Published ahead of print on May 28, 2003, doi:10.1164/rccm.200305-707OE
© 2003 American Thoracic Society
Our Strategies for Fighting Severe Acute Respiratory Syndrome (SARS)Guangzhou Institute of Respiratory Disease, First Affiliated Hospital, Guangzhou Medical College, Guangzhou, China Correspondence and requests for reprints should be addressed to Dr. Nan Shan Zhong, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital, Guangzhou Medical College, 51 Yanjiang Road, Guangzhou, China 510120. E-mail: nanshan{at}vip.163.com On March 12, 2003, the World Health Organization (WHO) issued a global alert on an atypical pneumonia, now called severe acute respiratory syndrome (SARS). We could not have predicted the catastrophe that ensued when a patient with high fever of unknown origin was referred to Guangzhou Institute of Respiratory Diseases (GIRD) at the end of 2002. At that time, the Chinese people were looking forward to the New Year. Never had a previous case been treated or a similar condition been documented. We describe our initial experience below. THE FIRST CASE TO GUANGZHOU INSTITUTE OF RESPIRATORY DISEASES A 41-year-old businessman had been healthy with the exception of a chronic relapsing cough during the preceding 3 years. He was admitted to a local hospital in Heyuan, a small county of Guangdong, for an evaluation of the cough. In the same ward was another patient who died of what proved later to be atypical pneumonia. Three days after his admission, the patient suddenly developed high fever (temperature, 39.6°C), chills, malaise, and myalgia. He was treated with ofloxacin with no improvement. After 3 days, he was transferred to the Guangzhou Institute of Respiratory Diseases. Upon arrival on December 22, he did not have severe respiratory symptoms, but had a persistent fever with a total leukocyte count of 8. 3 x 109/L and radiologic features of a left lower pneumonia. These signs did not suggest an intractable pneumonia, although he had a lingering fever that was responding poorly to broad-spectrum antibiotics. On December 26, his condition worsened, with severe dyspnea, respiratory rate of 38 breaths per minute, and an oxygen saturation of 89%. He was given supplemental oxygen by mask. The chest radiograph showed diffuse haziness of both lower lung fields that deteriorated into patchy infiltrates and then ground glass opacities by the afternoon of the following day. The patient was treated with bilevel positive-pressure ventilation (BiPAP), but his clinical status worsened (respiratory rate of 55 breaths per minute and oxygen index of 137), and he was intubated for a presumed diagnosis of acute lung injury or acute respiratory distress syndrome. His lungs were surprisingly stiff with poor compliance. On December 29, he developed bilateral pneumothoraces and pneumomediastinum, which required tube thoracostomy drainage. Because of persistent fever and similarities to acute respiratory distress syndrome, he was given high-dose corticosteroids (methylprednisolone 160 mg/day). The corticosteroids were associated with considerable improvement in oxygen saturation and pulmonary infiltrates, and the temperature gradually returned to normal. His condition gradually came under control, and after prolonged ventilator support, he was extubated on February 17 and discharged on March 5, 2003. While we were astounded by the rapid progress, the poor antibiotic response, and the potential pulmonary damage, we became aware of another striking fact: eight persons (including family members and medical professionals) who had been in close contact with our patient developed similar symptoms. Other stories of cases identical to that of our patient arose from Zhongshan and Heyuan. It was named "infectious atypical pneumonia" (now named SARS) because of the lack of a leukocytosis, poor response to antibiotics, and its contagious propensity. THE WAR AGAINST SARS A war without gunsmoke is spreading throughout China and many other countries. As of the time of writing, SARS has swept through nearly 30 countries and regions. Globally, more than 7,900 people have been infected, with over 660 deaths. More than 5,200 in the Chinese mainland have been infected, and about 290 have died (1). It is estimated that SARS has caused a financial loss over U.S. $30 billion worldwide. We didn't expect or plan for it, but we have not been daunted by this new health crisis. Medical workers in mainland China—especially professionals in respiratory and infective diseases—charged to the front line in the war against SARS. Like soldiers and flood-fighters, many medical workers devoted their lives to this mission. Such sacrifice, bravery, and dedication to our patients reflects their enduring loyalty to the Hippocratic Oath. THE STEPS AHEAD Over the course of history, humanity has successfully fought plague, smallpox, and tuberculosis, and has effectively held back the spread of AIDS. These achievements can be attributed to the hard work of innumerable scientists and scholars. Likewise, in tackling the enemy of today, collaboration among experts in pathogenesis, etiology, epidemiology, clinical practices, preventive medicine, and social psychology is indispensable to gain a comprehensive understanding of SARS. Researchers have isolated a new virus belonging to the family Coronaviridae from two patients (2–4). Using reverse transcription-polymerase chain reaction specific for this virus, they found evidence of infection with the virus in 90% of patients with SARS, thus indicating that SARS is caused by a coronavirus (4). Antibodies to the SARS-associated coronavirus were found in serum samples only from patients who were convalescing after SARS, and not in human serum samples banked before the SARS outbreak. This observation suggests that the SARS-associated coronavirus is new to the human population (5). Several laboratories have sequenced the genome of the coronavirus and noted that the SARS-associated coronavirus is not closely related to any of the previously characterized coronaviruses (6–8). There are reports that sequences of SARS-associated coronavirus vary among different strains, perhaps because of mutation. The hope is that the virus might attenuate its properties as its replication goes on down to some generations. Experimental analysis of viral evolution shows that genomic stability in a specific host is a function of viral population size—passage of limiting dosages may lead to decreased replicative fitness and attenuation because of adventitious trapping of deleterious mutations (9). But a recent study by Ruan and coworkers demonstrates remarkable genetic conservation since the outbreak of SARS (8). There are a handful of mutations between the isolates, but these may have arisen from adaptation in culture. Accordingly, SARS-associated coronavirus may not change rapidly into a benign infection. Instead, it may persist as a threat with a worrisome epidemiologic trend. Conversely, the apparent genetic stability makes a vaccine a possibility. As the epidemic continues, more questions arise as to how the virus mutates, what biological features the virus possesses (such as its in vitro survival and its toxicity in association with environment), and the possible involvement of causes of atypical pneumonia other than coronaviridae. Answers to these questions will be essential for rational prevention and treatment. The naming of SARS by the WHO, in itself, indicates that the condition apparently has a different pathogenesis from classical pneumonia. Samples obtained by open-lung biopsy from patients with SARS at our institution revealed pathologic changes in both lungs with many features of acute lung injury or acute respiratory distress syndrome: little neutrophilic infiltration, thickened interstitium, hyalinization of the airway basal membrane, proliferation of type II alveolar cells, and subepithelial and interalveolar fibroblasts. At autopsy, the lungs were grossly edematous and congested, the consolidated cut surface was spotted with necrosis and hemorrhage, and thrombosis was seen in pulmonary arteries. Alveolitis and bronchitis with desquamation of pneumocytes were prominent and consistent features on light microscopy. The airspaces of affected alveoli were packed with proliferated alveolar cells, exudated monocytes, lymphocytes, and plasmacytes. Some alveolar cells were fused into a multinucleated syncytium. Eosinophilic viral inclusions equivalent in size to a red blood cell were observed in the epithelial cytoplasm—globe-shaped and with a transparent halo. Exudates inside the alveoli had features of progressive organization and fibrosis. A better elucidation of the pathogenesis would be most helpful, not only for understanding the diseases itself, but also for understanding the pulmonary fibrosis that develops during the course of the infection. So far, the diagnosis of SARS is based on clinical and epidemiologic considerations. Importantly, the criteria for confirmed or suspected diagnosis are not perfect. First, a history of close contact is sometimes doubtful. Second, some patients are subsequently diagnosed with influenza pneumonia, because this pathogen was detected in their upper airway secretions, despite clinical manifestations mimicking SARS. Third, fever, which is usually thought essential for diagnosis, is also seen in patients with the common cold; thus, it is problematic to define "suspected cases" on the basis of fever. Recent studies also indicate that a few patients who have underlying diseases (such as hypertension, diabetes, cancer, or chronic obstructive pulmonary disease) or in the postoperative state will present without fever at the early stage of infection. Therefore, the clinical diagnostic criteria have important limitations that may lead to false positive or negative diagnoses. We further highlight three aspects of the case definition: (1) a history of close contact traceable to an index patient; (2) persistent fever and rapidly worsening radiologic findings during follow up; and (3) specific laboratory tests (IgG and reverse transcription-polymerase chain reaction, among other tests under development). Newly developed tests, including the rapid polymerase chain reaction test for coronaviridae RNA in secretions and viral antibodies in serum, will be of great value in defining and differentiating SARS from other acute pulmonary diseases. The mortality of patients with SARS patients is considerable (4–10%). Early detection and recognition of patients with severe involvement, and timely prevention and management, are critical in decreasing mortality. As early as March 2003, China first summarized its experience in the management of SARS, and in particular of the severe form (10, 11). First, the acute onset of fever and myalgia should be treated with a combination of traditional Chinese medicine and Western medicine. Second, when fever persists for more than 3 days or radiologic findings suggest persistent lung involvement or progressive deterioration, high-dose corticosteroids should be used to prevent the development of pulmonary fibrosis. Third, when oxygen saturation is less than 93% while receiving 3–5 L/minute of oxygen, respiratory rate greater than 30 breaths per minute, or the chest radiograph shows progressive deterioration, BiPAP should be applied in a timely manner to improve oxygen supply, prevent alveolar collapse, and thus reduce the need for intubation. Endotracheal intubation is indicated when there is deterioration despite continuous positive airway pressure (or BiPAP), with oxygen saturation less than 93% (while receiving oxygen at 5 L/minute by mask), enlarged pulmonary consolidation, or intolerance of continuous positive airway pressure (or BiPAP). Fourth, monitoring for complications, especially nosocomial infection, should be done, and these should be treated in a timely manner. These four points must be considered as our empirical approach, and will likely require modification as experience grows. Finally, the confirmed transmission route of SARS is direct transmission via close contact with droplets or secretions. But increasing epidemiologic evidence reveals that the disease may also be transmitted indirectly through water, clothing, hands, and food contaminated by secretions or even excreta (e.g., feces) from patients. Investigations indicate that the Amoy Garden SARS outbreak was caused by virulent virus originating in the stools of a patient with diarrhea, passing through sewage, and escaping by leakage in the form of aerosol, which in turn spread into a narrow lightwell and reached elsewhere (12). Clarification of the route of transmission is of great importance for more efficient prevention of the disease, especially among health care workers. OUR STRATEGIES AND EXPECTATIONS It took 3 years for scientists to sequence the AIDS virus gene after it was discovered. But it has taken only 3 months to complete the sequential analysis of the coronavirus. This represents a remarkable achievement of collaboration of scientists worldwide. SARS is an evil affecting all humanity, not just some country or region. The appearance of new cases has started to stabilize in Guangzhou and Beijing, but the outbreak of SARS is not yet under control in some other regions such as Hebei, Shangxi, and Inner Mongolia. To fight this extremely contagious and fatal disease, we need continued collaboration among fields involving etiology, epidemiology, clinical practices, preventive medicine, and molecular biological engineering; and the cooperation of advanced technical forces from different regions and countries. With such collaborations, we are confident that we will soon be able to overcome this major epidemic of the twenty-first century. Acknowledgments N.S.Z. has no declared conflict of interest. G.Q.Z. has no declared conflict of interest. Received in original form May 22, 2003; accepted in final form May 23, 2003 REFERENCES
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