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