Advertisement

1-Year Pulmonary Function and Health Status in Survivors of Severe Acute Respiratory Syndrome

      Study objectives

      To characterize the long-term pulmonary function and health status in a prospectively identified cohort of patients who survived the severe acute respiratory syndrome (SARS).

      Design

      Prospective follow-up cohort study.

      Setting

      University-affiliated hospital.

      Patients

      Ninety-four patients who recovered from SARS were assessed at a uniform time point of 1 year after hospital discharge.

      Measurements

      The study included the measurement of static and dynamic lung volumes, the determination of the diffusing capacity of the lung for carbon monoxide (Dlco), and a health status evaluation using the St. George Respiratory Questionnaire (SGRQ).

      Results

      Eleven patients (12%) had mild impairment of FVC, 20 (21%) had mild impairment of FEV1, 5 (5%) had mild impairment of the FEV1/FVC ratio, and 17 (18%) had mild impairment of the Dlco. There was one patient (1%) who had moderate impairment of FVC, one patient (1%) who had moderate impairment of the FEV1/FVC ratio, and three patients (3%) who had moderate impairment of the Dlco. No pulmonary function abnormalities were detected in 59 patients (63%). Mean scores were significantly higher (ie, worse) than the population norms in the activity (p < 0.001), impacts (p < 0.001), and total (p < 0.001) domains of the SGRQ.

      Conclusions

      One year after recovery from SARS, persistent pulmonary function impairment was found in about one third of patients. The health status of SARS survivors was also significantly worse compared with the healthy population. The main determinants of morbidity in recovered SARS patients need to be further defined.

      Key words

      Abbrevationss:

      ATS (American Thoracic Society), CoV (coronavirus), Dlco (diffusing capacity of the lung for carbon monoxide), Fio2 (fraction of inspired oxygen), LDH (lactate dehydrogenase), SARS (severe acute respiratory syndrome), SGRQ (St. George respiratory questionnaire), TLC (total lung capacity)
      The severe acute respiratory syndrome (SARS) is a recently described condition caused by infection with a coronavirus (CoV)
      • Ksiazek TG
      • Erdman D
      • Goldsmith CS
      • et al.
      A novel coronavirus associated with severe acute respiratory syndrome.
      and is characterized by both an atypical pneumonia and efficient nosocomial transmission.
      First recognized in March 2003, SARS spread across the globe, caused many major outbreaks, and had an overall mortality rate of 11%,
      • Rainer TH
      Severe acute respiratory syndrome: clinical features, diagnosis, and management.
      but was successfully contained in < 4 months. Although it has been > 1 year since the illness was successfully contained, published data on the condition of those who survived the illness are limited. Several studies
      • Han Y
      • Geng H
      • Feng W
      • et al.
      A follow-up study of 69 discharged SARS patients.
      ,
      • Peng M
      • Cai BQ
      • Liu T
      • et al.
      Assessment of pulmonary function in SARS patients during the convalescent period.
      ,
      • Liu T
      • Peng M
      • Cai BQ
      • et al.
      Assessment of health-related quality of life in cured SARS patient.
      ,
      • Xie LX
      • Liu YN
      • Hao FY
      • et al.
      Prognostic analysis of lung function and chest X-ray changes of 258 patients with severe acute respiratory syndrome in rehabilitation after discharge.
      ,
      • Tian Q
      • Liu YN
      • Xie LX
      • et al.
      Comparative study of clinical characteristics and prognosis of clinically diagnosed SARS patients with positive and negative serum SARS coronavirus-specific antibodies test.
      ,
      • Hsu HH
      • Tzao C
      • Wu CP
      • et al.
      Correlation of high-resolution CT, symptoms, and pulmonary function in patients during recovery from severe acute respiratory syndrome.
      ,
      • Ong KC
      • Ng AWK
      • Lee LSU
      • et al.
      Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
      have reported persistent symptoms, as well as radiologic and functional abnormalities during follow-up several weeks or months after hospital discharge, but the prevalence and severity of the long-term sequelae of SARS remain largely unknown. Because lung function is known to improve for up to 1 year after discharge from the hospital in survivors of other causes of acute lung injury,
      • Herridge MS
      • Cheung AM
      • Tansey CM
      • et al.
      One-year outcomes in survivors of acute respiratory distress syndrome.
      ,
      • Lee CM
      • Hudson LD
      Long-term outcomes after ARDS.
      it is imperative that long-term studies of SARS survivors be conducted in order to determine the persistence of abnormalities in pulmonary function, and whether these abnormalities contribute to permanent impairment and disability. As the majority of patients with SARS survive the illness
      • Rainer TH
      Severe acute respiratory syndrome: clinical features, diagnosis, and management.
      and medical personnel, physicians, nurses, and hospital workers are among those commonly infected in most countries,
      • Rainer TH
      Severe acute respiratory syndrome: clinical features, diagnosis, and management.
      an additional requisite for the identification and quantification of morbidity among survivors may be for the consideration of awarding compensation.
      The purpose of this study was to characterize the long-term pulmonary function and health status in a prospectively identified cohort of patients who survived SARS in Singapore.

      Materials and Methods

       Patient Selection

      There were 206 cases of SARS in Singapore reported to the World Health Organization as of June 26, 2003.
      • Hsu LY
      • Lee CC
      • Green JA
      • et al.
      Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts.
      According to the World Health Organization case definition, probable SARS was diagnosed in all of these patients, and they were admitted to a single hospital (Tan Tock Seng Hospital). Survivors at 1 year after hospital discharge were eligible for enrollment in the study if they were ≥ 21 years of age. Patients were excluded from the study if they had been immobile before being admitted to hospital for SARS, had a history of pulmonary resection, or had a documented neurologic or psychiatric disease. We obtained written informed consent from patients prior to pulmonary function testing. This study was approved by the institutional ethics committee.
      One hundred seventy-four consecutive SARS survivors were evaluated for this study (Fig 1). Twenty-seven patients were excluded from the study for the reasons outlined in Figure 1. Seventeen patients were uncontactable, and 7 were overseas during the study period. Of the remaining 123 patients, 29 declined to participate in this study. The diagnosis of SARS was confirmed by a positive serology result for SARS-CoV in all except 1 of the 94 patients enrolled in this study.
      Figure thumbnail gr1
      Figure 1Enrollment of patients and follow-up at 3 months after hospital discharge.

       Pulmonary Function Testing

      Pulmonary function tests at 1 year after hospital discharge included spirometry, and measurements of total lung capacity and diffusing capacity of the lung for carbon monoxide (Dlco). The protocol and equipment used for pulmonary function testing in this study were similar to those used in an earlier study
      • Ong KC
      • Ng AWK
      • Lee LSU
      • et al.
      Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
      that we conducted among recovered SARS patients. Spirometry was performed in accordance with recommended standards.
      American Thoracic Society. Standardization of spirometry.
      All of the lung function tests were performed with the subjects seated and on the same day, but after patients had answered the health status questionnaire. FVC and FEV1 were measured with a clinical spirometer ( V˙max 229; SensorMedics; Yorba Linda, CA). Total lung capacity and its subdivisions were measured by the nitrogen washout method with the spirometer, the testing adhered to standard criteria.
      • Quanjer PH
      • Tammeling GJ
      • Cotes JE
      • et al.
      Lung volumes and forced ventilatory flows: Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal; Official Statement of the European Respiratory Society.
      The Dlco was determined by the single-breath carbon monoxide technique
      American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique; 1995 update.
      using an infrared analyzer ( V˙max 229). Dlco was adjusted for a hemoglobin concentration of 14.6 g/dL for men and 13.4 g/dL for women.
      American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique; 1995 update.
      The spirometry, lung volumes, and Dlco measurements were expressed as the percentages of predicted normal values using reference values taken from the prediction equations of Chia et al
      • Chia SE
      • Wang YT
      • Chan OY
      • et al.
      Pulmonary function in healthy Chinese, Malay and Indian adults in Singapore.
      and Poh and Chia.
      • Poh SC
      • Chia M
      Respiratory function tests in normal adult Chinese in Singapore.
      The rating of impairment was made according to the American Thoracic Society (ATS) statement
      American Thoracic Society. Evaluation of impairment/disability secondary to respiratory disorders.
      for the evaluation of impairment/disability secondary to respiratory disorders.

       Health Status Measurement

      All of the eligible patients completed the Singapore-English version of the St. George respiratory questionnaire (SGRQ). The SGRQ is a standardized, self-administered, pulmonary-specific health status questionnaire containing 50 items and 76 weighted responses that is divided into three subscales, as follows: (1) symptoms (8 items); (2) activity (16 items); and (3) impacts (26 items). SGRQ scores were calculated using score calculation algorithms and missing data imputation recommended by its developer. For each subscale and for the overall questionnaire, scores range from 0 (no impairment) to 100 (maximum impairment). Mean scores obtained from a sample of persons (n = 74) between 17 and 80 years of age (mean age, 46 years) who had no history of respiratory disease (mean FEV1, 95%) served as reference values (P.W. Jones, MD; Scoring Manual of the SGRQ May 2003).

       Statistical Analysis

      Comparisons between groups were done with the Student t test for normally distributed continuous variables and with Mann-Whitney U tests for nonnormally distributed continuous variables. The linear regression model was used to study the association between known prognostic indicators of SARS and the 1-year pulmonary function outcomes, as well as the association between mechanical ventilation parameters during the acute illness and 1-year pulmonary function outcomes. Results were reported as the mean ± SD. The conventional level of statistical significance of 0.05 was used for all of the analyses.

      Results

      The baseline characteristics of the enrolled patients during their hospital admission for SARS are shown in Table 1. Forty-seven of the 94 patients (50%) were health-care workers. The mean (± SD) of the percentage of lung involvement based on the worst chest radiograph appearance during the acute illness using a scoring system similar to that of Wong et al
      • Wong KT
      • Antonio GE
      • Hui DS
      • et al.
      Severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients.
      was 40.6 ± 29.9%. Eleven patients (12%) required admission to the ICU, and the mean Pao2/fraction of inspired oxygen (Fio2) ratio among these patients in the ICU was 95.5 ± 65.6. Seven of these patients required mechanical ventilation. All seven of the patients had a Pao2/Fio2 ratio of ≤ 200 while receiving mechanical ventilation with a positive end-expiratory pressure of ≥ 5 cm H2O and evidence of airspace changes in all four of the quadrants on chest radiography. Overall, seven patients (7%) had a history of cigarette smoking. Nineteen patients (20%) had significant preexisting medical conditions. The four most common preexisting illnesses were hypertension (six patients), bronchial asthma (five patients), treated pulmonary tuberculosis (three patients), and diabetes mellitus (two patients).
      Table 1Characteristics of Patients With SARS During Hospital Admission (n = 94)
      Values given as mean ± SD or No., unless otherwise indicated.
      VariableValues
      Age, yr37.0 ± 12.0
      Male sex, %26
      Smokers, %7
      Preexisting medical illnesses, %20
      Preexisting pulmonary disease, %9
      Length of hospitalization, d13.0 ± 14.5
      Intensive care unit admission, %12
      Highest serum LDH level, U/L664.5 ± 454.5
      Ribavarin prescription, %54
      Steroids prescription, %10
      * Values given as mean ± SD or No., unless otherwise indicated.
      Comparing the SARS survivors who were enrolled in this study with those who were not included, there was no significant difference with regard to age, gender, steroid exposure, or severity of the acute illness as indicated by the length of hospitalization, the requirement for intensive care or mechanical ventilation, and the highest recorded serum lactate dehydrogenase (LDH) level (Table 2). Of the seven enrolled patients who had required mechanical ventilation, the mean duration of mechanical ventilation was 15 days compared with 11 days for the five patients who required mechanical ventilation among the 80 survivors who were not included in this study. The difference in the mean duration of mechanical ventilation between these two subsets of patients was not statistically significant (p = 0.443).
      Table 2Comparison of Enrolled SARS Survivors With Those Who Were Not Included in This Study
      Values given as mean ± SD or No., unless otherwise indicated.
      VariablePatients Enrolled (n = 94)Patients Excluded (n = 80)p Value
      Age, yr37.0 ± 12.037.6 ± 18.20.969
      Male sex, %26300.556
      Length of hospitalization, d13.0 ± 14.519.9 ± 21.40.187
      ICU admission, %12100.519
      Mechanical ventilation, %760.747
      Highest serum LDH level, U/L664.5 ± 454.5690.0 ± 440.50.305
      Steroids prescription, %1080.534
      * Values given as mean ± SD or No., unless otherwise indicated.
      At 1 year after hospital discharge, with regard to respiratory symptoms that were present at least a few days a month over the preceding year, 28 patients (30%) had cough, 19 (20%) had increased sputum production, 28 (30%) had shortness of breath, and 7 (7%) had occasional wheezing. The mean body mass index of the group at this time was 23.4 ± 4.5.
      The pulmonary function test results of the 94 patients are shown in Table 3. The group means of forced expiratory volumes, static lung volumes, and diffusion capacity were all within normal limits (ie, > 80% predicted). However, several cases of abnormalities in FVC, FEV1, FEV1/FVC ratio, and Dlco were detected. According to the ATS recommendations
      American Thoracic Society. Evaluation of impairment/disability secondary to respiratory disorders.
      for evaluating respiratory impairment, 11 patients (12%) had mild impairment of FVC, 20 (21%) had mild impairment of FEV1, 5 (5%) had mild impairment of FEV1/FVC ratio, and 17 (18%) had mild impairment of Dlco. There was one patient (1%) with moderate impairment of FVC, one patient (1%) with moderate impairment of FEV1/FVC ratio, and three patients (3%) with moderate impairment of Dlco. Because there were cases of patients with impairment in more than one of the four variables, the number of patients with mild and moderate impairment according to the ATS recommendations was 30 (32%) and 5 (5%), respectively. Table 4 shows the pulmonary function data of these 35 patients who had respiratory impairment. The majority of the impairment in FEV1 and FVC suggests a restrictive abnormality, but in only eight patients was the total lung capacity (TLC) < 80% predicted. Two patients had obstructive abnormality with an FEV1/FVC ratio < 70% predicted, and one of them (patient No. 17 in Table 4) had a history of poorly controlled bronchial asthma. The other patient (patient No. 12 in Table 4) had a significant history of cigarette smoking. None of the other patients who had respiratory impairment were current or ex-smokers. The preexisting medical conditions that may affect pulmonary function in the patients with pulmonary function abnormalities are as shown in Table 4.
      Table 3Results of Pulmonary Function Tests at 1 Year After Hospital Discharge (n = 94)
      Values given as mean ± SD (range). FRC = functional residual capacity; RV = residual volume; VA = alveolar volume; VC = vital capacity.
      VariableResults
      FVC
       L2.9 ± 0.7 (1.7–5.4)
       % predicted99.1 ± 15.5 (53.0–131.0)
      FEV1
       L2.5 ± 0.6 (1.3–4.3)
       % predicted93.4 ± 14.4 (61.0–119.0)
      FEV1/FVC, %85.6 ± 7.6 (59.0–99.0)
      TLC
       L4.3 ± 0.9 (2.7–6.9)
       % predicted98.4 ± 14.4 (68.0–133.0)
      RV
       L1.3 ± 0.4 (0.3–2.4)
       % predicted97.2 ± 31.3 (16.0–175.0)
      FRC
       L2.2 ± 0.6 (1.0–4.0)
       % predicted96.1 ± 19.4 (47.0–144.0)
      VC
       L3.0 ± 0.7 (1.7–5.5)
       % predicted103.0 ± 15.0 (66.0–135.0)
      Dlco
       mL/min/mm Hg7.3 ± 1.8 (3.5–13.0)
       % predicted88.8 ± 15.2 (48.0–134.0)
      Dlco/VA ratio
       mL/min/mm Hg1.7 ± 0.3 (0.8–2.6)
       % predicted84.6 ± 14.3 (43.0–127.0)
      * Values given as mean ± SD (range). FRC = functional residual capacity; RV = residual volume; VA = alveolar volume; VC = vital capacity.
      Table 4Clinical and Pulmonary Function Data of Patients With Pulmonary Function Impairment (n = 35)
      Values given as % predicted, unless otherwise indicated. VHD = valvular heart disease.
      Patient No.Age, yrPreexisting IllnessesFVCFEV1FEV1/FVC. %DlcoTLC
      13010682738098
      22672759910568
      329Asthma7979896979
      4438578849195
      5517271859280
      6505361957984
      773105118884890
      8378585856376
      937Asthma9988767896
      10231051069772113
      11438578849195
      12699168606291
      13507275905579
      1428105887973107
      15231071109971112
      1642Pulmonary tuberculosis7974848375
      1757Asthma, hypertension88625980118
      185176758613499
      1943Hypothyroidism8979818089
      2031107958372105
      21568282836678
      22457871829891
      2322Pulmonary tuberculosis7574966297
      24407569838477
      25268774818596
      2649VHD, hypertension6766867878
      2756102816982119
      2854124102709691
      29341291138276126
      30241311168677117
      31291017670105118
      32387677927682
      33238484967584
      34358579867683
      356193105925482
      * Values given as % predicted, unless otherwise indicated. VHD = valvular heart disease.
      Table 5 shows the serial pulmonary function data of 17 patients in the present study who were detected to have abnormalities from among a group of patients who had been evaluated at 3 months after hospital discharge in an earlier study.
      • Ong KC
      • Ng AWK
      • Lee LSU
      • et al.
      Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
      The mean Dlco improved significantly by 8.3% (p = 0.047) at 1 year, but no significant changes were detected in the other pulmonary function variables of these 17 patients.
      Table 5Serial Data of Patients With Pulmonary Function Impairment Assessed at 3 Months and Reassessed at 1 Year After Hospital Discharge (n = 17)
      Values given as % predicted, unless otherwise indicated.
      Patient No.3 mo1 yr
      FVCFEV1FEV1/FVC, %DlcoFVCFEV1FEV1/FVC, %Dlco
      191909072978983111
      28977817087748185
      3109938078105887973
      49078798497868189
      57271877867668678
      693928810588625980
      790646152931059254
      8789094721021068791
      98991925475698384
      107576937784849675
      118082847079748483
      129410089701241098283
      137871838010610787112
      14888694741151119382
      157674876575749662
      16117104826785798676
      178079878889798180
      * Values given as % predicted, unless otherwise indicated.
      Comparing the pulmonary function of patients who required ICU care and mechanical ventilation during hospitalization for SARS with those who did not, there was no significant difference in FVC, FEV1, FEV1/FVC ratio, or Dlco between the two groups. Using multivariate analysis to analyze the association between known prognostic indicators of SARS,
      • Rainer TH
      Severe acute respiratory syndrome: clinical features, diagnosis, and management.
      namely, age, gender, comorbidity, serum LDH level, ribavarin level, and steroid use, and the 1-year pulmonary function outcomes, we found that only age was significantly associated with the FVC percent predicted (every year increase, −0.34; 95% confidence interval, −0.6 to −0.08; p = 0.01) and with the FEV1 percent predicted (every year increase, −0.26; 95% confidence interval, −0.5 to −0.01; p = 0.04), but none of the prognostic factors were significantly associated with the Dlco percent predicted. Among patients who required intensive care and mechanical ventilation during the acute illness, there was no significant association among the duration of mechanical ventilation, the Pao2/Fio2 ratio on admission to the ICU, steroid usage, and the pulmonary function parameters at 1 year after hospital discharge. All 94 of the patients completed the SGRQ. Domain scores other than the symptoms domain of the SGRQ were significantly higher (ie, worse) than the population norms (Table 6).
      Table 6SGRQ Domain Scores of SARS Survivors Compared With Healthy Subjects
      Values given as mean ± SD, unless otherwise indicated.
      DomainSARS SurvivorsHealthy Subjectsp Value
      Total15.1 ± 16.16< 0.001
      Symptoms15.1 ± 18.4120.104
      Activity22.7 ± 22.89< 0.001
      Impacts10.7 ± 14.82< 0.001
      * Values given as mean ± SD, unless otherwise indicated.

      Discussion

      Impaired pulmonary function is present in about one third of patients 1 year after their recovery from SARS. The most common pulmonary function impairment was of the FEV1 and Dlco. As measured by the SGRQ, SARS survivors had significant worsening in health status compared with the healthy population.
      To date, reported studies on the functional outcomes of patients during the recovery stage of SARS are limited,
      • Han Y
      • Geng H
      • Feng W
      • et al.
      A follow-up study of 69 discharged SARS patients.
      ,
      • Peng M
      • Cai BQ
      • Liu T
      • et al.
      Assessment of pulmonary function in SARS patients during the convalescent period.
      ,
      • Liu T
      • Peng M
      • Cai BQ
      • et al.
      Assessment of health-related quality of life in cured SARS patient.
      ,
      • Xie LX
      • Liu YN
      • Hao FY
      • et al.
      Prognostic analysis of lung function and chest X-ray changes of 258 patients with severe acute respiratory syndrome in rehabilitation after discharge.
      ,
      • Ong KC
      • Ng AWK
      • Lee LSU
      • et al.
      Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
      and none has evaluated the outcomes at a uniform 1-year time point. In assessing long-term outcomes after acute lung injury, it is important to attempt the consecutive enrollment of survivors with defined time points for study, because there is a possibility of bias toward the selection of sicker patients with abnormal pulmonary function test results if studies enrolled any patient who returned for a follow-up evaluation. In an earlier prospective study
      • Ong KC
      • Ng AWK
      • Lee LSU
      • et al.
      Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
      of pulmonary function tests in 46 recovered SARS patients at a uniform time point of 3 months after hospital discharge, we found 7 patients (15%) with mild impairment of FVC, 12 patients (26%) with mild impairment of FEV1, 17 patients (37%) with mild impairment of Dlco, and 1 patient (2%) with moderate impairment of Dlco. Overall, pulmonary function defects were detected in half of the recovered SARS patients at 3 months after hospital discharge. The finding in the present study of persistent pulmonary function abnormalities in a significant proportion of SARS patients 1 year after hospital discharge is notable, not only for the long-term follow-up and management of these patients but also as a highlight of the permanent respiratory impairment that can result from the acute infection. Viral pneumonia usually resolves without any clinical or radiologic sequelae, whereas SARS-related radiologic sequelae appear to be quite common among survivors, as observed by several studies.
      • Hsu HH
      • Tzao C
      • Wu CP
      • et al.
      Correlation of high-resolution CT, symptoms, and pulmonary function in patients during recovery from severe acute respiratory syndrome.
      ,
      • Antonio GE
      • Wong KT
      • Hui DS
      • et al.
      Thin-section CT in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience.
      The finding of higher prevalence of dynamic lung volume abnormalities than Dlco impairment in the present study, together with the significant improvement in Dlco but not dynamic lung volumes in serial lung function testing of a subset of our patients, suggest that Dlco abnormalities can improve with time. In contrast, ventilatory abnormalities are more likely to persist in the long term. This appears to be in contrast to information from several reviews
      • Luhr O
      • Aardal S
      • Nathorst-Westfelt U
      • et al.
      Pulmonary function in adult survivors of severe acute lung injury treated with inhaled nitric oxide.
      ,
      • Herridge MS
      Long-term outcomes after critical illness.
      on survivors of the ARDS documenting the persistence of a mild reduction in Dlco as the most common abnormality found in pulmonary function testing, and that Dlco remained low in long-term follow-ups. Interestingly, all of the articles on ARDS survivors reporting normal lung volumes or very low rates of either obstruction or restriction were published earlier when cohorts were likely more heterogeneous, and lung injuries in the surviving population were most likely less severe.
      • Buchser E
      • Leuenberger P
      • Chiolero R
      • et al.
      Reduced pulmonary capillary blood volume as a long-term sequel of ARDS.
      ,
      • Ruhle KH
      • Schuster A
      • Vogel W
      • et al.
      Follow-up examinations of lung function in patients with shock lung [in German].
      ,
      • Klein JJ
      • van Haeringen JR
      • Sluiter HJ
      • et al.
      Pulmonary function after recovery from the adult respiratory distress syndrome.
      In more recent studies, the proportion of patients with ventilatory impairment has ranged constantly higher, from 18 to 33% for airway obstruction and from 15 to 45% for lung restriction.
      • Mc Hugh LG
      • Milberg JA
      • Whitcomb ME
      • et al.
      Recovery of function in survivors of the acute respiratory distress syndrome.
      ,
      • Bachofen M
      Prognosis following extubation in severe ARDS [in German].
      ,
      • Peters JI
      • Bell RC
      • Prihoda TJ
      • et al.
      Clinical determinants of abnormalities in pulmonary functions in survivors of the adult respiratory distress syndrome.
      ,
      • Ghio AJ
      • Elliot CG
      • Crapo RO
      • et al.
      Impairment after adult respiratory distress syndrome: an evaluation based on American Thoracic Society recommendations.
      In particular, Neff et al
      • Neff TA
      • Stocker R
      • Frey HR
      • et al.
      Long-term assessment of lung function in survivors of severe ARDS.
      have reported that residual restrictive and obstructive types of functional impairment remained common (25% of patients with each type) in survivors of severe ARDS, and only 12.5% of patients had impairment in Dlco.
      The exact pathologic cause(s) of the pulmonary dysfunction in recovered SARS patients is not known. Adverse long-term pulmonary sequelae of the ARDS include lung fibrosis, but untreated bronchiolitis obliterans-organizing pneumonia and bronchiolitis obliterans may also contribute to the physical morbidity in ARDS survivors.
      • Herridge MS
      • Cheung AM
      • Tansey CM
      • et al.
      Long term outcomes in survivors of ARDS [abstract].
      In addition, neuromuscular weakness may also contribute to the decline in pulmonary function.
      • Aggarwal AN
      • Gupta D
      • Behera D
      • et al.
      Analysis of static pulmonary mechanics helps to identify functional defects in survivors of acute respiratory distress syndrome.
      A recent study
      • Hsu HH
      • Tzao C
      • Wu CP
      • et al.
      Correlation of high-resolution CT, symptoms, and pulmonary function in patients during recovery from severe acute respiratory syndrome.
      correlating high-resolution CT scan findings and pulmonary function in survivors of SARS during the early recovery phase (ie, 25 to 38 days after hospital discharge) found that FEV1, FVC, TLC, residual volume, and Dlco correlated well with the severity of ground-glass opacification and fibrosis. The presence of fibrosis was associated with significantly lower pulmonary function variables. It would be interesting to compare structural and functional changes in survivors of SARS during late recovery to see whether a similar correlation persists and whether these changes are different from those observed in ARDS survivors whose condition is not related to SARS.
      In contrast to the results of the earlier study
      • Liu T
      • Peng M
      • Cai BQ
      • et al.
      Assessment of health-related quality of life in cured SARS patient.
      among patients averaging 28 days in the posthospital discharge period, significantly worse scores were not found in the symptoms domain of the SGRQ among our SARS survivors at 1 year. This is likely attributable to an improvement in symptoms with time of recovery. In studies among survivors of ARDS, it is known that nearly all of the patients are symptomatic at hospital discharge, but there is significant improvement over the first year after ARDS in most patients.
      • Lee CM
      • Hudson LD
      Long-term outcomes after ARDS.
      In addition, survivors of ARDS are also much less symptomatic than other patients with chronic lung disease.
      • Lee CM
      • Hudson LD
      Long-term outcomes after ARDS.
      Nonetheless, the mean activity score of our patients measuring disturbances to their daily physical activity and their mean impacts score covering a wide range of disturbances of psychosocial function remain significantly worse compared with those in healthy subjects. Physical morbidity in SARS survivors may also stem from extrapulmonary causes. In an earlier study
      • Ong KC
      • Ng AWK
      • Lee LSU
      • et al.
      Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
      evaluating pulmonary function and exercise capacity among patients from the same cohort, we found no evidence of exercise limitation solely because of ventilatory constraints, and there were very few patients with significant oxygen desaturation during exercise. Hence, the disability represented by an increased (ie, worse) score on the SGRQ activity domain in the present study is not likely to be specific to intrinsic pulmonary dysfunction, especially given that pulmonary dysfunction in our patients is modest, but may instead reflect any cause of impaired physical functioning, such as muscle loss/weakness or neuromuscular disease. Corticosteroid myopathy may be a contributory factor, although only a small percentage of our patients had received treatment with steroids during their acute illness.
      There are several limitations of this study that we would like to acknowledge. First, the heterogeneity of acute lung disease encompassed by the case definition of SARS may account for the observed variation in pulmonary and extrapulmonary sequelae among our patients. Second, the proportion of patients who declined evaluation may have led to a bias toward the selection of sicker patients with abnormal pulmonary function. This is likely, because most of the patients who declined participation in the study offered a lack of symptoms and inconvenience as the main reasons for doing so. Third, evaluations of arterial blood gas levels and exercise testing were not performed in this study. However, we did not anticipate that there was significant hypoxemia in these patients, because none of them was found to have hypoxemia or was assessed as requiring oxygen supplementation during routine follow-up. Cardiopulmonary responses to exercise in SARS survivors had been evaluated in an earlier study
      • Ong KC
      • Ng AWK
      • Lee LSU
      • et al.
      Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
      at 3 months after hospital discharge, but we do not have any longer term data on this. Fourth, only a respiratory-specific measure of health status was used in this study. A generic health status measure, such as the Medical Outcomes Study 36-item short-form health survey, would have provided a more global assessment of the patients, especially with regard to their role limitations as a result of emotional problems, mental health, bodily pain, and general health perceptions. The interaction of the data obtained from generic and disease-specific measures of health status may also have helped to determine the contributions of pulmonary and nonpulmonary factors to the long-term health status of SARS survivors.
      In summary, 1 year after recovery from SARS, persistent pulmonary function impairment was found in about one third of patients. The health status of SARS survivors was also significantly worse compared with that of the healthy population.
      ACKNOWLEGEMENTS: We acknowledge the work of research coordinators M. Lee and W-F. Chong in the preparation of the manuscript, as well as that of the staff of the Respiratory Function Laboratory, Tan Tock Seng Hospital.

      References

        • Ksiazek TG
        • Erdman D
        • Goldsmith CS
        • et al.
        A novel coronavirus associated with severe acute respiratory syndrome.
        N Engl J Med. 2003; 348: 1953-1966
        • Rainer TH
        Severe acute respiratory syndrome: clinical features, diagnosis, and management.
        Curr Opin Pulm Med. 2004; 10: 159-165
        • Han Y
        • Geng H
        • Feng W
        • et al.
        A follow-up study of 69 discharged SARS patients.
        J Tradit Chin Med. 2003; 23: 214-217
        • Peng M
        • Cai BQ
        • Liu T
        • et al.
        Assessment of pulmonary function in SARS patients during the convalescent period.
        Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2003; 25: 529-532
        • Liu T
        • Peng M
        • Cai BQ
        • et al.
        Assessment of health-related quality of life in cured SARS patient.
        Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2003; 25: 16-19
        • Xie LX
        • Liu YN
        • Hao FY
        • et al.
        Prognostic analysis of lung function and chest X-ray changes of 258 patients with severe acute respiratory syndrome in rehabilitation after discharge.
        Zhonghua Jie He He Hu Xi Za Zhi. 2004; 27: 147-150
        • Tian Q
        • Liu YN
        • Xie LX
        • et al.
        Comparative study of clinical characteristics and prognosis of clinically diagnosed SARS patients with positive and negative serum SARS coronavirus-specific antibodies test.
        Zhonghua Yi Xue Za Zhi. 2004; 84: 642-645
        • Hsu HH
        • Tzao C
        • Wu CP
        • et al.
        Correlation of high-resolution CT, symptoms, and pulmonary function in patients during recovery from severe acute respiratory syndrome.
        Chest. 2004; 126: 149-158
        • Ong KC
        • Ng AWK
        • Lee LSU
        • et al.
        Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.
        Eur Respir J. 2004; 24: 436-442
        • Herridge MS
        • Cheung AM
        • Tansey CM
        • et al.
        One-year outcomes in survivors of acute respiratory distress syndrome.
        N Engl J Med. 2003; 348: 683-693
        • Lee CM
        • Hudson LD
        Long-term outcomes after ARDS.
        Semin Respir Crit Care Med. 2001; 22: 327-336
        • Hsu LY
        • Lee CC
        • Green JA
        • et al.
        Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts.
        Emerg Infect Dis. 2003; 9: 713-717
      1. (World Health Organization. Case definitions for surveillance of severe acute respiratory syndrome (SARS). 2003; 4. Available at: Accessed August 7, 2004)
      2. American Thoracic Society. Standardization of spirometry.
        Am J Respir Crit Care Med. 1995; 152: 1107-1136
        • Quanjer PH
        • Tammeling GJ
        • Cotes JE
        • et al.
        Lung volumes and forced ventilatory flows: Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal; Official Statement of the European Respiratory Society.
        Eur Respir J Suppl. 1993; 16: 5-40
      3. American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique; 1995 update.
        Am J Respir Crit Care Med. 1995; 152: 2185-2198
        • Chia SE
        • Wang YT
        • Chan OY
        • et al.
        Pulmonary function in healthy Chinese, Malay and Indian adults in Singapore.
        Ann Acad Med Singapore. 1993; 22: 878-884
        • Poh SC
        • Chia M
        Respiratory function tests in normal adult Chinese in Singapore.
        Singapore Med J. 1969; 10: 265-271
      4. American Thoracic Society. Evaluation of impairment/disability secondary to respiratory disorders.
        Am Rev Respir Dis. 1986; 133: 1205-1209
        • Wong KT
        • Antonio GE
        • Hui DS
        • et al.
        Severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients.
        Radiology. 2003; 228: 401-406
        • Antonio GE
        • Wong KT
        • Hui DS
        • et al.
        Thin-section CT in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience.
        Radiology. 2003; 228: 810-815
        • Luhr O
        • Aardal S
        • Nathorst-Westfelt U
        • et al.
        Pulmonary function in adult survivors of severe acute lung injury treated with inhaled nitric oxide.
        Acta Anaesthesiol Scand. 1998; 42: 391-398
        • Herridge MS
        Long-term outcomes after critical illness.
        Curr Opin Crit Care. 2002; 8: 331-336
        • Buchser E
        • Leuenberger P
        • Chiolero R
        • et al.
        Reduced pulmonary capillary blood volume as a long-term sequel of ARDS.
        Chest. 1985; 87: 608-611
        • Ruhle KH
        • Schuster A
        • Vogel W
        • et al.
        Follow-up examinations of lung function in patients with shock lung [in German].
        Prax Klin Pneumol. 1983; 123: 492-495
        • Klein JJ
        • van Haeringen JR
        • Sluiter HJ
        • et al.
        Pulmonary function after recovery from the adult respiratory distress syndrome.
        Chest. 1976; 69: 350-355
        • Mc Hugh LG
        • Milberg JA
        • Whitcomb ME
        • et al.
        Recovery of function in survivors of the acute respiratory distress syndrome.
        Am J Respir Crit Care Med. 1994; 150: 90-94
        • Bachofen M
        Prognosis following extubation in severe ARDS [in German].
        Schweiz Med Wochenschr. 1991; 121: 1552-1556
        • Peters JI
        • Bell RC
        • Prihoda TJ
        • et al.
        Clinical determinants of abnormalities in pulmonary functions in survivors of the adult respiratory distress syndrome.
        Am Rev Respir Dis. 1989; 139: 1163-1168
        • Ghio AJ
        • Elliot CG
        • Crapo RO
        • et al.
        Impairment after adult respiratory distress syndrome: an evaluation based on American Thoracic Society recommendations.
        Am Rev Respir Dis. 1989; 139: 1158-1162
        • Neff TA
        • Stocker R
        • Frey HR
        • et al.
        Long-term assessment of lung function in survivors of severe ARDS.
        Chest. 2003; 123: 845-853
        • Herridge MS
        • Cheung AM
        • Tansey CM
        • et al.
        Long term outcomes in survivors of ARDS [abstract].
        Am J Respir Crit Care Med. 2002; 165: A254
        • Aggarwal AN
        • Gupta D
        • Behera D
        • et al.
        Analysis of static pulmonary mechanics helps to identify functional defects in survivors of acute respiratory distress syndrome.
        Crit Care Med. 2000; 28: 3480-3483