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SARS: An Emerging Infectious Threat

Physicians, epidemiologists, public health practitioners, and other experts came together to discuss the emerging threat of SARS and how it can be dealt with.

Published July 1, 2003

By Rosemarie Foster
Academy Contributor

Image courtesy of samunella via stock.adobe.com.

It seems to appear out of nowhere: A virulent foe that bears a striking resemblance to other pathogens in its class – and yet deals a quick and lethal blow to many it infects – reared its menacing head in February.

It was only a matter of weeks before the mysterious new illness, called SARS (a pithy nickname for Severe Acute Respiratory Syndrome, a constellation of symptoms that cannot be attributed to any known infection), was linked to a coronavirus, which is the same family of viruses that cause the common cold. In a very short period of time – by biomedical research standards – the scientific and medical community had identified the enemy, deciphered its genetic code, and made swift and effective strides in controlling its spread.

Yet for all this success, SARS still presents more questions than answers, as demonstrated at a May 17, 2003, conference called SARS in the Context of Emerging Infectious Threats. The conference was presented by The New York Academy of Sciences (the Academy). As of that date, SARS – characterized by a high fever, dry cough, difficulty breathing, and sometimes diarrhea – had infected 7,761 people worldwide and claimed 623 of those lives.

Answering Questions

Where did it come from? Did it start in an infected animal and mutate to infect humans? Why do some people succumb to its grip while others survive? Why does it claim more victims in China than in other countries? What is the natural course of the disease? Are patients who recover still able to spread the infection to others? Can we create targeted therapies that throw a wrench in the viral replication process? Can we develop a vaccine to prevent SARS infection and, if so, what is the best approach?

These were among the questions tackled by 15 scientists, physicians, public-health officers and pharmaceutical representatives who made presentations at the Academy’s meeting, assembled in just three weeks and one of the first to transpire so early in the course of this medical story.

The meeting was sponsored by the Academy in partnership with Columbia University’s Mailman School of Public Health and the National Institute of Allergy and Infectious Diseases (NIAID). It was organized by two Columbia faculty, Scott M. Hammer, MD., chief of the Division of Infectious Diseases and the Harold C. Neu Professor of Medicine, and W. Ian Lipkin, MD., director of the Center for Immunopathogenesis and Infectious Disease, professor of Epidemiology and Neurology, and Special Advisor to China for Scientific Research and International Cooperation in the Fight Against SARS.

Due to respiratory symptoms that began following a trip to Beijing, Lipkin participated by phone from his home, where he was in quarantine through May 25. He is now asymptomatic and is not believed to have had SARS. Generous support for the meeting was provided by Pfizer Inc, Bristol-Myers Squibb Company, Merck Research Laboratories, and Novartis.

Where Did It Come From?

Coronaviruses owe their crown-like appearance to a multitude of spike (S) proteins studding their surfaces, explained Paul S. Masters, PhD, an investigator and professor of molecular genetics at the Wadsworth Center of the New York State Department of Health. These S proteins take on the task of fusing the virus to a victim’s cells, enabling the pathogen to set up shop in the cell. The coronavirus’ other three proteins – the membrane (M) protein, envelope (E) protein, and nucleocapsid (N) protein – then go to work, essentially turning the host cell into a factory that manufactures and exports newly formed coronaviruses that can attack other cells.

Coronaviruses are highly species-specific, noted Kathryn V. Holmes, PhD, a molecular biologist at the University of Colorado Health Sciences Center in Denver. They cause a variety of respiratory, gastrointestinal and neurologic infections in animals and humans. But because host cell receptors differ between species, a coronavirus that causes a respiratory infection in a pig, for example, has no effect on humans or chickens…unless the virus mutates. Such mutation might explain the origin of the SARS virus, which researchers speculate may have come from an animal in south China, where the first SARS cases materialized.

“Many of these viruses have probably been with their hosts for a long time,” Holmes said. “But how much change does there have to be for a virus to jump to a different host?” Holmes studies the mouse hepatitis virus, a coronavirus that may shed light on the behavior of the SARS virus. She outlined several potential targets for treating the SARS coronavirus, including those that interfere with its replication machinery as well as vaccines. “If we can develop these therapies, they will be applicable not only to SARS, but also to a large number of diseases in animals,” she concluded.

Pigs and Cows

Two species that could be especially helped by such treatments are pigs and cows. Linda J. Saif, PhD, a professor and researcher with The Ohio State University’s Agricultural Research and Development Center, described coronaviruses that cause severe and often fatal respiratory and gastrointestinal infections in these animals. Studies have shown that these infections may be exacerbated when the virus is administered via aerosol, at high doses, with immunosuppressive drugs, or in the presence of other viral or bacterial infections – data that may yield clues about who is most vulnerable to SARS infection.

Moreover, cows that co-mingle with other cattle from different farms and/or have experienced stress during shipping (causing “shipping fever”) are more susceptible to coronaviral infections. “We see something similar to this in SARS patients who recently experienced the stress of travel,” noted Saif. She described various vaccines that have been developed for these infections in animals. Some are effective, but most offer limited protection.

Thanks to a mix of classic and modern techniques, scientists are refining methods of detecting the SARS virus, explained Thomas G. Ksiazek, DVM, PhD, acting chief of the Special Pathogens Branch in the Division of Viral and Rickettsial Diseases at the Centers for Disease Control and Prevention (CDC). He chronicled the efforts of medical detectives to isolate and characterize the virus – initially using immunohistochemical staining, and later confirming its identity and genome with RT-PCR sequencing and array technology.

A Disease of Tribes

Indirect fluorescent antibody testing and ELISA have been employed to garner more information. “The sequencing of the virus’ genome so rapidly is a good use of modern technology, and will make diagnosis of the infection and therapy with vaccines possible in the future,” concluded Ksiazek.

Catherine Laughlin of the National Institute of Allergy and Infectious Diseases discusses the status of drug screening; Larry Anderson of the U.S. Centers for Disease Control and Prevention; Donald E. Low discusses the outbreak in Toronto. Photo by Michael Gaffney.

The first appearance of SARS in people began last fall, when sporadic cases began to emerge in the southern Chinese province of Guangdong. But the seminal event triggering the current epidemic took place on February 21, when a doctor from Guangdong stayed on the ninth floor of Hong Kong’s Metropole Hotel. Ten other people contracted his infection, taking it with them as they continued to travel. Within weeks, the illness popped up in other nations, including Vietnam, where it took the lives of healthcare workers such as Carlo Urbani, the World Health Organization doctor who first identified the outbreak.

Spreads in Hospitals

The virus most frequently has been spread in hospital settings, indicating that community transmission is less likely, said Larry Anderson, MD., chief of the CDC’s Respiratory and Enteric Viruses Branch. “There is a likelihood that with good infection control practices, we can control the spread of SARS,” he contended. Indeed, the infection already has been addressed in Canada, Singapore, Thailand, Vietnam, and the United States. “The good news is that the SARS outbreak has been controlled in some settings,” he said, adding: “We still have a great deal to learn.”

Who, for example, is most likely to develop severe, if not fatal, SARS? Evidence to date indicates that elderly patients and those with diabetes or certain other co-existing chronic medical conditions are more likely to succumb, but more data are needed to confirm and explain these associations. Investigators also want to know more about the optimal time during the illness to collect specimens such as urine, respiratory secretions, and stool samples so they can correlate their findings with disease progression.

Cases in Canada

In Toronto, investigators are analyzing the blood of 100 healthcare workers who were exposed to SARS and 100 others who were not, to see if they can pinpoint any indicators of early SARS infection. Donald E. Low, MD., chief microbiologist at Toronto’s Mount Sinai Hospital, discussed the SARS outbreak that, as of May 17, had taken 23 lives and caused economic hardship for the city.

Their saga began when a woman returned to Toronto after visiting Hong Kong. She developed SARS symptoms and died on March 5, but not before infecting her husband and her son. They, in turn, infected two other men in nearby hospital beds, setting off a chain of infection that included relatives, members of a church group that had been visiting the hospital emergency room and patients at other Toronto hospitals.

As of mid-May, however, Low asserted, “It is safe to come to Toronto.” He noted the valuable lessons learned from Toronto’s SARS experience. One is that strict infection control is a must. Second, the disease is more often spread in hospitals – via droplets and contact – than via casual contact in the community. And finally, Low called SARS “a disease of tribes,” be they family members, hospital workers, or close communities such as religious groups.

Recent reports from China indicate that SARS may be abating there as well. Scott Hammer delivered a presentation prepared by Chen Zhu, Sc.D., vice president of the Chinese Academy of Sciences, who could not be at the meeting. According to his presentation, China has established a central command and 10 task forces, and is evaluating potential treatments (including the serum of convalescent patients), building international collaborations and establishing research centers to study the virus.

Turning Challenge into Opportunity

“The situation in China illustrates the awakening and the multidimensional approach that China is taking to control SARS,” said Hammer. “It’s not just a public health event, but a major political and economic event for China.”

Despite more than two decades of research, the clever HIV pathogen has continued to elude us. But some new good may come out of all those years of study: The coronavirus that causes SARS appears to fuse to host cells in much the same way as HIV. Harnessing this knowledge, David Ho, MD., scientific director of the Aaron Diamond AIDS Research Center at The Rockefeller University – who has scrutinized HIV for 22 years – and his team have designed a peptide that may inhibit this fusion.

Preliminary studies in Hong Kong are producing promising results in tissue culture. Ho speculates that this peptide would have little toxicity in clinical applications. “There are still many obstacles in the way, but this is an example of what one can do in a very short time,” he concluded.

Since so little is known about the virus’ behavior, some doctors have been treating SARS patients with ribavirin and steroids such as dexamethasone, a treatment approach that has not been effective. In fact, corticosteroids may actually delay viral clearance in patients with viral respiratory infections, explained Frederick G. Hayden, MD., professor of internal medicine and pathology at the University of Virginia School of Medicine.

Proceeding Cautiously

“One has to be very cautious about the effects of corticosteroids on viral replication, particularly in the absence of antiviral drugs,” Hayden asserted. Antiviral agents that appear intriguing for use in SARS patients include oseltamivir, zanamivir, and interferon. “We need a better understanding of the natural history of the infection, including mechanisms of injury and host immunopathologic responses,” he added. “Controlled clinical trials are going to be essential to understand what really works in this illness.”

Drugs with the potential for treating SARS will go through an intensive screening process jointly coordinated by the CDC, the U.S. Army Medical Research Institute of Infectious Diseases, and the NIAID. “There are many steps in the viral life cycle where fusion inhibitors might play a role,” said Catherine Laughlin, PhD, chief of the Virology Branch of the Division of Microbiology and Infectious Diseases at the NIAID. Other potential drug targets include cysteine protease, RNA-dependent RNA polymerase, helicase, genome replication and transcription, and the N protein. Laughlin hypothesized that the most effective treatment will probably be a combination of an antiviral agent and another drug that interferes with the viral replication process.

The Race is On

From left: David Ho, Frederick G. Hayden, Catherine Laughlin, C. Richter King, Thomas Monath, Richard Colonno (Bristol-Myers Squibb), Michael Dunne (Pfizer), and Emilio Emini (Merck). Photo by Michael Gaffney.

The race is on between pharmaceutical companies setting out to make a name for themselves in the SARS arena. GenVec, Inc., a Maryland-based biopharmaceutical company, is developing a vaccine against SARS using its adenovector technology, in collaboration with the Vaccine Research Center of the NIAID and the U.S. Navy Medical Research Center. C. Richter King, PhD, vice president of research at GenVec, explained that the “AdVaccine” is based on an adenovirus that is modified to contain a therapeutic protein. The resulting adenovector bears a therapeutic gene capable of triggering an immune response. Moreover, King noted that the highly targeted vaccine is safe and well tolerated, and easily manufactured.

Acambis, a pharmaceutical company specializing in vaccine development, has begun its own investigations into a vaccine for SARS, hoping to build on the success it has had creating vaccines against smallpox and travel-related diseases. Thomas Monath, MD., chief scientific officer at Acambis, noted the scarcity of effective vaccines to treat coronavirus infections in animals, and highlighted the need for a suitable animal model of SARS. (So far, macaque monkeys have been the only animals offering promise in this regard.)

He cautioned that it could take at least five to six years to develop an effective vaccine, at a cost of some $60-100 million and requiring the collaboration of academic and industrial scientists. “We need to understand the natural history of this disease and develop appropriate animal models, and that will allow us to develop rational approaches,” he advised.

The session concluded with a panel discussion that also included representatives from Bristol-Myers Squibb Company, Pfizer Inc, and Merck Research Laboratories.

An Emerging Threat

Ebola. West Nile. And now SARS. “Every year or two we see a new virus, an old virus that wasn’t supposed to be here, or an old virus doing something new,” noted C.J. Peters, MD., professor of microbiology, immunology, and pathology at the University of Texas Medical Branch in Galveston. He described how viruses travel with their hosts, bringing them to areas they may not have been able to get to on their own. “Viruses can’t just pick up and go – they are ecologically constrained. The age of exploration started mixing viruses. But today we don’t have to wait for Columbus – there’s the airplane.”

Peters explained how the genetic variability of viruses, multiple ecologic niches, urbanization and global travel have combined to create evolutionary opportunities for viruses. But we have to learn to understand social, cultural and economic differences among populations in order to control viruses effectively. “We have to find a way to get ahead of this. If SARS gets into certain areas of the world, we will not eradicate it,” he contended.

An Effective Public Health Response

When SARS does strike, especially in a major urban area, an effective public health response is critical for controlling its spread, said Marcelle Layton, MD., assistant commissioner for communicable diseases for the New York City Department of Health. Such a response includes prompt detection of the outbreak, notification of key partners (including the medical community and law enforcement agencies), epidemiologic surveillance, medical and public health interventions (such as mass treatment or mass prophylaxis), and – most importantly – accurate and ongoing public communication.

“Effective communication underlies every aspect of a successful response,” emphasized Layton. “If you don’t communicate well, and if you lose trust with misinformation, it’s extremely hard to regain.”

“We really are facing an important problem,” added John La Montagne, PhD, deputy director of the NIAID. “SARS is an unpredictable and serious disease with dramatic impacts. It could have happened here (in this country) – we’re very lucky.” La Montagne supported continued collaboration both nationally and internationally, and credited the toils of SARS investigators. “It is an unbelievable testimony to the effectiveness of our public health institutions – not just nationally, but globally – that so much work and so much progress have been achieved in such a short period of time.”

Also read: What Science Tells Us About the New Coronavirus


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