Severe acute respiratory syndrome (SARS)

Severe acute respiratory syndrome (SARS) is the first emergent and highly transmissible viral disease to appear during the twenty-first century. Patients with SARS develop flu-like fever, headache , malaise, dry cough and other breathing difficulties. Many patients develop pneumonia , and in 5-10% of cases, the pneumonia and other complications are severe enough to cause death. SARS is caused by a virus that is transmitted usually from person to person—predominantly by the aerosolized droplets of virus infected material.

SARS cases provided a test of recent reforms in International Health Regulations designed to increase surveillance and reporting of infectious diseases—and to enhance cooperation in preventing the international spread of disease. Although not an act of bioterrorism , because the very same epidemiologic principles and isolation protocols might be used to both initially determine and initially respond to an act of bioterrorism, intelligence and public heath officials closely monitored the political, scientific, and medical responses to the SARS outbreak. In many regards, the SARS outbreak provided a real and deadly test of public health responses, readiness, and resources.

Common to both responses of the SARS outbreak and a potential deliberate biological attack using pathogens such as smallpox or anthrax is the need to rapidly develop accurate diagnostic tests, treatment protocols, and medically sound control measures.

At the end of April 2003, SARS had the potential to become a global pandemic. Scientists, public health authorities, and clinicians around the world struggled to both treat and investigate the disease. The first known case of SARS was traced to a November 2002, case in Guangdong province, China. By mid-February 2003, Chinese health officials tracked more than 300 cases, including five deaths in Guangdong province from what was at the time described as an acute respiratory syndrome.

Many flu causing viruses have previously originated from Guangdong province because of cultural and exotic cuisine practices that bring animals, animal parts, and humans into close proximity. In such an environment, pathogens can more easily genetically mutate and make the leap from animal hosts to humans. The first cases of SARS showed high rates among Guangdong food handlers and chefs.

Chinese health officials initially remained silent about the outbreak, and no special precautions were taken to limit travel or prevent the spread of the disease. The world health community, therefore, had no chance to institute testing, isolation, and quarantine measures that might have prevented the subsequent global spread of the disease.

On February 21, Liu Jianlun, a 64-year-old Chinese physician from Zhongshan hospital (later determined to have been "super-spreader," a person capable of infecting unusually high numbers of contacts) traveled to Hong Kong to attend a family wedding despite the fact that he had a fever. Epidemiologists subsequently determined that, Jianlun passed on the SARS virus to other guests at the Metropole Hotel where he stayed—including an American businessman en route to Hanoi, three women from Singapore, two Canadians, and a Hong Kong resident. Jianlun's travel to Hong Kong and the subsequent travel of those he infected allowed SARS to spread from China to the infected travelers' destinations.

Johnny Chen, the American businessman, grew ill in Hanoi, Viet Nam, and was admitted to a local hospital. Chen infected 20 health care workers at the hospital including noted Italian epidemiologist Carlo Urbani who worked at the Hanoi World Health Organization (WHO) office. Urbani provided medical care for Chen and first formally identified SARS as a unique disease on February 28, 2003. By early March, 22 hospital workers in Hanoi were ill with SARS.

Unaware of the problems in China, Urbani's report drew increased attention among epidemiologists when coupled with news reports in mid-March that Hong Kong health officials had also discovered an outbreak of an acute respiratory syndrome among health care workers. Unsuspecting hospital workers admitted the Hong Kong man infected by Jianlun to a general ward at the Prince of Wales Hospital because it was assumed he had a typical severe pneumonia—a fairly routine admission. The first notice that clinicians were dealing with an usual illness came—not from health notices from China of increasing illnesses and deaths due to SARS—but from the observation that hospital staff, along with those subsequently determined to have been in close proximity to the infected persons, began to show signs of illness. Eventually, 138 people, including 34 nurses, 20 doctors, 16 medical students, and 15 other health-care workers, contracted pneumonia.

One of the most intriguing aspects of the early Hong Kong cases was a cluster of more than 250 SARS cases that occurred in a cluster of high-rise apartment buildings—many housing health care workers—that provided evidence of a high rate of secondary transmission. Epidemiologists conducted extensive investigations to rule out the hypothesis that the illnesses were related to some form of local contamination (e.g., sewage, bacteria on the ventilation system, etc.). Rumors began that the illness was due to cockroaches or rodents, but no scientific evidence supported the hypothesis that the disease pathogen was carried by insects or animals.

Hong Kong authorities then decided that those suffering the flu-like symptoms would be given the option of self-isolation, with family members allowed to remain confined at home or in special camps. Compliance checks were conducted by police.

One of the Canadians infected in Hong Kong, Kwan Sui-Chu, return to Toronto, Ontario, and died in a Toronto hospital on March 5. As in Hong Kong, because there were no alert from China about the SARS outbreak, Canadian officials did not initially suspect that Sui-Chu had been infected with a highly contagious virus, until Sui-Chu's son and five health care workers showed similar symptoms. By mid-April, Canada reported more than 130 SARS cases and 15 fatalities.

Increasingly faced with reports that provided evidence of global dissemination, on March 15, 2003, the World Health Organization (WHO) took the unusual step of issuing a travel warning that described SARS is a "worldwide health threat." WHO officials announced that SARS cases, and potential cases, had been tracked from China to Singapore, Thailand, Vietnam, Indonesia, Philippines, and Canada. Although the exact cause of the "acute respiratory syndrome" had not, at that time, been determined, WHO officials issuance of the precautionary warning to travelers bound for southeast Asia about the potential SARS risk severed notice to public health officials about the potential dangers of SARS.

Within days of the first WHO warning, SARS cases were reported in United Kingdom, Spain, Slovenia, Germany, and in the United States.

WHO officials were initially encouraged that isolation procedures and alerts were working to stem the spread of SARS, as some countries reporting small numbers of cases experienced no further dissemination to hospital staff or others in contact with SARS victims. However, in some countries, including Canada, where SARS cases occurred before WHO alerts, SARS continued to spread beyond the bounds of isolated patients.

WHO officials responded by recommending increased screening and quarantine measures that included mandatory screening of persons returning from visits to the most severely affected areas in China, southeast Asia, and Hong Kong.

On March 29, Urbani, the scientist who reported a SARS case, died of complications related to SARS.

In early April 2003, WHO took the controversial additional step of recommending against non-essential travel to Hong Kong and the Guangdong province of China. The recommendation, sought by infectious disease specialists, was not controversial within the medical community, but caused immediate concern regarding the potentially widespread economic impacts.

World attention—focused largely on the ongoing war in Iraq—began to focus on SARS. Within China, under a new generation of political leadership, a politically unique event occurred when Chinese official publicly apologized for a slow and inefficient response to the SARS outbreak. Allegations that officials covered up the true extent of the spread of the disease caused the dismissal of several local administrators including China's public health minister and the mayor of Beijing.

Mounting reports of SARS showed a increasing global dissemination of the virus. By April 9, the first confirmed reports of SARS cases in Africa reached WHO headquarters, and eight days later, a confirmed case was discovered in India.

Scientists scrambled to isolate, identify, and sequence the pathogen responsible for SARS. Modes of transmission characteristic of viral transmission allowed scientists to place early attention on a group of viruses termed coronaviruses—some of which are associated the common cold. There was a global two-pronged attack on the SARS pathogen, with some efforts directed toward a positive identification and isolation of the virus, and other efforts directed toward discovering the genetic molecular structure and sequence of genes contained in the virus. The development of a genomic map of the precise nucleotide sequence of the virus would be key in any subsequent development of a definitive diagnostic test, the identification of effective anti-viral agents, and perhaps a vaccine.

The development of a reliable and definitive diagnostic test was considered of paramount importance in keeping SARS from becoming a global pandemic. A definitive diagnostic test would not only allow physicians earlier treatment options, but would also allow the earlier identification and isolation of potential carriers of the virus.

Without advanced testing, physicians were initially forced to rely upon less sensitive tests that were unable to identify SARS prior to 21 days of infection, in most cases too late to effectively isolate the patient.

In mid-April 2003, Canadian scientists at the British Columbia Cancer Agency in Vancouver announced that they that sequenced the genome of the coronavirus most likely to be the cause of SARS. Within days, scientists at the Centers for Disease Control (CDC) in Atlanta, Georgia, offered a genomic map that confirmed more than 99% of the Canadian findings.

Both genetic maps were generated from studies of viruses isolated from SARS cases. The particular coronavirus mapped had a genomic sequence of 29,727 nucleotides—average for the family of coronavirus that typically contain between 29,000-31,000 nucleotides.

Proof that the coronavirus mapped was the specific virus responsible for SARS would eventually come from animal testing. Rhesus monkeys were exposed to the virus via injection and inhalation and then monitored to determine whether SARS like symptoms developed, and then if sick animals exhibited a histological pathology (i.e., an examination of the tissue and cellular level pathology) similar to findings in human patients. Other tests, including polymerase chain reaction (PCR) testing helped positively match the specific coronavirus present in the lung tissue, blood , and feces of infected animals to the exposure virus.

Identification of a specific pathogen can be a complex process, and positive identification requires thousands of tests. All testing is conducted with regard to testing Koch's postulates—the four conditions that must be met for an organism to be determined to the cause of a disease. First, the organism must be present in every case of the disease. Second, the organism must be able to be isolated from the host and grown in laboratory conditions. Third, the disease must be reproduced when the isolated organism is introduced into another, healthy host. The fourth postulate stipulates that the same organism must be able to be recovered and purified from the host that was experimentally infected.

Early data indicates that SARS has an incubation period range of 2-10 days, with an average incubation of about four days. Much of the innoculation period allows the virus to be both transported and spread by an asymptomatic carrier. With air travel, asymptotic carriers can travel to anywhere in the world. The initial symptoms are non-specific and common to the flu. Infected cases then typically spike a high fever 100.4°F (38°C) as they develop a cough, shortness of breath, and difficulty breathing. SARS often fulminates (reaches it maximum progression) in a severe pneumonia that can cause respiratory failure and death in death in about 10% of its victims.

As of May 1, 2003, no therapy was demonstrated to have clinical effectiveness against the virus that causes SARS, and physicians could offer only supportive therapy (e.g. administration of fluids, oxygen , ventilation, etc.).

Before the advent of vaccines and effective diagnostic tools, isolation and quarantine were the principal tools to control the spread of infectious disease. The term "quarantine" derives from the Italian quarantine and quaranta giorni and date to the plague in Europe. As a precautionary measure, the government of Venice restricted entry into the port city and mandated that ships coming from areas of plague—or otherwise suspected of carrying plague—had to wait 40 days before being allowed to discharge their cargos.

The legal basis of quarantine in the United States was established in 1878 with the passage of Federal Quarantine Legislation in response to continued outbreaks of yellow fever , typhus , and cholera .

The public discussion of SARS related quarantine in the United States and Europe renewed tensions between the needs for public heath precautions that safeguard society at large and the liberties of the individual. During the later years of the nineteenth century and throughout the twentieth century, the law bent toward protecting the greater needs of protecting society. The fact that the poser of quarantine was sometime used to contain and discourage immigration, often made the use quarantine a political and well as medical issue. In other cases such, as with tuberculosis (TB), quarantine proved effective and courts wielded wide authority to isolate, hospitalize, and force patients to take medications.

Isolation and quarantine remain potent tools in the modern public health arsenal. Both procedures seek to control exposure to infected individuals or materials. Isolation procedures are used with patients with a confirmed illness. Quarantine rules and procedures apply to individuals who are not currently ill, but are known to have been exposed to the illness (e.g., been in the company of a infected person or come in contact with infected materials).

Isolation and quarantine both act to restrict movement and to slow or stop the spread of disease within a community. Depending on the illness, patients placed in isolation may be cared for in hospitals, specialized health care facilities, or in less severe cases, at home. Isolation is a standard procedure for TB patients. In most cases, isolation is voluntary; however, isolation can be compelled by federal, state, and some local law.

States governments within the United States have a general authority to set and enforce quarantine conditions. At the federal level, the Centers for Disease Control and Prevention's (CDC) Division of Global Migration and Quarantine is empowered to detain, examine, or conditionally release (release with restrictions on movement or with a required treatment protocol) individuals suspected of carrying certain listed communicable diseases.

As of April 27, 2003, the (CDC) in Atlanta recommended SARS patients be voluntarily isolated, but had not recommended enforced isolation or quarantine. Regardless, CDC and other public heath officials, including the Surgeon General, sought and secured increased powers to deal with SARS. On April 4, 2003, U.S. President George W. Bush signed Presidential Executive Order 13295 that added SARS to a list of quarantinable communicable diseases. The order provided heath officials with the broader powers to seek "...apprehension, detention, or conditional release of individuals to prevent the introduction, transmission, or spread of suspected communicable diseases..."

Other diseases on the U.S. communicable disease list, specified pursuant to section 361(b) of the Public Health Service Act, include "Cholera; Diphtheria; infectious Tuberculosis; Plague; Smallpox; Yellow Fever; and Viral Hemorrhagic Fevers (Lassa, Marburg, Ebola, Crimean-Congo, South American, Haanta, and others yet to be isolated or named)."

Canada, hit early and much harder by SARS than the U.S., responded by closing schools and some hospitals in impacted areas. Canadian health officials advised seemingly healthy travelers from areas with known SARS cases to enter into a 10-day voluntary quarantine. Once in isolation, individuals were asked to frequently take their temperature and remain separated from other family members. Within a month, almost 10,000 people were in some form of quarantine. Canadian government officials, including the Prime Minister Jean Chrétien complained bitterly when, on April 23, the WHO recommended a three-week postponement of non-essential travel to Toronto. After criticism and intense lobbying of WHO by Chrétien's government and Canadian public health officials, WHO discontinued the recommendation on April 30, 2003. When Canada's cases of SARS spiked, Toronto was returned to the WHO list, and was not removed until July 2, 2003. WHO officials kept in place similar warning about travel to Beijing and Hong Kong.

Faced with a more immediate danger and larger numbers of initial cases, an authoritarian government in Singapore was less hesitant in ordering quarantine of victims and those potentially exposed to the virus. One of the three Singapore women initially infected in Hong Kong was later identified as a super-spreader who infected more than 90 people. She recovered, but both her mother and father died of SARS.

Passengers arriving in Singapore coming from other countries with SARS were required to undergo questioning by nurses in isolation garb and then required to walk through a thermal scanner calibrated to detect an elevated body temperature. Soldiers immediately escort those with elevated temperatures into quarantine facilities. Those subsequently allowed to remain in their homes are monitored by video cameras and electronic wristbands.

By late April/early May 2003, WHO officials had confirmed reports of more than 3,000 cases of SARS from 18 different countries with 111 deaths attributed to the disease. Each new day brought new reports that increased these totals. United States health officials reported 193 cases with no deaths. Significantly, all but 20 of the U.S. cases were linked to travel to infected areas, and the other 20 cases were accounted for by secondary transmission from infected patients to family members and health care workers.

In China, fear of a widespread outbreak in Beijing caused a late, but intensive effort to isolate SARS victims and halt the spread of the disease. By the end of April 2003, schools in Beijing were closed as were many public areas were closed. Despite these measures, SARS cases and deaths continued to mount into late April 2003. Many of China's neighbors considered closing borders to all but essential travel. Health authorities assert that the emergent virus responsible for SARS will remain endemic (part of the natural array of viruses) in many regions of China well after the current outbreak is resolved.

Information on countries reporting SARS and the cumulative total of cases and deaths is updated each day on the WHO SARS Website at <http;//www.who.int/csr/sarscountry/en/>.

See also Genetic identification of microorganisms; Zoonoses.

Resources

periodicals

Ksiazek T.G., et al. "A Novel Coronavirus Associated with Severe Acute Respiratory Syndrome." New England Journal of Medicine. 10.1056 (April 10, 2003): a030781.

Rosenthal, E. "From China's Provinces, a Crafty Germ Spreads." New York Times. (April 27, 2003).

other

Centers for Disease Control and Prevention (CDC). "Severe Acute Respiratory Syndrome (SARS)." April 3, 2003. [cited April 27, 2003]. <http://www.cdc.gov/ncidod/sars/isolationquarantine.ht>.

World Health Organization. Communicable Disease Surveillance & Response (CSR). April 24, 2003 [cited April 27, 2003]. <http://www.who.int/csr/sars/en/>.

Brenda Wilmoth Lerner K. Lee Lerner