Eur J Cardiothorac Surg 2007;31:1115-1119. doi:10.1016/j.ejcts.2007.02.035
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia
Joo Hun Parka,1,
Dong Kwan Kimb,1,
Dong Soon Kima,*,
Younsuck Koha,
Sang-Do Leea,
Woo Sung Kima,
Won Dong Kima,
Seung Il Parkb
a Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-600, Republic of Korea
b Department of Thoracic Surgery, University of Ulsan, College of Medicine, Asan Medical Center, Republic of Korea
Received 10 November 2006;
received in revised form 23 February 2007;
accepted 26 February 2007.
* Corresponding author. Tel.: +82 2 3010 3132; fax: +82 2 3010 6968. (Email: dskim{at}amc.seoul.kr).
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Abstract
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Background: The overall safety of surgical lung biopsy in patients with idiopathic interstitial pneumonia (IIP) remains controversial. This study was performed to investigate the mortality and complication rate and identify the risk factors for surgical lung biopsy in patients with IIP. Methods: A total of 200 patients with IIP who underwent surgical lung biopsy at the Asan Medical Center, Korea, from April 1990 to August 2003, were enrolled. Complications and mortality were analyzed retrospectively. Results: (1) The mortality rate 30 days after the surgical lung biopsy was 4.3%, which was significantly higher than the control group. Biopsy performed at the time of acute exacerbation (AE) resulted in higher 30-day mortality (28.6%) compared to non-AE (3.0%; p
<
0.05). AE was followed by biopsy itself in three cases. (2) Univariate analysis indicated that lower FVC, lower DLCO, and presence of AE were significant risk factors for 30-day mortality (p
< 0.05). However, multivariate analysis revealed that only AE (OR: 11.334, 95% CI: 1.727–74.365, p
= 0.011) was an independent risk factor. (3) The patients with low DLCO (<50% predicted) had higher mortality and complication rate than high DLCO group. Conclusion: Our data suggested that the presence of acute exacerbation at the time of biopsy and lower DLCO were predictors of higher mortality after the surgical lung biopsy.
Key Words: Surgical lung biopsy • Mortality • Idiopathic interstitial pneumonia • Acute exacerbation • Diffusion capacity
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1. Introduction
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A surgical lung biopsy is often essential for the accurate diagnosis of an idiopathic interstitial pneumonia (IIP), especially for the differentiation between idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) [1,2]. However, surgical lung biopsy has not been performed as frequently as necessary [3–5], which appears to be due in part to the fear for the serious complications of surgical lung biopsy. The recent introduction of video-assisted thoracoscopic surgery (VATS) has reduced the complication compared to open lung biopsy (OLB), resulting in an increased use of surgical lung biopsy [6–9]. However, a recent report of a high mortality rate (21.7%) in the patients with IPF after surgical lung biopsy has raised safety concerns and debates on surgical lung biopsy in IPF patients [10]. Advanced age, rapid deterioration of underlying lung disease, requirement for mechanical ventilation, and immunosuppressed condition in patients with IIP were reported as risk factors of surgical lung biopsy [10–13]. The aim of this study is to investigate the mortality and complication rate and also to identify the risk factors of surgical lung biopsy in our large cohort of patients.
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2. Subjects and methods
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2.1 Subjects
Two hundred consecutive patients diagnosed as IPF (n
= 140), idiopathic NSIP (n
= 46, 8 cellular, 36 fibrotic), or cryptogenic organizing pneumonia (COP) (n
= 14) by surgical lung biopsy from April 1990 to August 2003 at Asan Medical Center in Seoul, Korea, were enrolled in this study. The subjects consisted of 123 males and 77 females with a mean age of 58.0 ± 10.1 years; 43% of the subjects were nonsmokers. FVC was available in 197 patients, diffusion capacity (DLCO) in 195 patients, and arterial blood gas data in 196 patients (Table 1
). The mean follow-up period of all patients after surgical lung biopsy was 32.1 ± 30.0 months (range: 0.3–151.8 months). The biopsy was taken at two or three sites either by VATS or OLB. All of our patients were intubated with double lumen endotracheal tube and single lung ventilation was performed during the operation. Among IPF group, 17.9% (25 out of 140 patients) had a history of treatment with steroid alone or with cytotoxic drugs prior to surgical lung biopsy, and 6.5% (3 out of 46 patients) of NSIP group and 14.3% (2 of 14 patients) of COP group had been under treatment with immunosuppressive agents before surgical lung biopsy.
2.2 Diagnostic criteria
The diagnoses of IPF, idiopathic NSIP, and COP were made according to the American Thoracic Society/European Respiratory Society consensus classification after reviewing and reclassification of pathological specimen and HRCT [1,2]. The indication of surgical lung biopsy was the patients with clinical evidence of interstitial pneumonia who agree with doing surgical lung biopsy but without contraindication. American Thoracic Society/European Respiratory Society 2002 consensus classification recommended surgical lung biopsy in patients with suspected IIP to get a definite diagnosis of IPF, NSIP, or COP. The contraindications of surgical lung biopsy in our hospital were: (a) patients on mechanical ventilation before surgical lung biopsy and (b) contraindications of general anesthesia judged by anesthesiologist.
Complications of surgical lung biopsy were defined as: documented postoperative infections such as pneumonia, empyema, or other nosocomial infection; prolonged air leakage (5 days or more); pleurodesis or reinsertion of chest tube; respiratory failure requiring mechanical ventilation more than 72 h or documented acute exacerbation (AE); hospital readmission due to surgical complication after hospital discharge.
Acute exacerbation was defined by the criteria of Akira et al.: increase in dyspnea within 30 days, newly developing opacities on chest radiography or HRCT, decrease in PaO2 of more than 10 mmHg under similar conditions, and absence of apparent infectious agents and heart disease [14].
2.3 Methods
All the data were obtained retrospectively from medical records. A pulmonary function test and arterial blood gas analysis were obtained within a week before the surgery in most of the subjects.
2.4 Statistical analysis
SPSS version 11.0 was used for the analysis. All values are given as the mean ± standard deviation. A chi-square test and/or Fisher's exact test were used for categorical data. Student's t-test for parametric data and the Mann–Whitney test for nonparametric data were used for continuous data. When parameters were dichotomized for comparison, the point showing the highest sensitivity and specificity was decided based on a receiver operator characteristic (ROC) curve. Multivariate analysis was performed through logistic regression. A p-value of less than 0.05 was considered statistically significant.
This study has been approved by the Institutional Review Board at Asan Medical Center. Patient consent was not available because of retrospective design.
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3. Results
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3.1 Mortality after surgical lung biopsy (Table 2)
The mortality rate of surgical lung biopsy at 30 days was 4.0% in all patients with IIP. No patient in COP group died at 30 days. However, there was no significant difference in the 30-day or 90-day mortality rate between IPF, NSIP, or COP. Among the eight patients who died, two patients were in acute exacerbation state at the time of surgical lung biopsy and another three patients developed AE after the surgical lung biopsy and died. The mortality rate of the patients with AE was 28.6%. Excluding these patients, the 30-day mortality rate of patients with IIP was reduced to 3.1%.
3.2 Comparison between IPF patients with and without acute exacerbation at the time of biopsy (Table 2)
The pathology of seven patients who underwent surgical lung biopsy at the time of AE showed both diffuse alveolar damage and usual interstitial pneumonia patterns. Baseline pulmonary function and oxygenation status were worse in AE than in non-AE. Compared to the patients without AE, the patients with AE had higher mortality and also had more frequent complications such as prolonged ventilator care (p
<
0.05). In two cases of IPF (1.4%) and in one case of NSIP (2.2%), AE was induced by surgical lung biopsy.
3.3 Postoperative complication of surgical lung biopsy
Among the three groups of IIP, no significant difference was found in the duration of chest tube drainage or hospital stay (Table 1). Postoperative complication developed mostly due to prolonged air leak in COP and prolonged ventilator care in the patients with AE (Table 2
).
3.4 Comparison between surgical procedures (Table 3)
VATS was started in August 1995 and became a major procedure from 1998. Although there were slight differences in DLCO and oxygenation status represented by AaDO2 between the two groups, the duration of chest tube drainage was significantly shorter in the VATS group than in the OLB. However, the 30-day mortality did not show any meaningful difference between the VATS and OLB groups.
3.5 Risk factors for postoperative complication and mortality in patients with IIP
3.5.1 Risk factors for the mortality
In patients with IIP (Table 4
), non-survivors had lower baseline lung function (FVC and DLCO) with poor oxygenation, and complication rate was higher than survivors.
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Table 4 Comparison between survivors and non-survivors on 30 days after the biopsy among total subjects with idiopathic interstitial pneumonia
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In univariate analysis, a lower FVC, a lower DLCO, a more severe dyspnea (higher MRC score), and the presence of AE were significant risk factors for 30-day mortality in total patients with IIP after the adjustment for age, sex, smoking status, and IPF diagnosis (p
< 0.05; Table 5
). However, multivariate analysis revealed that the presence of AE was the only independent risk factor for 30-day mortality and lower DLCO had a tendency (Table 5).
Among the 12 patients with IPF who died within 90 days after surgical lung biopsy, mortality was due to disease progression (five patients, 41.7%), pneumonia (four patients, 33.3%), AE induced by VATS (two patients, 16.7%), and unknown cause (one patient). The causes of 90-day mortalities in four patients with NSIP were disease progression (n
= 1), pneumonia (n
= 1), AE induced by VATS (n
= 1), and unidentified case (n
= 1). One patient with COP expired owing to disease progression within 90 days of surgical lung biopsy.
3.5.2 Risk factors for complication
According to the univariate analysis, male gender, smoking, a lower DLCO, and the presence of AE were significantly correlated with the development of complication. However, multivariate analysis revealed that only low DLCO and male gender were independent risk factors (Table 6
).
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Table 6 Multivariate analysis of risk factors for the complication in total patients with idiopathic interstitial pneumonia
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3.6 Predictors of postoperative mortality and complication
Acute exacerbation at the time of surgical lung biopsy had 37.5% of sensitivity for 30-day mortality, 97.4% of specificity, 37.5% of positive predictive value, and 97.4% of negative predictive value. Regarding the 30-day mortality, with the cutoff value of 50% of DLCO, the sensitivity was 75%, specificity 73.8%, positive predictive value 10.9%, and negative predictive value 98.6%. In the low DLCO group (n
= 55, DLCO
< 50% predicted), both the 30-day mortality (10.9% in lower DLCO group vs 1.4% in higher DLCO group, p
< 0.05) and complication rate (23.6% in lower DLCO group vs 10.0% in higher DLCO group, p
< 0.05) were much higher compared to higher DLCO group (n
= 140, 
50% predicted), suggesting that a low DLCO may be used as a predictive marker of high risk.
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4. Discussion
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We found that AE at the time of biopsy was a main contributor to high mortality in the patients with IIP. The mortality at 30 days after surgical lung biopsy was 28.6% in AE-IPF in contrast to 3.0% in stable IPF.
The risk of surgical lung biopsy for interstitial lung disease has been regarded as being low, while previous reports on the 30-day mortality rate after surgical lung biopsy have varied from 2.7 to 12.0% [7,9,11,12,15–17]. Lettieri et al. reported 30-day and 90-day mortality rates of 4.8 and 6.0%, respectively, among 83 patients with IIP and described that the only predictors of perioperative mortality were the need for mechanical ventilation and an immunosuppressed state at the time of biopsy [12]. After exclusion of these subjects, the overall 90-day mortality rate was only 1.5% [12]. However, Utz et al. observed 10 among 46 patients with IPF died within 30 days of surgical lung biopsy, which raised concerns about the safety [10]. Based on these literatures, we hypothesized that certain subset of IIP may have higher risk for surgical lung biopsy. In the literature, advanced age, diffuse alveolar damage pattern on usual interstitial pneumonia, lower DLCO, poor oxygenation state, requirement for mechanical ventilation, and immunosuppression in patients with IIP were reported to be related to higher mortality of surgical lung biopsy [10–13]. In our study, multivariate analysis demonstrated that only AE was independent risk factor for predicting mortality and low DLCO had only a trend to high mortality. However, in total patient group, the 30-day mortality in the low DLCO (>50% of predicted) group was significantly higher (10.9%) than the high DLCO group (1.4%), suggesting it as a marker of risk factor. Utz et al and Tiitto et al reported that lower DLCO was the only preoperative parameter correlated with mortality in surgical lung biopsy [10,11].
Although IPF is known as a slowly progressing fibrotic lung disease, some patients developed AE, the rapid progression of the disease without other known causes [14,18,19]. The most important differential diagnosis of AE is infection; we performed all the possible procedures to exclude infections in most of our patients. The development of AE after the surgical procedures has been reported before [19,20]. AE has now been recognized more frequently and in our experience, the 2-year frequency was 9.6% [19]. The high mortality in previous reports was because they included the patients with AE in their subjects. However, they could not recognize it because the concept of AE was not perceived at that time. In fact, in the report of Utz et al. 70% of mortality cases were in AE at the time of biopsy [10], and all deaths within 30 days in the report of Tiitto et al. occurred in patients with suspected AE [11]. Our data confirmed these findings.
Because single lung ventilation by double lumen endotracheal tube was performed in all patients of our study, we cannot compare the difference between single lung ventilation and conventional ventilation. Previous studies reported that single lung ventilation can have some benefits in the patients with severe respiratory insufficiency; however, anesthesiologist's knowledge and experience can be the most critical factor [21–23]. There are several limitations in our study. Because our study was retrospective, we cannot accurately assess the clinical benefit of surgical lung biopsy. However, other studies have already shown the value of surgical lung biopsy in patients with IIP [24,25]. Because our hospital is a tertiary referral center, our subjects may not be representative of the general population of IIP. However, mortality and complication rates comparable to other reports suggest that our subjects are not much biased from the overall population of IIP. Because surgical lung biopsy was not conducted in patients on mechanical ventilation in our study, we cannot assess whether the need for mechanical ventilation is a risk factor or not [12]. Another limitation is that the number of 30-day mortality may be too small to get a definite conclusion.
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5. Conclusion
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In patients with IIP, acute exacerbation at the time of biopsy was a predictor of higher mortality. In addition, lower DLCO (less than 50% predicted) was an independent risk factor for complication and possibly mortality in patients with IIP.
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Footnotes
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1 Both the authors equally contributed to this paper as a first author. 
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Abstract
1. Introduction
