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Severe Acute Respiratory Syndrome: Radiographic Evaluation and Clinical Outcome Measures¹

¹ From the Departments of Diagnostic Radiology (C.G.C.O., P.L.K.) and Medicine (J.C.M.H., B.L., W.M.W., P.C.W., C.F.W., K.N.L., K.W.T.T.), University of Hong Kong, Queen Mary Hospital, Pokfulam Rd, Hong Kong Special Administrative Region, China; and Department of Radiology, Queen Mary Hospital, Hong Kong Special Administrative Region, China (W.C.Y.). Received May 10, 2003; revision requested May 30; revision received June 9; accepted June 18. Address correspondence to K.W.T.T. (e-mail: kwttsang@hkucc.hku.hk).

	ABSTRACT

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PURPOSE: To evaluate the relationship among chest radiographs, oxygen supplementation requirement, and treatment response in severe acute respiratory syndrome (SARS).

MATERIALS AND METHODS: Forty patients (20 women, 20 men; mean age, 42.90 years ± 14.01 [SD]; median age, 41.5 years; age range, 25–82 years) with SARS were evaluated. Daily chest radiographs were graded according to percentage of lung involvement during 20.15 days ± 5.56 (median, 20 days; range, 14–38 days). Times between symptoms and treatment and time to reach maximal radiographic score from admission and treatment day were determined. Daily oxygen saturation (SaO₂) and oxygen supplementation including mechanically assisted ventilation were recorded. Treatment response was defined as good, fair, and poor. Patterns of radiographic opacity at admission and at maximal radiographic score were noted. Differences in radiographic and clinical parameters with respect to oxygen supplementation and treatment response were respectively evaluated with Mann-Whitney and Kruskal-Wallis tests.

RESULTS: Larger maximal radiographic scores, lower SaO₂ at maximal radiographic change, longer time from treatment to maximal radiographic score (P < .01), and diffuse consolidation at maximal radiographic score were associated with oxygen supplementation. Parameters that influenced treatment response were time from symptom onset to treatment day (P = .003), time from admission to treatment day (P < .001), time to maximal radiographic score from treatment day (P = .001), maximal radiographic score (P = .009), SaO₂ at maximal radiographic score (P = .13), and treatment radiographic score (P = .03). Fair responders had shorter time between admission and treatment than did either good (P < .001) or poor responders (P = .002) and shorter time between symptoms and treatment (P < .001) and lower treatment radiographic score (P = .012) than did good responders. Good (82%), poor (36%), and fair (33%) responders developed maximal chest radiographic scores within 4 days of treatment (P = .008). Radiographic patterns at both admission and maximal radiographic score did not influence treatment response.

CONCLUSION: There are significant relationships among radiographic parameters, oxygen supplementation, and treatment response, and these relationships appear to be clinically useful in the treatment of SARS.

© RSNA, 2003

Index terms: Lung, infection, 60.212, 60.4134 • Oxygen • Severe acute respiratory syndrome (SARS), 60.212, 60.4134

	INTRODUCTION

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Severe acute respiratory syndrome (SARS) is a new disease entity that was first identified in East Asia (1–3) in November 2002, and it rapidly spread by means of international air travel to the rest of Asia, to North America, and to Europe (4–7). The clinical features of this syndrome have been well documented in the current literature. It is primarily a respiratory illness with a prodrome of fever, with temperature higher than 38°C (100.4°F), which is associated with malaise and chills followed by a dry nonproductive cough and dyspnea (2,3,5). Progressive airspace disease is characteristic on the chest radiograph, while ground-glass opacification and consolidation are the main thin-section computed tomographic (CT) features seen at initial evaluation (1–3,8–11). Residual changes alluding to fibrosis also have been reported in treated patients after discharge from the hospital (12).

A new coronavirus, genetically novel and different from those causing common colds, has been identified from tissues of infected patients (12–17). At present, little is known of the natural history of SARS, including clinical and radiologic responses to treatment. Between 20% and 50% of patients with SARS require oxygen supplementation, including assisted ventilation (2,3,5–7,15,18,19). Risk factors for complications of disease that could require intensive care unit and ventilatory support in one cohort were older age, severe lymphopenia, impaired alanine aminotransferase level, and delayed ribavirin and steroid treatment (15). In a separate cohort, advanced age, high peak lactate dehydrogenase level, and a total neutrophil count at presentation were predictive of a poor outcome that included intensive care unit admission and death (3). Because the chest radiograph represents a convenient means of daily assessment of lung changes in any pneumonia, it would be helpful to evaluate its clinical utility with clinical outcome measures such as oxygen supplementation requirement and treatment response. We therefore conducted this study to evaluate the relationship among chest radiographs, oxygen supplementation requirement, and treatment response in SARS.

	MATERIALS AND METHODS

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Patients
Forty consecutive adult Chinese patients (20 women, 20 men; mean age, 42.9 years ± 14.01 [SD]; median age, 41 years; age range, 25–82 years) who were treated for SARS at Queen Mary Hospital, Hong Kong, China, were included in this study during a 6-week period. Diagnosis of SARS was determined according to established diagnostic criteria for probable cases, as proposed by the Centers for Disease Control and Prevention on March 27, 2003, and these criteria have been updated recently by the World Health Organization on May 2, 2003 (20,21). In all 40 patients, results from serologic tests subsequently confirmed that they had SARS-CoV infection (14). Mean age for women was 37.5 years ± 9.5 (median age, 35.5 years; age range, 25–53 years) and that for men was 48.3 years ± 15.8 (median age, 46.5 years; age range, 25–82 years). All patients received combination therapy with intravenous (8 mg per kilogram of body weight thrice daily) or oral (1.2 g thrice daily) ribavirin and corticosteroids after a mean time of 3.4 days ± 3.6 (median, 2 days; range, 1–19 days) after admission. The corticosteroid was hydrocortisone (2 mg/kg administered every 6 hours for three days followed by oral prednisolone, 2 mg/kg, administered at a reducing dose), intravenous methylprednisolone (2–3 mg/kg administered daily for 3 days followed by oral prednisolone, 2 mg/kg, administered at a reducing dose), or intravenous pulsed methylprednisolone (500 mg administered daily for 3–5 days followed by oral prednisolone, 50 mg twice daily at a reducing dose).

The same 40 patients were evaluated in a separate study (19) in which the relationship between radiographic scores and clinical parameters such as oxygen saturation (SaO₂) and alanine aminotransferase and aspartate aminotransferase levels were determined. The differences between methods used in this study and those used in the other include a longer assessment period, categorization of the radiographic pattern at both admission and maximal radiographic score, and the acquisition of a different clinical dataset. The latter includes determination of treatment response as outlined later, oxygen supplementation requirement, time from treatment to development of maximal radiographic score, and time between admission and start of treatment. Clinical parameters that were used previously and that are also used in the present study are SaO₂ level, time from admission to development of maximal radiographic score, and time between onset of symptoms and treatment (19). All clinical parameters and chest radiographs were collected and assessed from the day of admission for a minimum of 14 treatment days. The mean duration of clinical and radiographic review for all cases was 20.15 days ± 5.56 (median, 20 days; range, 14–38 days).

Treatment response was assessed 5 days after initiation of therapy, which consisted of either intravenous or oral hydrocortisone with or without one pulsed steroid regime with intravenous methylprednisolone (500 mg per day for 3–5 days) and ribavirin. A patient’s condition was classified as having a good response when all of the criteria were met as follows: reduction of temperature to less than 37°C (98.6°F), improvement in radiographic scores by 20% from pretreatment scores, and either reduction of oxygen requirement by at least 1 L or a 2% improvement in SaO₂ level. When a patient’s condition failed to meet these criteria within 5 days and the patient required further or increased pulsed steroid therapy to achieve a response, the patient was classified as having a fair response. Patients whose conditions failed to respond to repetitive pulsed and high-dose (>500 g methylprednisolone per day) steroid therapy and who required continual dependence on supplemental oxygen with or without immunomodulating therapies, such as intravenous immunoglobulins, were classified as having a poor response. Some clinicians were responsible for clinical data collection (J.C.M.H., B.L., W.M.W., C.F.W.), whereas others (P.C.W., K.N.L., K.W.T.T.) defined the type of clinical response in each patient. Institutional review board approval was obtained for the study. Informed patient consent was not a requirement.

Imaging and Evaluation
All daily chest radiographs, which were obtained in the anteroposterior position at the bedside with a mobile radiographic unit (Mobilette; Siemens, Erlangen, Germany), for the whole assessment period in each patient were reviewed together by two radiologists (C.G.C.O., P.L.K.), and any differences were resolved in consensus, as previously described (19). One of the radiologists (C.G.C.O.) was an experienced radiologist for 14 years who served as a thoracic radiologist for the past 8 years, whereas the other (P.L.K.) was an experienced radiologist for 11 years. The radiographic opacities evaluated included airspace opacities (ie, ground-glass opacities, consolidation), nodular opacities, or reticular opacities (18). Briefly, ground-glass opacities were defined as hazy areas of increased opacity or attenuation without obscuration of the underlying vessels. Consolidation was defined as homogeneous opacification of the parenchyma with obscuration of the underlying vessels. The distribution of consolidation at admission and the maximal radiographic score were categorized as unifocal (single area of abnormality), multifocal (more than one focus), or diffuse (continuous involvement of at least one-half of the lung) (19). Since unifocal consolidation was found in only two patients on the admission radiograph, we considered focal and multifocal consolidation as a single group for statistical analysis with respect to admission radiographs. The total number of radiographs evaluated per patient was greater in this study (20 radiographs ± 5) than it was in the other parallel study (19) (13 radiographs ± 6).

We used the same method of evaluation for extent of disease on chest radiographs as was used in the other study (19). Essentially, areas of opacification on serial radiographs of each lung were systematically graded on the basis of the area of the lung involved expressed as a percentage of the total lung area (score 0, normal; score 1, 10% of the total lung area; score 2, 20% of the total lung area; and up to score 10, 100% of the lung area). Summation of scores from both lungs provided the total chest radiographic score (maximum score, 20). Chest radiographic scores at the day of admission (admission radiographic score), at the day of treatment (treatment radiographic scores), and at the day when scores were maximal (maximal radiographic scores) were extracted for statistical analysis.

Statistical Analysis
Patients were stratified into good (n = 17), fair (n = 9), and poor (n = 14) treatment response groups, and differences with respect to chest radiographic and clinical parameters, which included age, were evaluated by using the Kruskal-Wallis test. Intergroup comparisons were considered significant with a P value of less than .018. Sex differences in treatment response were evaluated with the Pearson ² test. Differences in radiographic and clinical parameters that included age with respect to oxygen supplementation were evaluated with the Mann-Whitney test. The relationships between radiographic patterns at presentation, radiographic patterns at maximal radiographic score, time from admission to maximal radiographic score, time from the start of treatment to maximal radiographic score, with treatment response and supplemental oxygen requirement, were evaluated with the Pearson ² and Fisher exact tests. A difference with P < .05 was regarded as statistically significant for all tests other than intergroup comparisons.

	RESULTS

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Findings
At admission, seven chest radiographs were normal (Fig 1). Ground-glass opacification (Figs 2, 3) was noted in 21 patients; multifocal consolidation (Fig 4), in eight; and diffuse consolidation (Fig 4), in four. Opacities reached maximal scores at 4.97 days ± 4.43 (median, 4 days; range, 0–18 days) after treatment and at 5.95 days ± 4.15 (median, 5 days; range, 0–18 days) after admission. The radiographic pattern at the day maximal scores were reached was unifocal (Fig 3), multifocal (Fig 1), and diffuse consolidation (Fig 2b) in 14, 14, and 12 patients, respectively. The four patients who died at the end of the assessment period had a poor response to treatment. The remaining 36 patients remain alive at the time of this writing.

View larger version (169K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Posteroanterior chest radiographs obtained in a 27-year-old man with SARS who had a 5-day history of fever and dry cough. (a) Image obtained at presentation was normal. Treatment was instituted because of findings at thin-section CT. (b) Image obtained 5 days after treatment shows maximal lung abnormalities, with bilateral lower zone patchy consolidation. Radiographic score was 10.

View larger version (145K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Posteroanterior chest radiographs obtained in a 27-year-old man with SARS who had a 5-day history of fever and dry cough. (a) Image obtained at presentation was normal. Treatment was instituted because of findings at thin-section CT. (b) Image obtained 5 days after treatment shows maximal lung abnormalities, with bilateral lower zone patchy consolidation. Radiographic score was 10.

View larger version (168K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Anteroposterior chest radiographs obtained in a 46-year-old woman with a 3-day history of fever who had SARS. (a) Image obtained at admission shows ground-glass opacification in the lower lobe of the right lung. Admission radiographic score was 3. (b) Image obtained 10 days later. Maximal radiographic score of 18 was reached when diffuse consolidation was present in both lungs.

View larger version (138K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Anteroposterior chest radiographs obtained in a 46-year-old woman with a 3-day history of fever who had SARS. (a) Image obtained at admission shows ground-glass opacification in the lower lobe of the right lung. Admission radiographic score was 3. (b) Image obtained 10 days later. Maximal radiographic score of 18 was reached when diffuse consolidation was present in both lungs.

View larger version (172K): [in this window] [in a new window] [Download PPT slide]   Figure 3a. Anteroposterior chest radiographs obtained in a 35-year-old woman with SARS. (a) Image obtained at admission shows focal ground-glass opacification in the right lower lung zone. (b) Image obtained 4 days later shows that the focal opacity had become larger and more opaque.

View larger version (154K): [in this window] [in a new window] [Download PPT slide]   Figure 3b. Anteroposterior chest radiographs obtained in a 35-year-old woman with SARS. (a) Image obtained at admission shows focal ground-glass opacification in the right lower lung zone. (b) Image obtained 4 days later shows that the focal opacity had become larger and more opaque.

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figure 4a. Anteroposterior chest radiographs obtained at admission show two other patterns of initial radiographic abnormalities in two patients. (a) Image shows bilateral multifocal consolidation. Admission radiographic score was 5. (b) Image shows bilateral diffuse consolidation. Admission radiographic score was 16.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   Figure 4b. Anteroposterior chest radiographs obtained at admission show two other patterns of initial radiographic abnormalities in two patients. (a) Image shows bilateral multifocal consolidation. Admission radiographic score was 5. (b) Image shows bilateral diffuse consolidation. Admission radiographic score was 16.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 5a. Box plots show treatment response in relation to maximal radiographic score and in relation to time to maximal radiographic score (in days). (a) Graph shows that poor responders have significantly higher maximal radiographic scores compared with those of both good (P = .006) and fair responders (P = .02). (b) Graph shows that in both fair (P = .01) and poor (P < .001) responders time to development of maximal radiographic score from beginning of treatment was longer than it was in good responders.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 5b. Box plots show treatment response in relation to maximal radiographic score and in relation to time to maximal radiographic score (in days). (a) Graph shows that poor responders have significantly higher maximal radiographic scores compared with those of both good (P = .006) and fair responders (P = .02). (b) Graph shows that in both fair (P = .01) and poor (P < .001) responders time to development of maximal radiographic score from beginning of treatment was longer than it was in good responders.

	DISCUSSION

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The age of patients with SARS has consistently been reported to be the most important prognostic factor associated with fatalities in the older age group (>65 years) and accounts for 12% of cases but 57% of fatalities (3,9,13,15,18). Children younger than 10 years appear to fare better and have a much milder course of the disease (18). However, in our cohort, age did not have a substantial role in the determination of an adverse outcome with respect to oxygen supplementation or treatment response. In patients who required oxygen supplementation, the radiographic scores were higher and the SaO₂ levels were lower at maximal radiographic score than were those of their counterparts, and the time from initiation of treatment to development of the maximal radiographic score after initiation of treatment was twice as long. The radiographic pattern at admission was not related to either oxygen supplementation or treatment response. This is perhaps not surprising, because temporal radiographic change occurs rapidly in the early phase of SARS (2,3,9,11) and invariably culminates in multiple areas of lung opacification (2,3,9,11). Our study findings show that diffuse consolidation at the maximal radiographic score is associated with an increased likelihood of the requirement for oxygen supplementation.

Parameters that were associated with treatment response included delay in treatment after onset of symptoms, time to development of maximal radiographic score after treatment, maximal and treatment radiographic scores, and SaO₂ level at maximal radiographic score. When the three treatment groups were analyzed separately, poor responders had significantly higher radiographic scores, lower SaO₂ levels at maximal radiographic score, and longer times from treatment to the development of the maximal radiographic score compared with either good or fair responders. Admission radiographic scores of poor responders were not significantly different from those of good responders. Hence, initial radiographic severity was not a factor that differentiated a good from a poor responder, but severity at maximal radiographic score and the time from initiation of treatment to reach that stage were.

Fair responders had lower treatment and maximal radiographic scores and a longer time to attain a maximal radiographic score than did the other two groups. The majority of good responders (14 of 17), however, developed maximal radiographic scores within 4 days of treatment, compared with 38% (five of 13) and 33% (three of nine) of poor and fair responders, respectively. They also had a longer time between symptom onset and initiation of treatment. These observations suggest that the clinical presentation in SARS bears a spectrum of disease severity, with good responders having faster but reduced lung response compared with the lung response in poor responders. Fair responders, on the other hand, may have a different response to viral load or other exposure factors that make their disease refractory to conventional steroid treatment, or treatment may have been instituted before the maximal body hyperreactivity phase was reached. This process may have suppressed the normal tissue response at target organs, primarily the lungs. The fact that these patients had an early presentation also may suggest that this group of patients may have had a more severe prodrome phase or that they may have come from a community outbreak group that prompted them to seek medical attention early.

It was not within the scope of our study to evaluate the different cofactors, such as viral load, magnitude of viral exposure, and comorbidities, that may have affected treatment response in our patients. This limitation may have influenced our findings. Other limitations include the use of anteroposterior chest radiographs obtained at the bedside, the application of a consensual evaluation system that does not allow for interobserver variability, and the evaluation of only extent of disease. However, this study was conducted during an epidemic crisis when chest radiographs were kept in isolation with the patients, and thus access to them was limited. Despite its limitations, our method of evaluation included statistically significant correlations between the radiographic score and the clinical and laboratory parameters (19) in addition to the findings of the present study.

In conclusion, our study findings show that there are substantial relationships among radiographic parameters, oxygen supplementation, and treatment response, and these relationships could be clinically useful in the treatment of SARS. The natural history of SARS appears to be highly individualized in severity and speed of progression. These individual variations might reflect an underlying difference in host susceptibility and viral load.

	ACKNOWLEDGMENTS

 
The authors thank the following people without whom this study would not have been possible: nurses, radiographers, and medical personnel at Queen Mary Hospital for their dedication and care and the patients with SARS.

	FOOTNOTES

 
See also the other article by Ooi et al in this issue.

Abbreviations: SaO₂ = oxygen saturation, SARS = severe acute respiratory syndrome

Author contributions: Guarantors of integrity of entire study, K.N.L., K.W.T.T.; study concepts, C.G.C.O., K.W.T.T.; study design, C.G.C.O., P.L.K.; literature research, B.L., W.C.Y.; clinical studies, C.F.W., P.C.W., J.C.M.H., W.M.W.; data acquisition, C.G.C.O., P.L.K., W.C.Y., J.C.M.H., B.L., W.M.W.; data analysis/interpretation, C.G.C.O., P.L.K., K.W.T.T.; statistical analysis, C.G.C.O., P.L.K., K.W.T.T.; manuscript preparation, C.G.C.O., P.L.K., B.L., W.C.Y.; manuscript definition of intellectual content, K.N.L., K.W.T.T.; manuscript editing, J.C.M.H., W.M.W., P.C.W.; manuscript revision/review, C.G.C.O., P.L.K., K.W.T.T., B.L., W.C.Y.; manuscript final version approval, K.N.L., J.C.M.H., W.M.W., P.C.W., C.F.W.

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