SARS: Are we still at risk?

After emerging as the first new pathogen of the 21st century, the
SARS virus rapidly caused a worldwide pandemic. The risk it poses
to health care workers should make all providers exceedingly vigilant.

Frank A. Acevedo, MS, PA-C; Salvatore Barese, MS, EdD, PA-C

Frank Acevedo is Assistant Professor/Associate Program Director/Academic Coordinator and Salvatore Barese is Assistant Professor/Program Director, both in the Department of Physician Assistant Studies, New York Institute of Technology, Old Westbury, NY. The authors have indicated no relationships to disclose relating to the content of this article.

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SARS—or severe acute respiratory syndrome—is a relatively new clinical entity whose origin has been traced to Foshan city in China’s southern Guangdong province. The earliest identified case of this severe, febrile lower respiratory tract illness developed in a man living in Foshan who became ill on November 16, 2002. In March 2003, the syndrome appeared in Hong Kong and from there spread rapidly to Vietnam, Singapore, Thailand, Taiwan, Germany, Ireland, Canada, and the United States. During the peak of the SARS outbreak, between November 2002 and June 2003, 8,437 cases were reported, with 813 deaths.¹

Through the work of the late Dr. Carlo Urbani,² who succumbed to SARS while taking steps to contain the outbreak, the World Health Organization (WHO) was made aware of and mobilized resources to contain the evolving pandemic. The WHO issued a global health alert advising all clinicians to watch for patients presenting with an atypical pneumonia in association either with travel to Asia or with exposure to those who had recently been there.

The rapidity of response by the WHO was put to the test when SARS spread quickly as a result of international air travel. Internet resources disseminated clinical information to practitioners and researchers alike. The combination of collaborative efforts by the worldwide medical community and agencies such as the WHO and the CDC slowed the spread of SARS, with eventual suppression of new cases.

This success, however, should not encourage clinicians to let down their guard, as many scientists predict that SARS has found a suitable human reservoir. A reemergence of SARS in April 2004 in China may very well have demonstrated that this syndrome will not simply disappear and may emerge in the future on a global scale. This new outbreak involved a total of eight patients and required the surveillance of nearly 1,000 contacts. Two of those who contracted the disease were researchers at the National Institute of Virology in Beijing. With this scenario looming, primary care clinicians must be aware of the salient clinical, diagnostic, and therapeutic options currently available for SARS. This syndrome must also be distinguished from influenza, from influenzalike diseases, and from the dangerous avian influenza that could represent the next pandemic.

Epidemiology of a pandemic

The development of a cluster of cases of atypical pneumonia in the Guangdong province of China went relatively unnoticed because it was first thought to represent an outbreak of influenza. Retrospectively, we now know that this November 2002 outbreak was, in fact, the first cluster of SARS cases. A Chinese physician (Patient A) from that cluster traveled to Hong Kong and stayed at the Metropole Hotel (Hotel M). He infected 12 contacts, who then, with the help of international air travel, helped to spread SARS around the world.

Teams of epidemiologists from the CDC, the WHO, and other international, national, and local health agencies quickly mobilized to piece together the chain of transmission. Epidemiologic study revealed that Patient A infected Patients B, C, D, E, F, I, J, and K while they stayed on the same floor at the hotel. Patients G and H stayed on other floors, and their infections strongly supported the theory that SARS could be transmitted through droplets. Patients L and M did not stay at the hotel while patient A was there but became infected through contact with their spouses, Patients G and H. This epidemiologic detective work, along with the work of Dr. Urbani in Vietnam, was a critical preliminary step in recognizing the transmissibility of this disease. With this information now available, the WHO issued a global alert in March 2003.

The epidemiologic study of SARS also revealed that a significant risk factor was travel to affected areas or close contact with persons who had traveled to these regions. Even with the availability of epidemiologic data, the widespread dissemination of this syndrome was not readily recognized during investigations by multiple health care agencies. Though the epidemiologic data revealed that the atypical pneumonia was transmissible, the causative organism remained unidentified during the early stages of the pandemic.

Etiology of SARS

Initially, the SARS outbreak led scientists to consider a number of potential causes of this atypical pneumonia, including Yersinia, Mycoplasma, and Legionella organisms, Coxiella burnetii, Rickettsiaceae organisms of the group causing Rocky Mountain spotted fever and typhoid fever, influenza viruses A and B, respiratory syncytial virus, human metapneumoviruses, Mastadenoviridae, Herpetoviridae, Picornaviridae, Arenaviruses, and Hantaviruses.³ Investigators tested for these infectious agents by utilizing variants of polymerase chain reaction (PCR), which also included reverse-transcription PCR (RT-PCR). Although some of the agents listed were isolated in various patients, none could explain the syndrome complex as manifested. Not until March 24, 2003, was an etiologic agent identified with any certainty. The cause of SARS turned out to be a novel coronavirus that had not been previously known.^3-5

SARS-associated coronavirus Coronaviridae are enveloped, single-stranded RNA viruses that can be transmitted via droplets produced during coughing or sneezing, direct contamination, fomite contamination, and aerosolization. These viruses get their name from their characteristic appearance when viewed under electron microscopy: There is a spike (S) glycoprotein on the virus’s surface as it projects outward, giving the virus a halo or crownlike appearance.

In humans, coronaviruses cause upper respiratory tract disease and necrotizing enterocolitis. Previous research has revealed that they are responsible for 15% to 30% of common colds.^5-6 They are rarely responsible for lower respiratory tract disease in humans, but they have been known to cause significant epizootics involving the lower respiratory tract and the neurologic, hepatic, and enteric systems in domestic livestock and poultry.

Before the SARS-associated coronavirus was identified, three groups of Coronaviridae were recognized. DNA sequencing of the 29,751 base pairs of the new virus revealed that it was distinctly different from the other three.⁷ The newly discovered virus has been named SARS-associated coronavirus, or SARS-CoV. The hypothesis that it is the cause of SARS is supported and virtually confirmed by two findings: no antibody to the virus is detected in the sera of patients not exposed to SARS, and primates develop clinical and pathologic features of SARS when they are injected with the virus.

Zoonotic disease Current scientific theory is that SARS has crossed over from an animal reservoir to humans; it is thereby classified as a zoonotic disease. Epidemiologic investigations into possible animal reservoirs of the SARS virus in the Guangdong province have identified a coronavirus almost identical to SARS-CoV in masked-palm civets, raccoon dogs, and an endemic badger species. The identification of the virus in these animals is just the preliminary step in determining the extent of the animal reservoir.

Pathogenesis

The clinical syndrome known as SARS appears to be initiated when the virus is transmitted via droplets and, in some cases, via fecal material or aerosolization of pulmonary secretions during intubation and other respiratory interventions. Once the virus enters the respiratory tract, it utilizes its S glycoprotein to bind to receptors on host cells and fuse membranes.⁵ After fusion, the membrane (M) protein, envelope (E) protein, and nucleocapsid (N) protein function together to turn host cells into viral replicating machines.

Patients experience peak viral loads during the early phases of the disease, but signs and symptom actually worsen as the disease progresses and the viral load decreases. This further deterioration in patient condition is probably not related to viral load but is instead linked to inflammatory and immunologic responses mediated by cytokines, nitric oxide, and oxygen free radicals.

The exposure of pulmonary tissue to the SARS virus results in a pattern of diffuse alveolar damage, foamy macrophages, multinucleated syncytial cells, and hyaline-membrane formation. These pathologic changes are similar to those seen in early acute respiratory distress syndrome (ARDS). The pulmonary effects of SARS likely explain the high incidence of ventilatory failure in these patients,⁸ as well as the subsequent radiologic findings. Pathogenesis of the disease appears to be amplified in older persons and in those with conditions such as diabetes mellitus, chronic obstructive pulmonary disease, cancer, or heart disease.

Clinical features

The incubation period for SARS is 2 to 10 days and sometimes as long as 14 days. Infections typically occur in adults aged 25 to 70 years who were previously well, with very few cases in those younger than 15 years.⁹

Patient presentation The clinical features of SARS are highly nonspecific, and the disease can mimic any atypical lower respiratory tract infection. Most commonly, patients present with fever higher than 38¼C (100.4¼F); chills, rigors, or both; and myalgia and malaise, although other prodromal symptoms have also been noted (see Table 1).^9-11 Initial very high fever with chills and rigors may represent increased viremia in the host.

Respiratory phase Approximately 3 to 7 days after the typical febrile prodrome, patients progress to a respiratory phase during which significant hypoxemia may develop. In older patients, this initial febrile period may be absent or markedly attenuated. Hypoxemia may be so profound and refractory to increasing concentrations of supplemental oxygen that 10% to 20% of patients may require mechanical ventilation.⁹

Clinicians, especially respiratory therapists, anesthesiologists, PAs, and nurses, should be extremely careful to observe infection control policies and procedures with patients who have SARS, particularly if intubation is required. During intubation, aerosolization of the pathogen is a particular risk, and infectivity can increase significantly for all personnel (see Table 2).

Physical findings Physical findings in SARS may be subtle and can include fever, basilar crackles, and signs of pulmonary consolidation. Other features include chills, rigors, myalgia, malaise, dry cough, headache, and dyspnea. Less frequently, patients may also present with nonspecific findings such as sputum production, rhinorrhea, nausea, vomiting, and diarrhea.¹² Erythematous rash has been reported in some patients. The nonspecific clinical findings in SARS present a clear diagnostic dilemma—particularly during flu season, when SARS may be assumed to be influenza.

Diagnosis At the time of this writing, no readily available rapid diagnostic test exists to detect SARS. It remains a diagnosis of exclusion, although some findings strongly suggest the syndrome. Clinicians must take a detailed travel and potential exposure history from patients, as these are necessary components of the case definition (see Table 3).¹¹ The clinical presentation and the contact history must remain the cornerstones of SARS diagnosis, regardless of available laboratory investigations.¹³

Imaging and laboratory studies

Radiographic evaluation that includes anteroposterior and lateral films should be performed in every patient suspected of having SARS. Up to 25% of patients may have normal radiographic evaluation at the time of presentation.¹⁴

Radiologic features have been stratified into early stage and advanced findings. During the early stage of the disease, peripheral/pleural-based opacifications may be seen with variants to a ground-glass appearance of frank consolidation. In advanced stages, patients may have widespread opacification that may involve multiple areas unilaterally or bilaterally. This later stage closely resembles, and may be indistinguishable from, ARDS. Interestingly, calcification, cavitation, pleural effusion, and lymphadenopathy have not been noted in patients with SARS.¹⁵

When reviewing films, clinicians should carefully examine the paraspinal region directly behind the heart. This is necessary because high-resolution CT (HRCT) performed later in these patients has revealed missed abnormalities in this region. Patients with suspected SARS who have negative chest radiograph findings should undergo further diagnostic workup with HRCT. Findings of note are solitary or multiple areas of pulmonary involvement, ground-glass opacification with thickening of interstitial or intrastitial pulmonary components, and consolidation.

Laboratory and other tests in patients with SARS should include pulse oximetry, blood cultures, sputum Gram’s stain and culture, CBC with differential, and a clotting profile. Electrolytes, liver function, C-reactive protein (CRP), creatine kinase, and lactic dehydrogenase (LDH) should also be measured. Blood cultures and Gram’s stain and cultures rule out other causes of atypical pneumonia. Electrolyte analysis may reveal numerous abnormalities, such as hypokalemia, hyponatremia, hypophosphatemia, hypocalcemia, and hypomagnesemia. Serum transaminase levels may be markedly elevated. The CRP level may be maximally elevated—a further manifestation of an immune-mediated response to the virus. Elevation of LDH levels has been observed in many patients and is recognized as one of the predictors of serious outcome in patients infected with SARS-CoV.^16,17 The CBC may reveal numerous abnormalities, the most common of which are lymphopenia, neutrophilia, thrombocytopenia, and reactive thrombocytosis.¹⁷

SARS-CoV can be identified through electron microscopy, enzyme immunoassay, indirect fluorescent-antibody testing, and RT-PCR testing. Samples should be submitted to state or local public health laboratories. The CDC recommends that a consent form be obtained from the patient before specimen submission, but laboratory testing will be performed without consent if needed because of the significant public health concern. Submission of serum, pulmonary secretions, or stool is necessary for virus identification. Specimens should be clearly labeled, laboratory personnel should be apprised of the preliminary diagnosis, and all clinical personnel who handle the specimen should adhere to strict safety guidelines. To date, positive results on tests to identify SARS-CoV have been strongly associated with the need for mechanical ventilation and with death.¹⁸

Treatment

Various drugs have been used to treat patients with SARS, but no specific cure has been found. Clinicians have empirically utilized antibiotic combinations aimed at providing coverage against atypical pneumonia organisms but without proven efficacy. Some anecdotal reports have cited improvement in patients who received oral and IV ribavirin, oseltamivir, and corticosteroids, but rigorous study has not proven these agents to be efficacious.

Ribavirin has been associated with the development of dose-dependent hemolytic anemia and a bone marrow suppression-mediated drop in hemoglobin values of up to 20 g/L, although both are reversible when the drug is discontinued.^17,19 This drop in hemoglobin can adversely affect patient management, particularly when hypoxemia is severe. Furthermore, ribavirin use has been associated with nausea, headaches, and occasional worsening of bronchospasm in patients and health care providers. The utilization of intravenous ribavirin in the United States requires phoning the CDC Emergency Operations Center at (770) 488-7100. The CDC has restricted ribavirin use by protocol, and to date no patient in the United States has been treated using this protocol. Serious concern still exists regarding ribavirin’s unproven efficacy and serious side effects.²⁰ These concerns should be addressed through controlled clinical trials if future SARS outbreaks occur.

Corticosteroids have been tried in an attempt to modulate the immune-mediated inflammatory response that probably underlies the worsening pulmonary picture in SARS. Their use has been called into question, as this is not a recognized standard of care in similar diffuse alveolar injury disease such as ARDS.²¹ Utilization of corticosteroids in patients with SARS appears even more questionable when animal parallels are studied. Some researchers have actually identified a worsening of coronavirus infections in cows, with prolongation of the viral shedding phase, when dexamethasone is administered.²²

In the search for other treatment options, researchers have tried interferon beta, either alone or as part of a multi-antiviral-drug approach.²³ Combination therapies incorporating traditional Chinese medicine along with western medical interventions have also been studied. Though this area needs further work, initial analysis of these integrated therapies has revealed positive effects on lung infiltrate absorption in patients with SARS.²⁴

Complications Complications in patients with SARS should be addressed promptly. Hypoxemia is treated initially with supplemental oxygen. Intubation with mechanical ventilation and positive end-expiratory pressure (PEEP) is instituted if hypoxemia becomes refractory. Whenever purulent or copious pulmonary secretions develop, the clinician should attempt to identify any secondary infections and provide appropriate antibiotic coverage.

Conclusion

The SARS virus rapidly emerged as the first new pathogen of the 21st century and quickly developed into a worldwide pandemic. SARS has been compared to the influenza pandemic of 1918, but there are some significant differences between the two illnesses. The 1918 influenza pandemic had an associated mortality of 2.5%, while SARS, thus far, has produced a significantly higher case fatality ratio of 9.6%. Influenza is readily transmitted from person to person, while transmission of SARS appears to require the type of close continued contact that places health care workers and close contacts of infected persons at greatest risk. And older patients seemed to be at the greatest risk of dying from SARS, while the 1918 influenza virus killed nearly 50% of the young, healthy adults it infected.

The risk it poses to health care workers should make all providers exceedingly vigilant for SARS because they will be caring for patients during times when SARS may be most prevalent. Coronaviruses cause disease primarily in the winter months.⁵ With this knowledge at hand, providers must include SARS in the differential diagnosis of patients with atypical lower respiratory tract disease.

Now is not the time to let our guard down, as SARS may emerge in a new wave of cases around the globe. Rigorous isolation of infected patients and quarantine of exposed but asymptomatic contacts brought SARS under control the first time. Even so, many of the infected were health care workers, demonstrating the need for renewed emphasis on personal protective equipment and its correct use.²⁵ Only through collaboration and utilization of all available resources will we be able to contain another outbreak should it arise.²⁶   •

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