Even as the SARS virus arrives in India, with the first case being reported from Goa, laboratories under the WHO continue to explore ways to counter the rapidly spreading disease.
WITH the spread of Severe Acute Respiratory Syndrome or SARS, a hitherto unknown atypical form of pneumonia, to more and more countries as a result of international travel, India could not have escaped for long. Since February 26, when the first case was detected in Hanoi, SARS has spread to 27 countries, including India. The first case of SARS in India was identified on April 16, in Prasheel Varde, a 32-year-old marine engineer from Goa. He had travelled to Hong Kong and Singapore - both categorised as SARS `affected areas' or hot zones - before returning to India on April 1.
A diagnostic test based on the Polymerase Chain Reaction (PCR) done by the Pune-based National Institute of Virology (NIV) confirmed the presence of the SARS virus in samples of the patient's blood, sputum and urine, which were sent by the Goa Medical College Hospital (GMCH) where he was being treated. In a press briefing on April 17, officials from the Health Ministry said that all the samples were found to be positive for the SARS virus. However, it is curious that even though the samples indicated the presence of the virus in the blood stream, the patient showed no clinical symptoms characteristic of the disease - high fever, cough, breathing difficulty and, most importantly, signs of pneumonia or respiratory distress syndrome in a chest X-ray.
Thus, the Indian SARS case, with an apparent mismatch between clinical symptoms and the diagnostic test, is a unique one. Since the cause or the aetiology of the disease was unknown till about four weeks ago, the case definition has been done solely on the basis of clinical symptoms specified by the World Health Organisation (WHO). Of the 3,461 suspected and probable SARS cases reported worldwide so far, the WHO has recorded the Indian case as one that has recovered.
Diagnostic tests are being developed after the causative agent was identified recently as a hitherto unknown form of coronavirus, a family to which the common cold virus belongs. But all the three different tests - Enzyme-Linked Immunosorbent Assay (ELISA), Immunofluorescence Assay (IFA) and PCR - seem to have their limitations. A PCR test that was developed in early April by the Centres for Disease Control and Prevention (CDC) of the United States is stated to be effective only in the early stages of the disease.
However, with the isolation and genetic sequencing of the SARS virus, primers - pieces of genetic material that are specific to a given virus and are the key pieces for a PCR test - have been made available to laboratories around the world by the Hamburg-based Bernhard-Nocht Institute for Tropical Medicine (BNI), one of the laboratories in the WHO consortium for research on SARS aetiology. Arcus Biotech, a Hamburg-based firm, has developed a real-time, ready-to-use PCR diagnostic kit that uses primers. The company has offered to supply these kits, which became available since April 14, free of cost to laboratories participating in the WHO network of 13 laboratories from 10 countries. No Indian institution is part of this network. Therefore, in all likelihood, the NIV test is based on the primer sequences that were made available by the WHO on its website.
According to Kumar Rai, head of the communicable diseases wing at the WHO's Regional Centre in New Delhi, as diagnostic tests are still being developed, there is also a high probability of the test indicating a "false positive" result. Christian Drosten, the BNI scientist who was responsible for identifying the primers and developing the PCR test, said: "The case definition of SARS does not include findings in PCR. Results of PCR can be used to complement clinical diagnostic evaluation. However, tests have not been validated for confirmation of cases or exclusion of the disease." Therefore, it is unclear why the WHO decided to confirm the Indian case, which is based entirely on the PCR test, as an instance of SARS.
PRASHEEL Varde, his wife and his father had sailed from Hong Kong, where they stopped for four hours on March 26, to Singapore, where they spent a couple of days. On April 1, the three arrived in Mumbai, where they spent a couple of days, before reaching Goa on April 4. On reaching Goa, Prasheel developed fever and cough and on April 8 he went to a private medical practitioner, who referred him to the medical college hospital. There, he was kept under observation from April 10 to 12 in an isolation ward and was treated with antibiotics. The treatment was effective, and since his X-ray did not reveal any pneumonia patch, he was discharged. Although the hospital had sent his samples to NIV for testing, by the time the test results became available on April 14, he had been discharged.
And in a strange and inexplicable move, on April 14 it was decided that he would be quarantined for 10 days, after he was allowed to mingle with the general public for two days. He was readmitted to the GMCH on the night of April 16. However, on April 18, Goa Chief Minister Manohar Parikkar announced that Prasheel would be discharged as he had been "cured" of SARS. So far, Prasheel's wife and father, who had been with him all along, have not developed any symptoms. However, post-diagnosis, they were advised not to be in his proximity.
There are several unanswered questions. Why did he see a doctor four days after he developed fever? Who were the people he came in contact with before being kept in the isolation ward on April 10? Did he develop fever in Mumbai or on the way to Goa? What was his mode of travel from Mumbai? These questions assume importance if the chain of possible transmission from him to others is to be traced. According to the WHO, there is no evidence to suggest that the human-to-human transmission occurs by means other than air-borne droplets of cough, sneeze and so on.
The first indication of the SARS-causing virus being a coronavirus came from research work done in Hong Kong on March 21. This was confirmed by researchers at the CDC. However, definitive proof can be obtained only after verifying Koch's Postulates, which stipulate four conditions for a pathogen to be the causal agent. The micro-organism must be found in all cases of the disease, it must be isolated from the host and grown in pure culture, it must reproduce specific symptoms when introduced into a susceptible host, and it must be re-isolated in the experimental host. The work at the Erasmus Medical Centre, Rotterdam, particularly relating to animal models, led to the definitive proof that the coronavirus causes SARS.
According to WHO, the virus from SARS patients across several countries has been isolated consistently by several network laboratories. The virus has been demonstrated to cause disease in African green monkey kidney cells (Vero cells) and Rhesus monkey kidney cells (FRhK-4 cells), which was found to be inhibited with serum from SARS convalescents. Significantly, signs of reactivity with the new coronavirus, namely the presence of antibodies, could not be detected in the serum samples of several non-affected individuals in the U.S., Canada and Hong Kong.
CORONAVIRUSES belong to a viral family called Coronaviridae, which infect vertebrates, especially warm-blooded vertebrates, including mammalian species such as human beings, cattle, cats, pigs, and rats, and a few avian species such as turkeys and chickens. The SARS virus has never been seen in humans before. In fact, its genetic make-up shows that it is only "distantly related" to known coronaviruses. It is not known whether it existed in other species earlier and jumped species recently, or whether it is an entirely new virus. "The WHO and the network of laboratories dedicate the detection and characterisation of the SARS virus to Carlo Rubani, the WHO scientist who first alerted the world to the existence of SARS in Hanoi and who died from the disease in Bangkok on March 29," a WHO release said.
This definitive determination was particularly important because earlier evidences from different laboratories suggested that the pathogen could be an unknown paramyxovirus. Indeed, Canadian researchers (Frontline, April 11, 2003) isolated a relatively new paramyxovirus, known as human metapneumovirus (hMPV). The finding was supported by some other laboratories in the network. In medical science, it is difficult to understand the aetiology of a disease in terms of two pathogens. According to the WHO, hMPV and antibodies against hMPV have been found in the serum samples of some SARS patients. Evidence of dual infection with hMPV and the new coronavirus has also been found. But the significance of hMPV in SARS remains unclear. Perhaps hMPV is in the nature of causing opportune infections, making the affliction worse.
David Heymann, Executive Director of the Communicable Diseases Cluster of the WHO said: "Because of an extraordinary collaboration among laboratories from countries around the world, we now know with certainty what causes SARS." He added: "Now we can move away from methods like isolation and quarantines and move aggressively towards modern intervention strategies, including specific treatments and eventually vaccination." He noted that if the vaccine or drug was to be developed by the private sector, it would want to be certain that the disease was a permanent resident in human beings, in order to recover its investment. Therefore, it had to be funded wholly by the public sector or in partnership with the private sector, he said. "The history of treating viral infections showed that anti-viral drugs were very difficult to develop, and even then, they had an effect only very early when the virus level was low," he observed.
Going by the rapidity with which the disease is spreading, SARS appears to be the first severe and easily transmissible disease of the 21st century, Heymann said. Although the causative agent of SARS has been identified in a remarkably short span of time, the potential of the disease was not clear, particularly whether it would become a permanent infectious disease, he said. All evidence points to the disease having spread from the Guangdong province of China. The outbreak seems to date back to November 16, 2002, when an initial case was reported in Foshan city.
WHEN a global alert against SARS was issued on March 12, it was hoped that SARS would not spread throughout Asia and the rest of the world. According to him, until the situation in mainland China, which had 1,482 cases, became clear and a number of key questions were answered, the future of the disease would not be known. Since April 3, four WHO teams have been working in Guangdong, Beijing and other major cities of the country to assess the situation.
An interim report on the Chinese situation was prepared by the WHO on April 9. The report concluded that while the health system in Guangdong responded well to the outbreak, all other provinces were less equipped to cope with the severity of the challenge.
In Guangdong, the team found an instance of what it has termed "super-spreaders", in which one person from the province is thought to have infected as many as 100 other persons. The phenomenon of a "super spreader", which is not a medical condition, dates back to the early days of the outbreak when SARS was not identified as a disease requiring special precautions of isolation and infection control. In the absence of such measures, a large number of health workers, family members, relatives and visitors to the hospital were exposed to the virus by a single unprotected case.
A "super spreader" has been traced in Singapore too. The report expressed particular concern on the situation in Beijing, where there could be underreported cases. According to the WHO, the situation in Beijing's military hospitals has been the source of many reports about the real magnitude of SARS in the Chinese capital. On April 13, President Hu Jintao appeared on state television and expressed concern about the situation. He has appealed for "accurate, timely and honest reporting" of cases.
At present, Hong Kong, with 1,327 cases and 69 deaths as of April 18, is the hardest-hit area. Healthcare workers continue to become get infected and hospitals are overwhelmed by the growing number of patients. A large cluster of 268 SARS cases has been reported from a single high-rise apartment block called Amoy Gardens Estate. It is the first known instance of a possible environmental spread of the SARS virus. The vast majority of the cases have been traced to vertically linked apartments in a single building. This pattern of transmission, according to the WHO, indicates that the disease has moved out of the healthcare setting and is now occurring within the community. Epidemiologists investigating the peculiar outbreak released a report on April 17, identifying the enviromental route as the source of the large cluster of cases.
As of April 15, 321 Amoy residents had been affected. Investigation has identified a sewage contaminated with the SARS virus as the probable source of exposure. According to the report, a 33-year-old man, who developed symptoms of SARS on March 14, visited a relative in the apartment building on the same day. His symptoms included diarrhoea and it is believed that the virus from his faeces was transmitted through the sewage route. The rapid spread to other residents has been attributed to defective U-traps in bathrooms, the amplifying effect of bathroom exhaust fans, a cracked sewer vent pipe, and an aerodynamic effect in a lightwell to which bathroom windows opened. Laboratory investigations confirmed the presence of the SARS virus in a swab from the toilet bowl in the bathroom of a SARS patient, but not in numerous other environmental samples. The study found no epidemiological or laboratory evidence that the SARS virus was transmitted by air, water, or infected dust aerosols. "It is reassuring that speculations about a possible airborne transmission have not been borne out by the evidence available to date," the WHO said.
According to Heymann, although the last decades of the previous century witnessed the emergence of several new diseases, SARS seems to present a particularly serious threat to international health. Although SARS has a low mortality rate - 4 per cent - its clinical and epidemiological features remain poorly understood. Except for the Human Immunodeficiency Virus-Acquired Immune Deficiency Syndrome (HIV-AIDS), most diseases that emerged during the past two and a half decades, or became endemic in new geographical areas, have features that limit their capacity to pose a major threat to international public health. Diseases such as avian influenza, and those caused by the Nipah virus, the Hendra virus and the Hanta virus failed to establish efficient human-to-human transmission. Others such as Escherichia coli O157:H7 and variant Creutzfeldt-Jakob disease depend on the food chain for transmission.
Although outbreaks of the Ebola haemorrhagic fever have been associated with high fatality rates - 53 per cent in Uganda to 88 per cent in Congo - person-to-person transmission requires close physical exposure to infected blood and other bodily fluids. Moreover, patients suffering from this disease cannot undertake travel. In contrast, SARS, whose mode of transmission has been likened to that of Ebola, is emerging in ways that suggest great potential for rapid international spread. Epidemiological data indicate that the gestation period for SARS is two to 10 days (an average of two to seven days), which gives ample time for the infectious agent to be transported from one city to another through an asymptomatic air traveller.
The Indian case and that of a patient travelling from Hong Kong to Vladivostok, have highlighted the emergence of another international path for the virus, namely the sea-route. Since the foci of the disease seem to lie in the West Pacific rim, it is surprising that even the WHO had not considered this as an important epidemiological factor. Should SARS continue to spread, the global economic consequences - already estimated at around $30 billion - could be enormous.
However, the outbreak of SARS has demonstrated how well the WHO can tackle a newly identified disease. The international collaborative research effort in understanding the cause of SARS was put together by the WHO in record time. The WHO believes that the system, which is now in operation can be applied to other pandemic outbreaks, including the release of a biological agent in an act of warfare or terrorism.
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