Continuing Education Activity

A new and rapidly progressive respiratory syndrome termed severe acute respiratory syndrome (SARS) was identified by the World Health Organization (WHO) in the Guangdong province of China as a global threat in March of 2003. SARS went on to spread globally over the following months to over 30 countries and became the first pandemic of the 21st century. This activity reviews the evaluation and management of severe acute respiratory syndrome (SARS) and highlights the role of the interprofessional team in evaluating and managing patients suspected of or with SARS.

Objectives:

• Review the etiology of the severe acute respiratory syndrome.
• Outline the appropriate evaluation of severe acute respiratory syndrome.
• Describe the management options available for the severe acute respiratory syndrome.
• Review the importance of improving care coordination among the interprofessional teams to improve outcomes for patients affected by severe acute respiratory syndrome as well as their communities.

Introduction

A new and rapidly progressive respiratory syndrome termed severe acute respiratory syndrome (SARS) was identified by the World health organization (WHO) in the Guangdong province of China as a global threat in March of 2003. SARS went on to spread globally over the following months to over 30 countries and became the 1st pandemic of the 21st century. It showed that the dissemination of an infectious microbe could be drastically increased in the era of globalization and increased international travel. The decade preceding the SARS outbreak featured the emergence of multiple novel pathogens, including H5N1 influenza, Hantavirus, Nipah virus, and Avian flu. However, SARS was unique among these as it had the ability for efficient person-to-person transmission.[1] By the end of the outbreak in July 2003, 8096 cases were reported leading to 774 deaths with a case fatality rate of over 9.6%.[2][3] SARS showed a unique predilection for healthcare workers, with 21% of cases occurring in these individuals.[4]

The WHO, along with its international partners, including the centers for disease control and prevention (CDC), was able to identify within two weeks the etiologic agent.[5][6] The agent was a novel coronavirus and was given the name SARS coronavirus (SARS-CoV). It was isolated in a number of SARS patients and suspected as the causative agent before ultimately being sequenced and fulfilling Koch postulates confirming it as the cause.[7]

The number of secondary cases produced by one SARS patient is thought to be in the range of two to four though a few patients, including the original index case, were suspected to be “super-spreaders” spreading to up to hundreds of others. The mode of transmission for the virus was largely through respiratory inhalation of droplets. Treatment was primarily supportive, and no specific anti-virals were effective. Since mid-2004, no new cases of SARS have been reported. Until the recent COVID-19 pandemic, the global reach of SARS had been matched only by the 2009 H1N1 Influenza pandemic.[8] Lessons learned from the SARS pandemic are currently used as a blueprint to fight the pandemic of COVID19.

Etiology

The SARS coronavirus (SARS-CoV) was established as the cause of severe acute respiratory syndrome (SARS) after fulfilling all of Koch postulates.[7] SARS-CoV was demonstrated in respiratory secretions of SARS patients by techniques including reverse-transcriptase polymerase chain reaction (RT-PCR) as well as in samples of urine, feces, and lung biopsy specimens.[7] Experimental infection of the virus in macaques produced a similar respiratory syndrome to SARS in humans, which other pathogens detected in SARS patients did not. Coronaviruses are named for their crown-like glycoprotein spikes on their surface. Coronaviruses are large single-stranded RNA viruses that have helical nucleocapsids.[7] They are usually associated with humans with the common cold, though, and in animals, they’re linked with a highly virulent disease.[7] SARS-CoV is thought to have jumped from an animal reservoir in the horseshoe bat through an intermediate host in the palm civet and then to humans.

Epidemiology

The first severe acute respiratory syndrome (SARS) cases were noted in the Guangdong province of China in November 2002 as an outbreak of atypical, acute community-acquired pneumonia cases.[7] The first cases were found in animal handlers who had contact with wild game food animals, including the palm civet, which was ultimately attributed as the intermediate host of the virus.[7] The illness then spread to Hong Kong with the index patient felt to be a provider who traveled there five days after onset of symptoms and who was likely a super-spreader of the virus.[7] Excluding super-spreader patients, the virus has a reproduction number or Rof 2-4.[7]

The illness spread rapidly from the Guangdong province and Hong Kong globally to over 30 countries in Asia, Europe, and North America.[7] China had the majority of cases (83%), while in the United States, there were only 27 probable cases identified and no noted deaths or secondary cases.[7] The outbreak in total led to 8096 cases, with 774 deaths attributed.[9] Higher mortality was associated with older age, with a mortality rate as high as 43% in patients over 60.[9] SARS mostly affected adults. Children were affected though in lesser numbers and with similar or milder presentations, and no deaths reported.[7] Of note, with regards to COVID-19, similar to SARS and Middle East respiratory syndrome (MERS), adults are affected more severely, and children are relatively spared.[10] Health care facilities were affected greatly and played a large role in amplifying transmission. Health care workers accounted for 21% of cases.[9] By July of 2003, no new cases were reported worldwide, leading the WHO to lift a travel advisory it had placed and to declare the end of the pandemic. Since the middle of 2004, no cases of SARS have been reported.[9] Of note, there was a brief reemergence of the virus at the end of 2003 into the beginning of 2004 from accidental lab exposure.[7]

SARS-CoV, like many other respiratory viruses, is transmitted predominantly person to person by face-to-face contact suggesting a droplet spread mechanism though also by direct contact with fomites or contaminated secretions.[9][7][4] After transmission, the incubation period is typically 2 to 7 days, with 95% of patients developing symptoms by day 10.[9][4] Fecal-oral, as well as airborne spread mechanisms, have also been speculated and may occur.[4] Peak viral shedding occurs in respiratory secretions 6 to 11 days after symptom onset.[9]

Pathophysiology

The SARS coronavirus (SARS-CoV) uses the angiotensin-converting enzyme 2 (ACE2) receptor for entry into its host.[4] SARS-CoV recognizes the host ACE2 receptor through the virus's receptor-binding domain. Mutation in this domain may allow this and other coronaviruses to cause new and increased cross-species infections.[11] The virus concentrates in the lungs and small bowel, which are areas with a high density of its receptors.[4] Specifically, the alveolar epithelium shows the highest focus of infection.[4] The infection leads to serous pleural effusions, pulmonary edema, and consolidations with relative sparing of the upper respiratory tract.[4] The lung injury is thought to be due to an out-of-control immune response by the host leading to excess quantities of pro-inflammatory cytokines.[4][12] Some patients will develop bacterial (i.e., Staphylococcus aureus, Strenotrophomonas maltophilia), viral, or fungal (i.e., Aspergillus, Candida) superinfections.[4] The histopathology features, which have been found during postmortem and may not be representative of all SARS cases, show epithelial cell proliferation, diffuse alveolar damage, and macrophage infiltration of the lung.[4]

History and Physical

The typical clinical presentation of the severe acute respiratory syndrome (SARS) includes fever, myalgia, cough, fatigue, and headache, with fever being the most common symptom.[7][4] SARS is unique among viral respiratory diseases in that it has a longer prodromal phase of 2 to 14 days, in which most patients have no respiratory symptoms.[7] At the end of the prodromal phase, the respiratory phase begins with typically a dry cough followed potentially by shortness of breath progressing to acute respiratory failure.[7] Productive cough and coryza are uncommon.[4] About 20% of patients present with diarrhea in one study.[7] The majority of patients (70%) develop shortness of breath, and while 30% of patients will improve within one week, many patients are ill into a second week. In severe cases, a wave of deterioration is seen towards the end of the second week.[7][4] When a death occurs in SARS, it usually occurs late in the course and is often attributed to adult respiratory distress syndrome (ARDS), secondary infections, septic shock, and thromboembolic complications.[7]

Evaluation

The case definition of the severe acute respiratory syndrome (SARS) is defined by both the WHO and the CDC. A case of SARS occurs in a person with laboratory confirmation of infection who meets the clinical criteria or who has worked in a lab with live SARS coronavirus. The clinical criteria include fever or a history of fever along with one or more symptoms of lower respiratory tract illness such as cough, shortness of breath, difficulty breathing and radiographic findings of pneumonia or acute respiratory distress syndrome (ARDS) or an autopsy finding of pneumonia or ARDS without an identifiable cause and no alternative explanation of the illness.[7] Laboratory diagnosis of SARS is confirmed if there are two samples obtained from two different sites or two samples from one site obtained at two different times, showing the presence of a virus by an assay for viral RNA using reverse transcriptase PCR.

When SARS is suspected in a patient, diagnostic workup should include complete blood count with differential, chest x-ray, pulse oximetry, blood cultures, Gram stain, and culture of sputum, Legionella, and Pneumococcal antigen testing as well as viral respiratory pathogen panels. Additionally, the samples for specific SARS-CoV testing should be performed in coordination with the local health department and the CDC or WHO.[7] SARS-CoV testing for diagnosis should be done via PCR from samples obtained from at least two sites and as early in the illness as possible and then repeated five to seven days later if symptoms continue. Serum antibody titers by ELISA is the most sensitive available test; however, seroconversion can take weeks to develop making it less useful for diagnosis at the time of care.[7]

Laboratory findings vary with the most common identified abnormalities being low total lymphocytes, elevated serum lactate dehydrogenase (LDH), and alanine aminotransferase (ALT) levels.[7] Elevated D-dimer and a mild increase in activated partial thromboplastin time activation have been noted.[7] Additionally, thrombocytopenia was noted typically as the respiratory phase of the illness was peaking.[7][4]

Radiographic findings are similar to other causes of viral pneumonia and may appear normal during the prodromal phase.[7][4] Chest imaging with radiographs shows patterns ranging from normal in appearance to peripheral infiltrates (typically in middle to lower lung fields) to diffuse interstitial infiltrates.[7][4] At illness onset, about 20% of patients will have a normal chest x-ray, so this is not adequate as criteria for exclusion.[7] Chest imaging by computed tomographic (CT) scanning showed additionally parenchymal abnormalities as well as ground-glass infiltrates, typically peripherally.[7]

Treatment / Management

There is no specific treatment for the severe acute respiratory syndrome (SARS), and supportive care is emphasized. To date, no antiviral agents have been found to be beneficial, nor were glucocorticoids shown to have a beneficial effect.[7] There are potential agents for use against SARS. Lopinavir-ritonavir has shown some activity though in vitro only thus far.[7] Additionally, the experimental agent for Ebola, remdesivir, has shown activity against both SARS and MERS coronaviruses.[6] Multiple vaccines have been attempted against SARS-CoV and other coronaviruses, often targeting the spike glycoprotein, with none being recommended at this time.[13] Patients should not be admitted solely for infection control reasons unless home infection control measures are impossible.[7]

Once suspected of SARS, the patient needs to be quickly identified and placed in isolation with appropriate infection control measures in place to avoid transmission. Triage using a set of clinical criteria and epidemiologic criteria should be in place to allow the rapid identification of suspected patients. Infection control precautions include contact precautions (gloves, gowns, and eye protection), droplet precautions (additionally a private room and limit movements), as well as airborne precautions (N-95 respirators and negative pressure isolation room).[7] If N95 respirators are not available, then a surgical mask should be worn.[7] Consistently wearing a surgical mask or N95 respirator was shown to be protective for nurses working in two Toronto critical care units.[7] Consistent use of eye protection, gloves, and gowns was associated with the reduced transmission of infection.[7] Precautions are especially important during high-risk patient care procedures such as endotracheal intubation, mechanical ventilation, nebulizer therapy, and suctioning.[7]

Differential Diagnosis

Other infectious causes of community-acquired pneumonia and ARDS must be considered as differentials of the severe acute respiratory syndrome (SARS).

• The bacterial causes include Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenza
• Viral causes include influenza, parainfluenza, respiratory syncytial virus, varicella, and hantavirus

Prognosis

Prognostic features identified by epidemiologic studies for poor outcomes include diabetes, chronic hepatitis B and other underlying comorbid conditions, older age, non-typical presentation, and an elevated serum lactate dehydrogenase (LDH) at the time of admission.[7] Diabetes mellitus and heart disease are especially notable among comorbid conditions as prognostic factors for a worse outcome.[7] A high viral load at presentation has also been independently associated with a worse prognosis.[7] Age is a very important prognostic factor. Patients older than 65 show the highest rates of mortality, exceeding 50%.[7] Children less than 12 years of age generally have uneventful courses and good outcomes.[7]

Complications

Severe acute respiratory syndrome (SARS) caused many pulmonary and extrapulmonary complications. These include:

• Spontaneous pneumomediastinum was reported in about 12% of cases in one study[7]
• Renal and hepatic impairment
• Leukopenia, thrombocytopenia
• Diastolic cardiac dysfunction
• Pulmonary hypertension
• Neurologic disorders
• Rhabdomyolysis[7]
• Nosocomial infections, including bacteremia, catheter-related sepsis, and pneumonia[7]
• Corticosteroid treatment was trialed in the early phase of the SARS epidemic before proving not to be beneficial. Complications of prolonged high-dose corticosteroid therapy such as avascular necrosis and disseminated fungal infection were identified in SARS patients on these therapies.[7]

Deterrence and Patient Education

While prevention modalities such as effective antiviral therapy, vaccines, monoclonal antibodies, or natural immunity are lacking, the public health measures of rapid case identification and containment are of the utmost importance. The fact that patients during the prodromal phase of the severe acute respiratory syndrome (SARS) have lower contagiousness allows the application of containment precautions once they become symptomatic to be effective in containing transmission.

Control of the disease relies on early identification of suspect cases, isolation, and strict infection control measures. SARS-CoV may also spread by the fecal-oral route as evidenced by the outbreak in the Amoy Gardens building in Hong Kong. Therefore, in addition to respiratory secretions, fecal material and urine should be considered infectious materials. SARS-CoV can remain viable on surfaces for several days.[7]

Enhancing Healthcare Team Outcomes

Knowledge of severe acute respiratory syndrome (SARS) by the interprofessional team members should help in the early detection as well as proper management of the disease should it recur. Moreover, this knowledge can be applied not just to a recurrence of SARS-CoV but to any other novel coronavirus, such as we are currently seeing with SARS-CoV2 or other infectious pandemics. This knowledge should enhance patient care, improve outcomes for patients as well as safety for healthcare workers, and improve performance throughout the healthcare team. This is of increased importance in a disease such as SARS, given that 1 in 5 cases was seen in healthcare workers, and healthcare centers were major amplifiers of the disease. Additionally, in the case of pandemics, the healthcare team extends from the frontline clinical workers to health departments, research laboratories, internal health organizations, and governments. Knowledge and coordination are important across all of these organizations and their team members.

Research during the years following the SARS pandemic revealed the existence of many different coronaviruses circulating in bats and other animals, suggesting that the emergence of another coronavirus into humans was not just possible but inevitable.[14] The lessons from SARS may prove invaluable in the management of these diseases. More than 10 years before the SARS outbreak, the Institute of Medicine (IOM) released a report on the risks of emerging microbial diseases and outlining factors they felt increased the threat in this global era we live in as well as steps they felt that could address them.[15] The report emphasized the need for increased surveillance and response capacity, things which proved of paramount importance in the management of the SARS outbreak. These factors and the entirety of SARS knowledge will be of the utmost importance in the battle against SARS-CoV2, which as of May 27, 2021, had already killed more people than SARS and MERS combined despite having a lower case fatality rate of 2%.[16]