A mystery killer

An unidentified form of killer pneumonia, originally suspected to be a variant of influenza, is reported from various parts of the world. The World Health Organisation is gearing up to face the challenge.

OVER the past decade, a number of viral diseases, both vector-borne and zoonotic, have emerged in South-East Asia and the Western Pacific region. While vector-borne diseases primarily infect human beings although they are transmitted by other organisms, zoonotic diseases occur primarily in the lower animals but sometimes infect human beings too. The locus of the current outbreak of killer pneumonia, an atypical or unusual form of the disease that progresses rapidly to cause severe respiratory distress and consequent death, also seems to lie in this region.

The disease has spread across continents in a matter of days, and evidence seems to suggest that the infection was transmitted worldwide chiefly from the Hong Kong Special Administrative Region of China. It reached there possibly from southern mainland China, and was transmitted to various parts of the world through international air travel via Hong Kong, a major traffic hub. However, unlike the earlier epidemic outbreaks in the region, this particular disease is virulent and the spread of infection is rapid. The aetiology or the cause has not been identified definitively yet a step necessary for developing the appropriate diagnostic test and determining a treatment regimen. Preliminary investigations seem to indicate that the pathogen maybe a new virus.

The first case of the disease, which has been called Severe Acute Respiratory Syndrome (SARS) by the World Health Organisation (WHO), was reported in Hanoi, Vietnam, on February 26 and within a month hundreds of people have been infected. As of March 22, 386 people across 13 countries were suspected to have been infected, and 11 of them had died.

While the `affected areas' include the Canadian city of Toronto, China's Guangdong province, the Hong Kong Special Administrative Region, Taiwan, Singapore and Hanoi, Hong Kong accounts for the largest number of cases (222). Cases have been reported in Ireland, Italy, Slovenia, Spain, Switzerland, the United Kingdom and the United States, but they have not been classified as `affected areas' as there has been no evidence of local transmissions in these regions. Cases have been reported in Australia - in New South Wales and Western Australia - too but the WHO figures do not reflect these. "This syndrome, SARS," said Gro Harlem Brundtland, Director-General of the WHO, "is now a worldwide health threat." The rapidity with which infection is spreading with the cumulative figure of cases numbering 167 on March 17, 219 on March 18, 264 on March 19, 306 on March 20, 350 on March 21 and 386 on March 22 is alarming at first sight. However, according to the WHO, SARS seems to be transmitted only through very close contact with an infected person. Cases have occurred almost exclusively among health workers treating or caring for SARS patients, family members and the like. There is no evidence so far of its spread through casual contact. Close contact with aerosolised droplets from the bodily secretions of an infected person appears to be an important source through which the disease spreads.

SARS was originally suspected to be a variant of influenza, given the outbreaks of A(H5N1) or `bird flu' and A(H9N2) in the region in recent times, the latest being cases of `bird flu' that were reported in Hong Kong in February. While influenza has been ruled out, the dose of the new pathogen needed to cause SARS, which is stated to be less infectious than the former, has not been determined.

The speed of international travel could contribute to the rapid spread of the disease. Countries with significant international traffic passing through them need to be vigilant. The Directorate-General of Health Services (DGHS) of the Government of India has mobilised a contingent of doctors at airports to monitor incoming passenger traffic and to handle cases according to WHO guidelines.

THE chief symptoms of SARS include the rapid onset of flu-like high fever above 38oC (100.4oF) coupled with one or more symptoms of respiratory illness, including cough, shortness of breath, difficulty in breathing or hypoxia or chest X-ray (CXR) findings of pneumonia or acute respiratory distress requiring assisted breathing on a respirator. Early laboratory findings may include low platelet count (thrombocytopenia) and low white cell count (leucopenia).

SARS may be associated with other symptoms, including headache, muscular stiffness, loss of appetite, malaise, confusion, rashes and diarrhoea. CXR is, at present, the key tool to distinguish between suspected and probable cases. The incubation period is short, estimated to range from two to seven days, with a period of three to five days being more common. The person should have either had close contact with a person suspected of suffering from SARS or should have travelled to an area reporting cases of SARS within 10 days of the onset of symptoms. Some patients respond to treatment but others remain critically ill. Broad-spectrum antibiotics have not proved to be effective in halting the progression of the disease but the intravenous administration of antiviral drugs such as Ribavirin seems to have some effect.

The first reported case was of a person who fell ill shortly after arriving in Hanoi from Shanghai and Hong Kong. After he was admitted, several members of the hospital staff developed similar symptoms. The person died on March 13 after being transferred to Hong Kong. Almost all the cases reported to date in Vietnam have had to do with direct contact with the hospital where the first case, or the index case, was treated.

The first cases in Hong Kong were detected on March 12, when 20 health care workers developed symptoms of SARS. On March 19, an epidemiological breakthrough was achieved when officials of the Hong Kong Department of Health succeeded in tracing the origin of the infection in the region and identified the index case in the city's Prince of Wales Hospital. "In an outstanding example of detective work," as the WHO put it, the epidemiologists determined that seven people who contracted SARS had stayed in or visited Hotel Metropole in Hong Kong's Kowloon district between February 12 and March 2. The seven persons investigated included three visitors from Singapore, two from Canada, one person from South China and a resident of Hong Kong.

The investigation revealed that all the seven persons had either stayed in or visited the same floor of the hotel. The Hong Kong resident was believed to be the index case, who subsequently infected other early cases in the outbreak. He had visited an acquaintance, a doctor from southern mainland China, and had stayed at the hotel from February 15 to 23. The Chinese visitor, who became sick a week before staying at the hotel, is considered to be the original source of the infection.

Infections in nearly all other parts of the world, including the case in Vietnam, appear to have some link to Hong Kong. For instance, on March 13, Singapore reported SARS in people who had recently returned from Hong Kong. Investigations in Hong Kong revealed that they had stayed at the Metropole.

On March 15, a physician from Singapore boarded a flight from New York to Singapore via Frankfurt, accompanied by his wife and mother-in-law. He was unwell, as were his wife and mother-in-law; he was said to have come into close contact with a reported case of SARS in Singapore.

German health authorities were notified and the three passengers were transferred to an isolation unit in Frankfurt as soon as the flight landed. The specimens investigated in Marburg and Frankfurt am Main yielded evidence that the new virus was the causative agent. Viral structures were found in the blood plasma of the mother-in-law, indicating that a state of viremia had set in. However, there has been no evidence of any further transmission of the disease in Germany.

Cases in Canada have occurred essentially in two extended family clusters. At least one member of both the families had travelled to Hong Kong a week before developing the symptoms. Investigations in Hong Kong revealed that they were the same people who had stayed at the Metropole. Cases in the U.K. and elsewhere in Europe have been linked to travel to affected areas or contact with SARS cases. The 22 cases in the U.S. essentially constitute three clusters, according to the Centres for Disease Control and Prevention (CDC). The source of infection in all the three clusters can be traced to persons who had travelled to SARS-affected areas in Asia. Two of the 22 cases are reported to have stayed at the Metropole, although on different floors.

The only case in Thailand, which was reported on March 15, was that of a health worker who had travelled from Hanoi to Thailand on March 11. Apparently, he had come into contact with the index case in Hanoi. The Taiwan-based unit of the CDC has determined that cases in Taiwan can be traced to those who had travelled to the Guangdong region.

THE linkages indicate that Hong Kong is the main source of infection worldwide. It has now been learnt that the doctor was from Guangdong and had come into contact with a possible SARS case. However, it is not yet clear how the doctor contracted the infection.

In the Table provided, there are blank spaces against China although it is believed to have reported cases with SARS-like symptoms. This is because it is not yet clear whether the cases of atypical pneumonia diagnosed in Guangdong in November 2002, were in fact SARS cases. The outbreak had peaked in mid-February but remained confined to that region. Also, Chinese authorities are yet to report to the WHO the exact number of such cases. But, it seems that the outbreak in Guangdong may well be of SARS.

According to the WHO, the Chinese authorities have issued a summary report with data on the diagnosis and management of 305 cases, including five that resulted in death, which is being analysed. It was found out that in two of the cases of death, there was chlamydia infection. The WHO expects this analysis to contribute to the understanding of SARS and possible links among the various outbreaks. Should a link be established, the WHO hopes that the data on a single outbreak involving the largest number of cases to date, might boost international efforts to establish effective treatment guidelines.

Apparently, the Chinese Ministry of Health has requested support from an international team. A five-member team constituted by the WHO, comprising specialists drawn from institutes participating in the WHO's Global Outbreak Alert and Response Network (GOARN) left for China on March 21. GOARN has a six-member team in Hong Kong and a nine-member team in Vietnam to assist in epidemiological investigations.

Investigations by scientists in Germany and Hong Kong based on throat swab and sputum samples of patients have indicated that the causative agent is probably a new virus belonging to the paramyxoviridae family of viruses. This has been confirmed by investigations in Singapore and two more laboratories under GOARN. Previous tests conducted in a number of top laboratories failed to detect any known bacteria or viruses, including the influenza virus, recognised as the cause for pneumonia or respiratory symptoms, and known to be widespread in the most affected geographical areas. The failure of all previous efforts seems to suggest strongly that the causative agent may be a novel pathogen.

Viruses in the Paramyxoviridae family include common, well-known agents associated with respiratory infections such as respiratory syncytial virus (RSV), and childhood illnesses, including the viruses that cause mumps and measles. Some of these are widespread, in particular RSV, particularly during winter. Particles of these common viruses could be detected while screening specimens. Therefore, the possibility that tests for the SARS agent are detecting such "background" viruses rather than the true causative agent cannot be ruled out.

Indeed, Wolfgang Preiser, of the JW Goethe-University in Frankfurt am Main, one of the centres that found clues to the SARS pathogen, has cautioned against arriving at any firm conclusions as yet. He said: "These preliminary results only indicate a suspicion. Furthermore, even if the presence of a paramyxovirus was confirmed, it is not clear at this stage whether this might represent the causal agent of SARS or rather a coincidental finding." The isolation of similar microbes from additional cases of SARS will be necessary. It is to achieve this that WHO's GOARN set up 11 laboratories in 10 countries on March 17.

IN recent years several new paramyxoviruses have been discovered. Paramyxoviruses are known to infect only vertebrates. Predominant among the paramyxoviruses are the Hendra virus and the Nipah virus, two related viruses isolated from bats in Australia and South-East Asia, which were responsible for the outbreak of severe diseases among human beings during the 1990s. These two are unusual in the family in that they can infect and cause potentially fatal diseases in a number of animal hosts, including humans. Most other viruses in the family tend to infect only a single animal species. No treatment was available for cases caused by both these viruses.

So far, evidence has been gathered essentially on the basis of observation of the virus particles through an electron microscope. The possibility of molecular differences between the new virus and the paramyxoviruses such as the Hendra and Nipah viruses, is strong. Therefore, the advanced polymerase chain reaction (PCR) technique may not immediately reveal the virus. But similar findings by several independent laboratories indicate that SARS might involve a new strain of paramyxovirus.

"More and more laboratories are finding paramyxoviridae virus," said Klaus Stohr, a virologist of the WHO who is coordinating GOARN's multi-centric laboratory efforts to identify the causative agent. "What is promising is that many other paramyxoviruses can be excluded. So we have a paramyxovirus-like particle which is not any of the known paramyxoviruses." According to him, one of the laboratories has been able to isolate and culture the virus outside the patient. This is a major step towards the development of a rapid diagnostic test. However, researchers at Health Canada's National Microbiology Laboratory in Winnipeg reported on March 22 that they have found evidence of human metapneumovirus (hMPV), a newly discovered pramyxovirus , which was isolated by Dutch scientists from children with respiratory tract disease in June 2001, in specimens from six of the eight cases they are studying.

Although it is known to cause respiratory disease in humans, including some cases of pneumonia, at the time of discovery hMPV showed a different transmission pattern and was much less severe than the SARS agent. WHO has said that "at this point, it cannot be ruled out that an entirely different virus from another family may be responsible for the SARS outbreak". This is because earlier, this particular paramyxovirus had been ruled out by some laboratories.

Scientists in the Department of Microbiology of the University of Hong Kong, have been able to isolate and culture the virus outside the patient. Using a special cell line, the virus was isolated from the lung tissue of the index case in Hong Kong. This is a major step towards the development of a rapid diagnostic test.

Indeed, scientists in Hong Kong have devised a basic test, relying on the technique of neutralising antibodies, and were able to detect tell-tale antibodies in sera taken from eight SARS patients. The consistency of these findings indicates that the test is reliably identifying SARS cases. This "hand-made" test will be developed further into a more sophisticated diagnostic test.

The achievement will facilitate the amplification and nucleotide sequencing of portions of the viral genome, which will help determine its relationship with other known paramyxoviruses. "This is not just some light at the end of the tunnel. This is a real ray of sunshine," remarked Stohr. Further steps would include more cell culture, and more trials in animals. "In essence, we are turning around information usually generated in months or years within hours and days," Stohr said.

The other important concern of the WHO is to assist vulnerable countries in the event that the disease continues to spread. Up to now, cases have occurred in countries that are well-equipped to institute WHO-recommended precautions, including isolation and `barrier nursing' practices, to prevent the spread of the disease.