Special Articles

Indian Pediatrics 2003; 40:645-651

Severe Acute Respiratory Syndrome: Providing Care While Minimizing Personal Risks

Niranjan Kissoon

Division of Pediatric Critical Care Medicine, University of Florida HSC/Jacksonville, Jackson-ville, Florida, USA.

Correspondence to: Dr. Niranjan Kissoon, Chief, Division of Pediatric Critical Care Medicine Univer-sity of Florida HSC/Jacksonville, 820 Prudential Drive, Suite 203, Howard Building, Jacksonville, FL 32207, USA.
E-mail: niranjan.kissoon@jax.ufl.edu

Abstract:

Severe acute respiratory syndrome (SARS) poses a threat to most countries because of easy and convenient travel across the globe in a matter of hours. SARS is a recently recognized infectious disease that may lead to death and severe pulmonary sequelae. It presents with non-specific signs and symptoms and because no definitive laboratory test is readily available, it poses a great risk to healthcare workers because quarantine of affected individuals may not occur early in its presentation. Healthcare workers should consider the diagnosis and institute prompt and thorough protective measures in suspected cases.

Key words: Severe acute respiratory syndrome, SARS, epidemic, respiratory, severe infection

Severe acute respiratory syndrome (SARS) is a new disease, which causes severe morbidity and mortality. Much is unknown about the true nature and long term effects of SARS. There is more likely widespread infection in the community, and the cases reported may represent the tip of the iceberg. In addition, the symptoms are non-specific and new findings indicate that respiratory symptoms and fever may not be common early in the illness as previously thought(1). The protean manifestations of the disease and the lack of a convenient diagnostic test confers risk to healthcare workers.

SARS has created international anxiety because of its novelty, communicability and the fear of a global pandemic (2). What should be of concern to healthcare workers is the fact that it has caused illness in large numbers of exposed medical and nursing personnel. The elegant detailed description of contacts in Toronto (3,4) and Hong Kong (5,6) all point to the high risk to medical personnel. In fact, in Vietnam after the index patient, all 38 infected individuals were members of the hospital staff(7). As the epidemic has unfurled worldwide it is apparent that at least half of those affected have been healthcare workers who were exposed during the course of their duty. While most have survived SARS, healthcare workers across the globe have died from SARS. In fact, Dr. Carlos Urbani of the World Health Organization (WHO) who first raised the alarm for SARS was one of its early victims(8).

There are reasons for optimism in that we may soon be able to diagnose SARS early with certainty. The etiological agent, SARS associated coronavirus, has been identified(9-11). It has satisfied all six criteria (Koch’s postulate as modified by Rivers) required to establish a virus as a cause of disease. However, while it is considered the primary etiological agent of SARS, this does not exclude the possibility of other pathogens including human metapneumovirus and chlamydia pneumoniae as other agents that may have exacerbated the disease in some SARS patients(12).

What is also remarkable is how the international community has banded together to attack SARS(13). The global response by the medical community including the WHO, led multi-center collaborative network of laboratories have led to testing for SARS coronavirus at unprecedented speed(14). Interestingly, research laboratories that are normally staunch competitors are working around the clock and are freely sharing information despite the fact that none will be the sole beneficiary of any success. With this level of cooperation from individual institu-tions to global institutions it is not surprising that progress is occurring at a geometric clip(15).

Case Definition

Because a definitive laboratory test is not yet widely available, it is important to recognize the clinical symptoms of SARS such that suspected individuals will be recognized and treated appropriately. The Center for Disease Control (CDC)(16) has established the following case definition: a fever (temperature >38ºC); a chest radiograph (a plain radiograph, a computed tomographic (CT) image of the thorax showing evidence of consolidation with or without respiratory symptoms (e.g., cough and shortness of breath); and a history of exposure to an index patient suspected to have SARS or direct contact with a person who became ill after exposure to an index patient. The WHO has a similar definition in that a suspected case of SARS is an individual with a fever (temperature >38ºC or 104ºF), cough with dyspnea, and contact with an individual believed to have SARS or having traveled to the region where there has been documented transmission of the disease. A probable case is an individual meeting criteria for a suspected case along with radiographic features of pneumonia, respiratory distress syndrome or an unexplained respiratory illness resulting in death with autopsy results demonstrating pathology of respiratory distress syndrome without an identifiable cause(17). A new screening clinic in Hong Kong however, has just reported that the negative predictive value of WHO guidelines for identifying or predicting SARS early in the illness was 85% with an associated sensitivity of 26%(1). New tests to identify SARS patients at the earliest stages of the disease are expected to be widely available soon(18). These tests will guide quarantine decisions and other public health measures to limit the spread of infection.

Clinical Features

The mean incubation period of the disease is estimated to be 64 days with the time from onset of clinical symptoms to hospital admission being 3-5 days, with longer times earlier in the epidemic(19) The clinical features of the disease in adults (including healthcare workers) are similar in all areas of the world(3-6,13). The most common symptoms include fever, chills, rigors, myalgia, cough, headache, dyspnea, and hypoxemia. Physical examination usually reveals crepitations on chest examination. These signs and symptoms are nonspecific and similar to those of an atypical pneumonia. However, a temperature of >38ºC, cough, shortness of breath and difficulty in breathing may not be prominent features in the early pre-hospital stages of SARS(1). Laboratory investigations that may differentiate SARS from atypical pneumonia include lympho-penia, elevated lactate dehydrogenase, and creatinine phosphokinase, and thrombo-cytopenia(13). Serial chest radiographs and high resolution CT scans of the chest usually demonstrate unilateral or bilateral infiltrates that are usually distributed in the peripheral segments of the lung(20).

In children, nonspecific symptoms including fever, cough, malaise, and loss of appetite are the most prominent symptoms (21,22). Dyspnea, tachypnea, and findings such as lung crepitations are uncommon. Despite radiographic changes in all children during the illness, 20/21 children in one report had a normal chest examination as compared to most adults who had inspiratory crackles at the bases(6,21).

Protective Measures

It is clear that hospitals and healthcare workers are particularly at risk from SARS. In fact, in Hong Kong in the first week of the outbreak, 25% of the patients with SARS were healthcare workers(6). In Toronto, Canada, about 50% of cases were in healthcare workers with several cases among protected workers(23). Protection of healthcare workers is difficult because screening potential cases of SARS is difficult as the signs and symptoms are vague and consistent with many viral illnesses. Follow-up of patients over a number of days is the only way to ascertain whether they have SARS.

Patients suspected of having SARS should be isolated with the use of negative pressure rooms when feasible and infection control measures should also include the use of N95 mask, gloves, disposable gowns and eye protectors. These measures have been shown to limit the spread.(24). Careful attention to hand washing or hand disinfection with an alcohol based product after removal of gloves is necessary. Cohorting of exposed health care workers should be attempted in order to minimize the number of persons who are exposed and the numbers of visitors be limited as much as possible. In addition, liberal use of disinfectants commonly used in hospitals such as quaternary ammonium-based, phenol-based and alcohol-based products are highly active against coronavirus and should be used.

Whether all suspected cases of SARS should be admitted to hospital is an issue. This is important that if a suspected case is admitted to the hospital, they may actually contact the disease in-hospital, while if they are discharged they may infect their family and friends. It would seem that secondary spread among suspected cases followed at home with strict quarantine is low(25). However, all patients with confirmed SARS should be admitted to the hospital. Guidelines for screening high risk contact and low risk non-contact subjects have recently been published although the utility and usefulness of these guidelines is not yet established(26).

SARS has fundamentally changed, inter-action between primary healthcare workers in much the same way that AIDS changed the way handled blood products with universal precautions to protect us from potential HIV infection. It is likely that in the future all healthcare providers in regions where SARS is endemic will use the standard droplet precautions of masks, goggles, gloves, and gowns for all patient contact. With effective infection control techniques, a specific diagnostic test for SARS associated coronavirus and concentrated efforts to develop effective therapies and vaccine; there is reason for optimism.

It may be possible to protect healthcare workers and others in high-risk areas by vaccination using live attenuated virus vaccines. This vaccine will need to be used prophylactically because of the short incubation period of SARS and would be unlikely to prevent disease after exposure to a SARS patient(18).

Laboratory Investigations

Because the differential diagnosis of SARS would involve cases of atypical pneumonia, specimens to rule out causes of atypical pneumonia should be obtained. Studies should include nasopharyngeal aspirate to be screened for common viruses including influenza A and B, respiratory syncytial virus, adenovirus, and parainfluenza virus types I, II and III using immuno-flourescence assays. In addition, when available, viral cultures using various cell lines such as Hep II, human embryonic lung fibroblasts and Vero cells should be done. Reverse transcriptase-polymerase chain reaction (RT-PCR) assays for influenza A and B, and respiratory syncytial virus may be used in some instances. Levels of anti-coronavirus IgG antibodies from saved serum samples can be measured using immunoflourescence assay based on Vero cells infected with coronavirus. Sputum and blood cultures should also be performed to complete microbiological workup. In addition, PCR assays for micro-plasma and chlamydia pneumoniae as well as legionella urinary antigen may be helpful. An idea of the specimens needed for SARS may be obtained from the CDC web page http://www.cdc.gov/ncidod/sars/casedefinition. htm.

Initial investigations should also include a complete blood count with a differential count, clotting profile, prothrombin time, activated thromboplastin time, international normalized ratio, d-dimer, and serum biochemical measurements (including electrolytes, renal and liver function tests, creatinine kinase and lactate dehydrogenase). It is also recommended that the blood tests outlined above and chest radiography be performed daily until fever has subsided for three days (6).

Treatment

There are no randomized clinical trials comparing treatment regimes in SARS. In Hong Kong, a standard protocol was followed(13). Initial treatment would include supplemental oxygen for hypoxemia as well as antibacterial agents for community-acquired pneumonia. Lee and colleagues used cefotaxime and clarithromycin (or levo-floxacin) to target common pathogens causing community acquired pneumonia based on current recommendations(27,28). The treat-ment for viral pathogens is empirical and may include a neuraminidase inhibitor such as Oseltamivir for treatment of influenza A and B. Oral or intravenous ribavirin as well as corticosteroid therapy has been given as a combined regimen(3-6). This combination is usually given for severe disease as evidenced by extensive or bilateral chest radiographic involvement, persistent chest radiographic involvement or high fever for two days, clinical radiographic findings suggestive of worsening or oxygen saturation of <95% in room air(13).

There has been some reservation with the use of ribavirin in that it has been associated with significant toxicity(4). Forty-nine per cent of patients in this Toronto study experienced a decrease in hemoglobin level of at least 2 g/dL after ribavirin was initiated. This was most commonly due to hemolysis as well as an inability to mount an adequate reticulocyte response. Patients also had elevations of transaminases (a 1.5 fold rise in aspartate or alanine transferase), while bradycardia and sore throat were also reported. These toxicities led to premature discontinuation of ribavirin in 18% of patients(4). Healthcare Canada recently stated that it would no longer provide access to ribavirin for the treatment of SARS because of the concern of side effects and lack of in vitro efficacy(29).

A rationale for the use of corticosteroids derives from the pathological findings suggestive of cytokine dysregulation and induction of inflammatory mediators with diffuse alveolar damage. Lee and colleagues reported CT studies showing ground glass opacities in the lung peripheries similar to that seen in bronchiolitis obliterans organizing pneumonia where corticosteroids have been used with some success(30). At the present time it would seem that most clinicians are favoring the use of corticosteroids in the treatment of SARS. However, there has been recent discussion in the media by a number of experts from the Centers for Disease Control and the National Institutes of Health about "relapse" of SARS. One current theory is that these cases have originated in Hong Kong where corticosteroids are used in the treatment of some cases. The risk and benefits of corticosteroid use in this condition therefore is undetermined.

Mechanical ventilation should be instituted for respiratory failure using traditional criteria strategies that minimize stretch induced lung injury as presently suggested for acute respiratory distress syndrome is recommended. Experience using other therapies such as convalescent plasma is limited(31).

Outcome

Because of the limited experience with SARS, the natural history of the disease is not fully elucidated. Reports indicate that approximately 20-30% of patients would be admitted to the ICU of which half would require ventilation. The estimated case fatality rate is 13.2% for those < 60 years of age and 43% for those greater(19,32). SARS is associated with significant morbidity and mortality in patients with diabetes or other co-morbid conditions, which are likely to decrease their immune response(6). Pulmo-nary fibroses have been reportedly seen on thin section CT scans of the chest of adults following discharge(33).

Two reports in children reveal that they are likely to be asymptomatic or suffer from milder disease and less morbidity and mortality as compared to adults(21,22). This difference between children and adults is intriguing. Whether this is due to infection with a different strain of the virus in children is unlikely. What is more plausible is that the body’s response in children may be different from adults such that lung damage is less. This is supported by Dr. Fauci’s contention that the immunological and inflammatory response of the body could be contributors significantly to damage of the lungs(34). Another possible explanation for better outcomes in children is the fact that they were previously healthy while the adults who died from SARS had significant co-morbidities. No explanation is satisfactory because they do not fully explain why children >12 years of age do worse than those <12(21). However, children with SARS are likely to pose special problems, which has not been thoroughly investigated. Quarantine may be more difficult for children, especially young children who are ill. Their separation from parents and families could lead to severe psychological scars which may be more longstanding that the disease itself. Moreover, the death of parents with SARS is also likely to have a long-term adverse effect on children.

It is likely that the Indian subcontinent may be spared of the devastating effects of SARS. However, it is prudent to be vigilant and prepared to deal with an outbreak of SARS. This would entail remaining on high alert for possible cases, reviewing infection control procedures within the hospitals, developing an evidence based approach to screening and quarantine procedures for potential cases, and having contingency plans for possible increase in demand for hospital beds and utilization.