|Home HIV Medicine||Free Journals Free Books Free Amedeo|
170 pages, PDF, 1.7 MB
8. Clinical Presentation and Diagnosis
Christian Hoffmann, Bernd Sebastian Kamps
There is no single test that can be used to diagnose SARS with a reasonable degree of accuracy. Diagnosis, therefore, continues to rely on the clinical examination, supported by case definitions that include a travel history. The initial symptoms of SARS are non-specific, complicating the differential diagnosis. Some features of the history, physical examination, radiological and laboratory findings, however, should alert clinicians to the possible diagnosis of SARS, even when the contact history is unreliable. These features are described below.
The most common symptom in SARS patients is fever with a body temperature of > 38.0°C (100.4°F). Fever is therefore a main criteria in the current WHO case definition for suspected or probable SARS. However, fever may be absent during the early stages of the disease and in individuals with co-morbidities who may be impaired in their ability to mount a fever.
Fever is mostly associated with other symptoms including chills, rigors, headache, dizziness, malaise, and myalgia (CDC, Lee, Tsang, Peiris, Chan-Yeung, Donnelly, Booth). The frequency of these symptoms within different cohorts are shown in table 1. Thus, the initial symptoms may resemble those of other forms of "atypical pneumonia" which are usually caused by legionella, mycoplasma and chlamydia species.
Sputum production, sore throat, coryza, nausea, and vomiting are less common (Lee, Booth). Inspiratory crackles may be heard at the base of the lung. Wheezing is generally absent. Diarrhea only seemed to be a prominent symptom in the Amoy Gardens' outbreak in Hong Kong (Peiris 2003b). Within the other cohorts published to date, diarrhea was less frequent.
It is unknown to what degree asymptomatic infections can occur. A comprehensive description of the spectrum of the clinical illness of SARS is dependent on large serosurveys in populations to which the SARS virus has spread.
During the course of illness, abnormal hematological values are common. Early studies have shown lymphopenia and thrombocytopenia to be frequent in SARS patients (Tsang, Lee, Poutanen). There is now one study which analyzed the hematological changes during SARS in more detail (Wong R). Progressive lymphopenia was found in the peripheral blood of 153/157 (98 %) patients with SARS, reaching its lowest point in the second week. Lymphopenia was also shown in hemato-lymphoid organs at postmortem examination. The lymphocyte count commonly recovered in the third week, but about 30% of patients were still lymphopenic by the fifth week of SARS.
Most patients had reduced CD4 and CD8 T cell counts during the early phase of illness, with mean CD4 and CD8 T cell counts of 287 cells/µl (normal: 410 to 1590 cells/µl) and 242 cells/µl (normal: 62 to 559 cells/µl), respectively. Low CD4 and CD8 lymphocyte counts at presentation were associated with an adverse outcome in this study (Wong R).
Transient leucopenia was found in 64% of patients during their first week of illness. However, during the second and third week of illness, 61% developed leucocytosis. Neutrophilia (> 7.500/µl) developed in 82% of patients, possibly reflecting the wide use of corticosteroids.
In total, 55% of patients developed a self-limiting thrombocytopenia, possibly caused by an immune mechanism. With the exception of 2% of patients, the degree of thrombocytopenia was mild (platelet counts >50.000/µl), reaching a low point at the end of the first week. No patient had major bleeding or required platelet transfusion (Wong R).
Other Laboratory findings
Common electrolyte and biochemical abnormalities include elevated levels of lactate dehydrogenase (LDH), aspartate and alanine aminotransferases and creatine kinase (Lee, Tsang, Poutanen, Peiris, Booth; Table 2). Since high lactate dehydrogenase levels are often seen in association with tissue damage, some authors propose that this finding indicates extensive lung injury (Lee). However, it seems possible that elevated levels of lactate dehydrogenase and transaminases may be, at least partially, secondary to the hemolytic effect of ribavirin treatment (Booth). In a multivariate analysis, elevated LDH was an independent predictor for poor outcome in SARS patients (Lee).
A substantial proportion of patients demonstrate low calcium, phosphorus, magnesium, sodium and potassium levels (Lee, Peiris, Booth). These abnormalities tend to worsen during hospitalization. Again, it remains unclear whether these changes reflect the natural course of the infection or whether they are secondary to the effects of treatment with ribavirin or other agents that affect renal tubular function (Booth).
There is evidence that the clotting profile (prothrombin time, activated partial-thromboplastin time, international normalized ratio, and D-dimer) may be deranged in a substantial number of patients (Lee).
n.a. = not available.
Not recognized or misdiagnosed SARS patients, if not discovered within a reasonable lapse of time, may become sources for super-spreading events such as those reported from Hanoi, Singapore, Hong Kong, Toronto, and Taiwan (see also Chapter 3: Transmission and Chapter 4: Epidemiology).
There are several reports on atypical clinical presentations of SARS. Patients may present without fever, or with diarrhea but no pneumonia (Hon). Fisher et al. describe four patients with atypical presentations of disease who were later diagnosed with SARS, emphasizing the difficulties in identifying SARS without a reliable diagnostic test. On admission, the patients did not have the SARS-typical fever (>38º because of chronic co-morbidities (Table 3). This raises questions about the sensitivity of temperature monitoring as a screening tool. Only some time later, the patients became febrile with clinical and radiological deterioration, and eventually met the SARS criteria. However, the four patients all showed lymphopenia and raised serum concentrations of lactate dehydrogenase. These nonspecific abnormalities could alert doctors in affected areas to atypical presentations (Fisher).
Thus, atypical presentations of SARS are a threat to patients, staff, and visitors. The WHO case definition is a useful epidemiological device; however, it is no substitute for daily, thorough clinical, laboratory, and radiological assessment of patients with symptoms of SARS (Fisher).
* modified from Fisher et al.
Chest Radiographic Abnormalities
Imaging plays an important role in the diagnosis of SARS and monitoring of response to therapy. A predominant peripheral location, a progression pattern from unilateral focal air-space opacity to unilateral multifocal or bilateral involvement during treatment, and lack of cavitation, lymphadenopathy, and pleural effusion are the more distinctive radiographic findings (Wong 2003b).
At the onset of fever, 70-80 % of the patients have abnormal chest radiographs (Booth, Wong 2003b, Peiris 2003b). It should be noted that, in a substantial proportion of cases, chest radiographs may be normal during the febrile prodrome, as well as throughout the course of illness. In other cases, radiological evidence of pneumonic changes may precede the fever (Rainer), particularly in individuals with co-morbidities who may be impaired in their ability to mount a fever (Fisher 2003a).
Chest X-ray findings typically begin with a small, unilateral, patchy shadowing, and progress over 1-2 days to become bilateral and generalized, with interstitial or confluent infiltrates. Air-space opacities eventually develop during the course of the disease. In patients who deteriorate clinically, the air-space opacities may increase in size, extent, and severity (Tsang, Lee).
In the first large cohort from Hong Kong, 55 % of the patients had unilateral focal involvement and 45 % had either unilateral multi-focal or bilateral involvement at the onset of fever (Lee). Within a prospective cohort, initial involvement was confined to one lung zone in 49% and was multi-zonal in 21% of the patients (Peiris 2003b).
The initial radiographic changes may be indistinguishable from those associated with other causes of bronchopneumonia. The research group from Hong Kong suggested that chest radiographs might offer important diagnostic clues, in particular when, after approximately one week, unilateral, predominantly peripheral areas of consolidation progress to bilateral patchy consolidation, and when the extent of the lung opacities is correlated with the deterioration in respiratory function (Lee).
There seems to be a predominant involvement of the peripheral-zone. Pleural effusions, cavitation, and hilar lymphadenopathy are usually absent. Respiratory symptoms and positive auscultatory findings are disproportionally mild compared with the chest radiographic findings (Lee).
One large study focused on radiographic appearances and the pattern of progression (Wong 2003b). Within this cohort of 138 patients, four patterns of radiographic progression were recognized: type 1 (initial radiographic deterioration to a peak level, followed by radiographic improvement) in 70.3%, type 2 (fluctuating radiographic changes) in 17.4%, type 3 (static radiographic appearance) in 7.3%, and type 4 (progressive radiographic deterioration) in 5.1% of the patients. Findings during deterioration are compatible with the radiological features of acute respiratory distress syndrome.
The predominant abnormalities found on initial CT scans are areas of sub-pleural focal consolidation with air bronchograms and ground-glass opacities (Tsang). The lower lobes are preferentially affected, especially in the early stages. Patients with more advanced cases show a more bilateral involvement (Wong 2003a). The lesions tend to be peripheral and smaller in the less severely affected lungs, also suggesting an earlier stage of the disease. In patients with more advanced cases, there is involvement of the central, perihilar regions by larger (>3 cm) lesions. The majority of the lesions contained an area of ground-glass opacification with or without consolidation. Other findings include intralobular thickening, interlobular septal thickening, a crazy-paving pattern, and bronchiectasis (Wong 2003a). Obvious bronchial dilatation is generally not found (Lee).
Radiographically, SARS may be indistinguishable from other severe forms of pneumonia. It also shares CT features with other conditions that result in subpleural air-space disease, such as the pneumonia of bronchiolitis obliterans and acute interstitial pneumonia (Tsang).
Radiologists from the Prince of Wales Hospital, Hong Kong, recommend the following protocol for diagnostic imaging of suspected SARS patients (Wong 2003a):
Identifying hospitalized patients with SARS is difficult, especially when no epidemiological link has been recognized and the presentation of symptoms is non-specific. Patients with SARS might develop symptoms common to hospitalized patients (e.g., fever or prodromal symptoms of headache, malaise, and myalgia), and diagnostic testing to detect cases is limited (MMWR 52: 547-50). Unless specific laboratory tests (PCR, detection of SARS antibodies; see Chapter 7: Diagnostic Tests) confirm the initial suspicion of SARS infection, the diagnosis of SARS is based on the clinical findings of an atypical pneumonia not attributed to any other cause, as well as a history of exposure to a suspect or probable case of SARS, or to their respiratory secretions or other body fluids.
As mentioned above, during the early stages, SARS may be difficult to differentiate from other viral infections, especially when symptoms are unspecific (Rainer). The initial diagnostic testing for suspected SARS patients should include chest radiography, pulse oximetry, bacterial cultures of blood, sputum, and urine, serology for mycoplasma, chlamydia, influenza, parainfluenza, respiratory syncytial and adenoviruses, nasopharyngeal aspirates for viral cell cultures, and direct sputum smear for Pneumocystis jiroveci by silver stain. A specimen for Legionella and pneumococcal urinary antigen testing should also be considered (CDC, http://www.cdc.gov/ncidod/sars/diagnosis.htm).
The radiographic appearance of peripheral air-space opacities is indistinguishable from other causes of atypical pneumonia, such as Mycoplasma, Chlamydia, and Legionella, and overlaps with other types of viral pneumonia. The presence of an air-space opacity on chest radiographs has been helpful in the confirmation of the diagnosis (Wong 2003b).
Clinicians should save any available clinical specimens (respiratory, blood, and serum) for additional testing until a specific diagnosis is made. Acute and convalescent (greater than 21 days after the onset of symptoms) serum samples should be collected from each patient who meets the definition criteria for SARS. Specific instructions for collecting specimens from suspected SARS patients are available on the Internet: http://SARSreference.com/link.php?id=19
The incubation period of SARS is short. Two large studies consistently noted a median incubation period of six days (Lee, Booth). However, the time from exposure to the onset of symptoms may vary considerably, ranging from 2 to 16 days (Lee, Tsang). This may reflect biases in reporting, different routes of transmission, or varying doses of the virus (Donnelly). The WHO continues to conclude that the current best estimate of the maximum incubation period is 10 days (WHO Update 49).
The clinical course of SARS is highly variable, ranging from mild symptoms to a severe disease process with respiratory failure and death. Clinical deterioration combined with oxygen desaturation, requiring intensive care and ventilatory support, generally occurs 7 to 10 days after the onset of symptoms (Lee, Peiris). In severe cases, SARS is a fulminant disease, progressing from being "comfortable" to respiratory failure requiring intubation within less than 24 hours (Tsang, Fisher).
The first prospective study on the clinical course was published on May 24, 2003, in the Lancet (Peiris 2003b). This 24-day study included 75 adult patients from Hong Kong. The clinical course of SARS was remarkably uniform in this cohort, following a tri-phasic pattern in most cases:
In total, 32% of patients required intensive care at a mean of 11.0 days after onset of symptoms, among whom 79% had to be intubated at a mean of 12.9 days. The mean length of stay for 75 patients was 22.1 days, whereas for the 15 patients who developed ARDS, the mean length of stay was 26.8 days at the time of writing. In this cohort, the total mortality was 7%.
The two retrospective cohorts from Canada and Hong Kong demonstrated a comparable outcome (Booth, Lee). Within both cohorts, 20-23% of the patients were admitted to the intensive care unit, and 59-69% of these received mechanical ventilation. Mortality was lower in these studies, ranging from 3.6% (Lee) to 6.5% (Booth) within the first 21 days.
However, it should be mentioned that the WHO revised its initial estimates of the case fatality ratio of SARS on May 7 (WHO Update 49). The revision was based on an analysis of the latest data from Canada, China, Hong Kong SAR, Singapore, and Vietnam. On the basis of more detailed and complete data, and more reliable methods, the WHO estimates that the case fatality ratio of SARS ranges from 0% to 50% depending on the age group affected, with an overall estimate of case fatality of 14% to 15%. According to the WHO, estimates of the case fatality ratio range from 11% to 17% in Hong Kong, from 13% to 15% in Singapore, from 15% to 19% in Canada, and from 5% to 13% in China.
Several studies have demonstrated a number of risk factors for a poor outcome. In most studies, multivariate analysis revealed an older age and co-morbid conditions as being independent predictors (Table 4).
There is currently no information as to whether virulent mutants of SARS viruses are associated with fatal cases. Comparison of the genomes of SARS isolates from fatal versus milder cases will identify any virus mutations that may be associated with an increased virulence (Holmes).
In a small percentage of patients, various degrees of pulmonary fibrosis have been reported following recovery. The pathophysiological mechanism of this finding is unclear. It will be important to perform follow-up evaluation of these patients to determine the long-term repercussions of SARS.
Quantitative RT-PCR of nasopharyngeal aspirates have shown a peak viral load at day 10 and a decrease to admission levels at day 15 (Peiris 2003b).
The increasing viral load at the end of the first week of the disease suggests that the symptoms and signs (recurrent fever, diarrhea, worsening of radiographic findings) could be related to the effect of viral replication and cytolysis (Peiris 2003b).
However, further deterioration at the end of week 2, when some patients had severe clinical worsening, may not be related to uncontrolled viral replication, but may rather be caused by immunopathological damage (Peiris 2003b). This assumption is supported by the progressive decrease in rates of viral shedding from the nasopharynx, stool, and urine from day 10 to 21 after the onset of symptoms. In addition, nearly half the patients had shifting radiographic shadows. If viral-induced damage was the primary pathological mechanism, such a flitting pattern of radiological change is difficult to explain (Peiris 2003b).
Taken together, these findings suggest that the lung damage at this phase is related to immunopathological damage as a result of an over-exuberant host response, rather than uncontrolled viral replication (Peiris 2003b).
The histopathological examination of a lung biopsy specimen from a patient with SARS showed a mild interstitial inflammation with scattered alveolar pneumocytes showing cytomegaly, granular amphophilic cytoplasm, and enlarged nuclei with prominent nucleoli. No cells showed inclusions typical of herpes virus or adenovirus infection (Peiris 2003a).
Postmortem histopathological evaluations of lung tissue from patients who died from SARS showed diffuse alveolar damage at various levels of progression and severity, consistent with the pathologic manifestations of acute respiratory distress syndrome (Ksiazek, Tsang, Poutanen).
The changes included hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation of pneumocytes in alveolar spaces (Ksiazek, Nicholls). There were also scattered foci of alveolar myxoid fibroblastic tissue, a finding consistent with the early organizational phase of progressive pneumonia. Interalveolar septa were mildly thickened, with a mild mononuclear infiltrate (Tsang). Bronchial epithelial denudation, loss of cilia, and squamous metaplasia were early features (Nicholls). The presence of hemophagocytosis supports the contention that cytokine dysregulation may account, at least partly, for the severity of the clinical disease (Nicholls).
Examination of the liver revealed microvesicular fatty change, focal hemorrhages, and hepatocyte necrosis with scattered acidophilic bodies. The spleen showed large areas of probable ischemic necrosis and some atypical lymphocytes in the periarteriolar sheaths (Poutanen).
In one series, autopsy of hemato-lymphoid organs from four patients showed neither enlarged lymph nodes in the peripheral soft tissues or other body parts, nor reactive lymphoid hyperplasia or T zone reaction. The splenic white pulps appeared atrophic with lymphoid depletion, and the red pulp was congested. Bone marrow appeared active with the presence of three lineages. No features of hypoplastic marrow or reactive hemophagocytic syndrome were noted (Wong R).
The duration of shedding of the SARS virus from respiratory secretions of SARS patients appears to be variable. Some animals can shed infectious coronavirus persistently from the enteric tract for weeks or months without signs of disease, transmitting the infectious virus to neonates and other susceptible animals (Holmes). Studies are being done to learn whether the SARS virus is shed persistently from the respiratory and/or enteric tracts of some humans without signs of disease (Holmes). In the meantime, all SARS patients should limit interactions outside the home and should not go to work, school, out-of-home childcare, or other public areas until 10 to 14 days after the fever and respiratory symptoms have resolved. During this time, the infection control precautions for SARS patients should be followed. In a small study of 14 patients, none reported secondary cases in their household following their discharge home (Avendano).
At a follow-up visit one week after discharge, all 14 patients in one series still felt weak and complained of dyspnea on exertion. They all reported significant weight loss during their acute illness (mean 7 kg). Two patients had had a low grade fever (up to 37.5°C) for 2-3 days following discharge. Only 2 patients had persistence of a slight dry cough. The chest radiograph was clear for 7 patients and, although improved, abnormalities on the chest radiograph persisted for the remaining 7 (Avendano). Two weeks later, the patients were no longer as weak, but still complained of easy fatiguability and dyspnea on climbing stairs. The cough was no longer present. The chest radiograph had cleared for an additional 2 patients. 5 patients still had an abnormal chest radiograph, but improvement was noted (Avendano).
Most patients express complaints consistent with depression and anxiety regarding various aspects of their disease, hospitalization, and personal and family impact (Maunder). Other patients report insomnia and nightmares. The psychosocial aspects associated with this illness should not be underestimated and warrant further investigation. In addition to the effect on the patients, the psychological impact on staff and their families was also noted to be significant (Avendano).
The WHO guidelines outlined below are constantly reviewed and updated as new information becomes available. Check the CDC website regularly for new updates. http://www.who.int/csr/sars/management/en/
WHO: Management of Severe Acute Respiratory Syndrome (SARS)
Revised: April 11
Management of Suspect and Probable SARS Cases
Definition of a SARS Contact
A contact is a person who may be at greater risk of developing SARS because of exposure to a suspect or probable case of SARS. Information to date suggests that risky exposures include having cared for, lived with, or having had direct contact with the respiratory secretions, body fluids and/or excretion (e.g. feces) of a suspect or probable cases of SARS.
Management of Contacts of Probable SARS Cases
Management of Contacts of Suspect SARS Cases
As a minimum the following follow-up is recommended:
If, as a result of investigations, suspected or probable cases of SARS are discarded (no longer meet suspect or probable case definitions) then contacts can be discharged from follow-up.
The editors and the authors of SARS Reference might agree - under certain conditions - to remove the copyright on their book for all languages except English and German.