NEW YORK—Since the World Health Organization (WHO) issued its global alert in March, the lay media have given considerable attention to the spread of severe acute respiratory syndrome (SARS). However, few of these reports have included detailed clinical descriptions of the new disorder.

As of mid-April, four groups had published initial descriptions of patients with SARS.[1-4] A comparison of their results is given in Table 1; more specific information about the disease’s clinical course and its radiographic and histologic findings is offered below.

What remains unclear is whether the patients described in these four studies are typical SARS patients or whether they illustrate only the most severe form of the disease. A recently identified coronavirus has been postulated to be the cause of SARS (see related story in this issue); according to the Centers for Disease Control and Prevention (CDC), viruses capable of causing respiratory illness usually result in a range of clinical manifestations, including asymptomatic colonization.[5] Indeed, evidence is growing that some SARS patients may have milder forms of the disease than is suggested by these studies.

Nevertheless, the findings of these four studies provide as good a description as is presently available of the disease’s clinical course.

CLINICAL COURSE

The typical incubation period seems to be two to seven days, but it may be as long as 10 or more days. The initial complaint is usually fever, which may be quite high. Other early symptoms are nonspecific (eg, chills and rigors, headache, malaise, myalgias); mild respiratory symptoms may also be present. Auscultation may reveal crackles. Rash and neurologic findings are absent. Only a few patients have diarrhea, but because some animal coronaviruses can be spread through fecal-oral contamination, special care should probably be taken if diarrhea is present. Lymphocytopenia is common in the early stages.

After three to seven days, lower respiratory symptoms become more prominent. Most patients experience a dry, nonproductive cough, dyspnea, or both; hypoxemia may be present. The majority of patients have fever by this point. During the early part of the respiratory phase, creatine kinase, lactate dehydrogenase (LDH), and aspartate aminotransferase are often increased; leukopenia and thrombocytopenia may also be seen. Lymphocytopenia may worsen as the disease progresses. Renal dysfunction is rare.

With good supportive management, most patients eventually recover, although convalescence may be prolonged. In some patients, progressive respiratory dysfunction warrants intubation and mechanical ventilation. In the four published reports, roughly 20% of the patients required intubation. It is difficult to predict when such deterioration may occur; it has been reported to develop within a few days of symptom onset—or almost two weeks later. The median appears to be around seven days.

Worldwide, the mortality rate associated with SARS has been about 5%. However, in some areas, such as Toronto, the death rate has been markedly higher. The reasons for these regional variations remain unclear. Susan M. Poutanen, MD, lead author of the Toronto study, suggested that Canada’s more stringent diagnostic criteria (which required evidence of severe, progressive disease) may have been a contributing factor—had the Toronto Study group used the WHO/CDC definition, more patients would have been given a diagnosis of SARS and thus the death rate would have been proportionately lower. However, Dr. Poutanen acknowledged that there were at least three other possible explanations:
• That the strain of the coronavirus encountered in Toronto was more virulent that those seen elsewhere.
• That the high doses of ribavarin used initially caused adverse reactions that contributed to the death rate.
• That the mortality rate in Toronto was simply the upper end of the normal distribution curve.

Death from SARS typically results from progressive respiratory failure due to widespread alveolar damage. Dr. Poutanen noted, however, that two of the patients in Toronto died following cardiac arrests at times when they were not extremely hypoxic, but it is not yet clear whether they arrested secondary to their hypoxia alone or whether other contributors, such as electrolyte abnormalities or primary cardiac involvement, were involved. Possible predictors of a poor prognosis include advanced age, comorbid disease, severe lymphopenia, neutropenia, and elevated peak LDH levels.

RADIOGRAPHIC ABNORMALITIES

Although the original WHO/CDC definition of probable SARS required evidence of radiographic abnormalities, it has since been suggested that, in a few patients, chest films may be normal throughout the disease course. This suggestion awaits confirmation; it is based largely on findings from patients with suspected SARS.

Most patients have chest film findings, particularly as the illness progresses. Early findings may be subtle or indistinguishable from those associated with other forms of bronchopneumonia. Focal infiltrates are often seen; these are followed by more generalized, patchy, interstitial infiltrates. Air-space shadowing may include ground-glass opacities. Pleural effusions have not been reported. As the disease progresses, air-space opacities increase in size, extent, and severity. Areas of consolidation may be found. Among survivors, improvement in chest film findings often occurs within about two weeks. In contrast, clinical deterioration is frequently accompanied by diffuse opacification suggestive of the adult respiratory distress syndrome (ARDS).

Computed tomography may reveal subpleural focal consolidation with air bronchograms and ground-glass opacities. These findings are similar to those associated with bronchiolitis obliterans organizing pneumonia (BOOP).

HISTOPATHOLOGIC FINDINGS

Examination of lung specimens from SARS patients has shown diffuse alveolar damage at various levels of progression and severity. Among the changes seen are hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation of pneumocytes in alveolar spaces. Less commonly, focal intra-alveolar hemorrhage, necrotic inflammatory debris in small airways, organizing pneumonia, and multinucleated syncytial cells are found.

DIAGNOSIS AND EVALUATION

Because initial findings are nonspecific, the CDC recommends the following tests: chest film, pulse oximetry, blood cultures, sputum Gram stain and culture, and testing for viral respiratory pathogens (including, once an accurate assay is available, the newly discovered coronavirus). Utmost caution should be used when handling specimens; up-to-date recommendations can be obtained from the CDC’s Web site. All specimens should be saved until a specific diagnosis is made.

TREATMENT

The therapies used to date in SARS patients have been empiric. Unfortunately, said David L. Heymann, MD, Executive Director of WHO’s communicable disease program, “no therapy has been shown to demonstrate any particular effectiveness.”

Because the early symptoms and signs of SARS are nonspecific, broad-spectrum antibiotics and antiflu drugs have been used extensively, at least until bacterial infection and influenza were ruled out. These drugs may continue to play a part in management until the role of coinfection in disease progression can be elucidated.

When mechanical ventilation has been required, most physicians have tried strategies similar to those used for ARDS. However, the outcome is often poor, even when positive end-expiratory pressures and fractions of inspired oxygen are high. Because coughing can help transmit the disease, intubation, if needed, should be performed as rapidly as possible. Forms of mechanical ventilation that are likely to spread respiratory droplets, such as continuous positive airway pressure, should be avoided.

Corticosteroids have been given to many patients; one of the rationales for their administration is the radiographic similarities between SARS and both ARDS and BOOP. Whether their use improves outcome remains uncertain, however.

Ribavirin has also been given extensively, and clinical trials of this drug have been organized. In the study by Peiris et al,[3] time to treatment with ribavirin and corticosteroids was a predictor of outcome. However, preliminary results from the US Army Medical Research Institute of Infectious Diseases indicate that concentrations of ribavirin sufficient to inhibit viruses known to be sensitive to this drug are insufficient to inhibit replication or cell-to-cell spread of the newly discovered coronavirus.[5] Thus, it is unclear what role ribavirin will play in disease management. In the absence of effective alternatives, the temptation to try ribavirin may be great. However, the drug is teratogenic and can induce severe hemolytic anemia, among other side effects.

The best approach to treatment may be to consult the CDC’s Web site frequently. Updated recommendations on treatment, as well as on infection control, are posted there almost daily.

—Mimi Zucker, PhD