARS. Producing the proof was a tour de force, taking a mere three weeks.

The team demonstrated that three different species other than humans could be infected with the coronavirus and displayed SARS symptoms. This, Osterhaus, suggested provides researcher with model systems that will allow them to study the disease’s early stages and to test vaccination and antiviral therapy.

Spotting SARS

The onset of illness in SARS can take anything up to 12 days after a person first comes into contact with the SARS coronavirus, explained Dr Maria Zambon Head of the Respiratory Virus Unit of the UK’s Health Protection Agency. Symptoms can persist for many days with most patients recovering but it being fatal in a large proportion of elderly people.

Robust tests and confirmatory checks are needed. The SARS virus can be detected in either the illness phase or by detecting footprints of the virus (antibodies) in the recovery phase, but ensuring the right test works at the right time will assist in an emergency by providing an accurate estimate of how many people have been affected or infected.

When SARS first emerged, medical researchers hunted for the virus in lung secretions. But it was soon found that the test results depended on the timing sample collection relative to the onset of illness, and that other samples including stool and blood samples might also be useful. This provides doctors with a dilemma – how to tell whether or not a patient suffering symptoms resembling SARS is infected with that or another virus with similar symptoms.

A robust test, said Zambon, will not only help doctors bring an epidemic under control, but would allow them to estimate the disease’s true burden. Albert Osterhaus, Malik Peiris and colleagues in proving SARS coronavirus to be the primary cause of the disease in April 2003 provided the basis for diagnostic tests.

Molecular tests have to be able to work fast, finding the telltale genetic fingerprints of the virus within 12 hours of sample collection to provide doctors with confirmation of a case. A rapid test is no simple task and raises quality control issues, such as ensuring good confirmation strategies and communication so that doctors understand that they have to cope with a margin of error when a negative result may be falsely negative.

To ensure the most robust and accurate tests are developed, requires a strong research infrastructure, Zambon emphasized. What you do in normal conditions determines what you do in an emergency. If you do not have a strong R&D capability, there will be no capacity to deal with an emergency, such as having to develop new tests quickly to meet an unanticipated threat, such as SARS.

Read more about emergent diseases in Session 3: Understanding disease transmission and control

David Bradley at the Royal Society, January 2004

SARS appeared in a world that is plagued by many emerging and re-emerging diseases that occur on every continent not just the developing world, stated Dr David Heymann WHO’s Executive Director of Communicable Diseases. Keep the map of global map of outbreaks current is challenging. For instance, at the time of the meeting there were outbreaks of a high-mortality respiratory syndrome in Afghanistan, acute diarrhoea in Mozambique/Burundi, H5N1 influenza A, meningitis, measles, acute respiratory syndrome in China, and cholera in Zambia.

There is great concern, said Heymann, that one day there may be deliberate use of microbiological agents to cause serious harm. Today, the agents that worrisome are bacterial, fungal and viral agents, and rickettsial agents that cause typhoid and fevers.

Our concerns are not new; there have been concern about infectious diseases for centuries, if not millennia. Efforts during the 19th and 20th centuries to control the spread of infection culminated in 1969 with the little-known International Health Regulations, which provide the framework for disease surveillance and response. They are endorsed by WHO member nations and the aim is to prevent the spread of disease with minimal interference to world traffic.

Recently, WHO has begun to network with research groups creating everything from formal collaborative links between laboratories around the world and informal internet discussion groups. Information is constantly being brought in through these routes to WHO, such active information exchange is in stark contrast to the passive system with only three diseases listed as there was in 1969 and where disease reporting was not even compulsory.

Information allows WHO to decide whether a reported disease outbreak is of urgent international health importance. If it is not, the nation will be asked to contain it. If it is, then a collaborative risk assessment is undertaken. This amounts, said Heymann, to a new and active approach to disease.

The SARS epidemic illustrated this new coordinated global response to disease, relying on the world’s best laboratory scientists, clinicians, and epidemiologists to investigate and provide guidelines for care and containment. An extensive knowledge-base concerning SARS is now in the public domain, which will provide vital information for dealing with this and other diseases.

Introduction to emergent pathogens

A very different disease - David Bradley at the Royal Society, January 2004

The SARS epidemic of 2002-2003 was rather unusual, began Professor Roy Anderson FRS of the Department of Infectious Disease Epidemiology, at Imperial College London. For instance, its transmission efficiency was low by comparison with viruses such as Influenza A, it had a high case fatality rate especially amongst the elderly, and there was a high incidence of infection and among health workers.

In regions badly affected by SARS there was much suffering, many deaths, serious disruption to social and work activities, and considerable economic losses. The isolation and quarantining of hundreds of thousands of people became essential to bring the disease under control as too were the tight restrictions on travel in some countries. The World Health Organization also played a vital role in co-ordinating the international response and helping to bring the disease quickly under control. We were very lucky this time round, he said. Draconian public health measures are relatively simple to implement in China and other neighbouring regions where this particular disease originated, but how would the people of North America and Western Europe cope with such restrictions on their liberties as mass quarantining? The cause of SARS was narrowed down to a single coronavirus and diagnostic tests of varying precision have been developed to help us detect it. Epidemiological research must now be carried out to help us understand how the disease spreads, especially given what is actually a very low transmissibility of the virus, compared with influenza. Data capture and information capture systems were put in place somewhat late during the epidemic. In future outbreaks this area needs to be improved so that researchers can gather knowledge about the disease’s epidemiology. During the SARS epidemic data capture systems were more effective in some regions and entirely ineffective in others. An international, centralised database would also allow doctors to record the effects of different medicines on the disease and so provide useful information for other doctors an in the longer-term epidemiologists.

We were extremely lucky with the SARS epidemic, said Anderson. SARS caused a around 800 or so deaths, influenza type A kills 30000 people in the USA every year. In the next global epidemic, we may not be so lucky in terms of biology or where the disease emerges. He suggested that we must keep SARS in perspective but not become complacent and assume that “we have been successful once, we will be again”.

The emergence of SARS

Professor Nan Shan ZHONG of the Guangzhou Respiratory Disease Research Institute suggested in his talk that he would probably raise more questions than he would make conclusions. The first case of SARS in China was recorded on 25th November 2002, and he saw his first definite case in December. The subsequent outbreak of the disease caught the world’s health systems unprepared. The worst Chinese epidemic was in Beijing with 2500 cases, while Guangdong province, where SARS first emerged, had some 1500 cases. The result was serious impact on social stability, particularly in China, and ultimately on the global economy.

From both the clinical epidemiological and virological points of view, SARS originated in the Guangdong province of China. Data showed that there may have been interspecies transmission between wild animals and humans, explained ZHONG, and a national campaign to kill rats as one possible source of infection was instigated by the government. As ZHONG pointed out, while rats harbour many diseases it is other animals, in particular the palm civet, which has been demonstrated to be the host of the emergent virus. The virus was found to be highly concentrated in the civets’ faeces and the first cases in 2002 occurred among animal traders. ZHONG believes it imperative these animals are culled and their use in cuisine be stopped.

ZHONG suggests that the health authorities must remain alert for the possible resurgence of SARS during the winter of 2003-2004 and into the spring. Indeed, the Provincial Department of Health in Guangdong has formulated a pre-warning policy based on early identification based on antibody lab tests. With early reporting, early isolation must be enforced to allow the health services to manage a resurgence.

Professionals have now been trained to identify the disease quickly and accurately and a report network has been established throughout mainland China to ensure a rapid response to new SARS cases. ZHONG told the meeting that in the previous three weeks three new cases of SARS had emerged.

Should the disease re-emerge, corticosteroid and non-invasive ventilation should be reiterated as the treatment of choice for patients with critical SARS. Traditional Chinese medicine (TCM) may also have use in early adjunctive therapy. An inactivated SARS vaccine is now in clinical trials and early results suggest it is safe and efficacious and may be available in an emergency.

Fighting SARS in China

Victory over the first SARS epidemic resulted from the efforts of the medical and scientific communities and the political commitment of the authorities in China with strong international support; the causative agent having been identified within two weeks of the outbreak, said Professor CHEN Zhu Vice President of the Chinese Academy of Sciences (CAS). Two weeks later, the SARS genome was unravelled.

Three programmes have now been implemented under the Chinese taskforce – research into causes and effects, diagnosis, treatment and prevention, and drug and vaccine development.

The initial SARS infections, which were seen among restaurant researchers in particular, were rather weak, and reminiscent of the state of play at the time of the meeting in the advent of a SARS second coming. It was then the infamous “Super-Spreader” event in Guangzhou Second Hospital, which evoked the epidemics in Guangzhou, the second phase, and then the Hotel M event that ultimately led to the massive scale of the SARS epidemic, the third phase to Northern China and other countries/regions in the world. Comparisons of the genome at each phase together with information about the relation between human SARS and the disease in the animal carriers, palm civets, is providing important clues about controlling SARS and vaccine development.

With regard to diagnosis, treatment, and protection, CHEN added that Guangzhou’s Prof. ZHONG Nan Shan is something of a hero in China for having first identified SARS as a new pathogen; he and his collaborators developed effective treatments using corticosteroids, antiviral drugs and non-invasive positive pressure ventilation, as well as integrating it with Traditional Chinese Medicine.

Diagnostic tools and kits have been developed in response to the first epidemic are now revealing themselves to be critical in controlling the recent appearance of SARS cases in 2004. Physical protective equipment for personal and hospital use are also being rapidly developed, added CHEN. The Chinese government has issued new security guidelines to help it cope with another outbreak. The scientific conservation of samples of the SARS coronavirus for further researchers is another important measure that CHEN mentioned briefly.

Beijing researchers had reported at the time of the meeting the effectiveness of inactivated SARS viral particle in laboratory tests, but says CHEN , many questions remain to be answered before a safe and effective vaccine will be ready.

The lessons of SARS have led to open reporting, especially in China, which means “next time”, the international health and research communities will be better equipped to respond.

The victims of SARS

Robert Maunder’s hospital, the Mount Sinai Hospital in Toronto, was on the frontline during the SARS epidemic. One aspect of such an epidemic that does not always immediately come to mind is the psychological impact on health workers.

The outbreak of SARS in 2003 provided a system-wide stress upon healthcare workers in the Toronto region, said Maunder, reminding us of when public-health messages were common and quarantine widely used. To understand the psychological impact on hospital staff and the wider community, we should recall the eighteenth century when hospitals were considered places to die rather than centres of healing.

The disease hit Toronto in two waves, said maunder. The first wave had a major impact on Mount Sinai Hospital allowing the researchers to survey of healthcare workers at three hospitals in late May. The effect of stringent controls put in place meant no visitors and non-essential staff ordered to stay home. The public perception of hospitals was severely affected, hospitals were seen as places with disease, and healthcare workers were seen as victims and carriers of disease.

Maunder’s team has studied data from two sources of information. First, observations by he and his colleagues of administrators and mental health professionals providing support during the SARS epidemic in March and April, and a survey of about 1600 healthcare workers at three Toronto hospitals in May and June. The results provide a picture of the factors which lead the SARS outbreak to be experienced as a psychological trauma.

Maunder described how more than 35% of those surveyed reported severe stress symptoms, including intrusive thoughts and feelings and avoidance and blunted feelings. The degree of risk of traumatic stress was related to degree and duration of exposure to SARS patients as well as other factors. These included isolation from family and colleagues, and the wider community as well as job stress, and problems with family life. Rules prevented colleagues shaking hands or eating in the hospital cafeteria compound the problems leading to poor sleep, anxiety, and preoccupation with signs of illness among many healthcare workers.

There is a psychological cost to controlling a disease like SARS, said Maunder. This must be considered when planning the public-health response and invaluable psychological support provided during the early stages of an outbreak.

New hosts for new diseases

Biologist Dr Diana Bell of the University of East Anglia, Norwich, immediately drew three conclusions about the nature of emerging diseases like SARS.

First, she suggested that the search for diseases of animal origin should be extended, not only geographically, but also to small carnivores other than the masked palm civet from which SARS emerged. Secondly, there are major ecological shifts favouring the emergence of zoonotic diseases, in South East Asia. Thirdly, new collaboration between conservation biologists and vertebrate ecologists would help in finding and controlling such diseases.

The search for disease has focused on the animal markets of Southern China, but many of the animals traded here are illegally imported. The animal reservoir for SARS and other viruses could extend far outside China. Moreover, China’s neighbours in the Indochina hotspot of biodiversity – Cambodia, Laos, Thailand – also exploit wild animals in the restaurant trades, traditional medicine, perfumes, skins for clothing, and as pets. The limelight has shone on three small carnivore species: the masked palm civet, Chinese ferret badger, and raccoon dog. Many other endangered species are also exploited.

Bell suggested that putative hosts must be screened across all routes from capture to marketplace and beyond. This would allow researchers to pinpoint at what point the animals first show signs of infection.

Wildlife trade is a global problem, not restricted to South East Asia. African civets are eaten as bush meat and should be screened. Moreover, the problem is very much a global one. Huge numbers of wild animals are imported into the USA each year, including 49 million live amphibians and 2 million live reptiles. The wildlife trade, Bell said, is not only a threat to biodiversity but seriously threatens human health.

To combat this trade, it is important to hit supply and demand, said Bell. Better law enforcement and community participation as well as education could be key to reducing the demand for wild meat.

Read on in Session 4: Planning for disease