Idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis. The 2002 international consensus classification of IIPs recommended by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) recognizes 7 distinct clinicopathologic entities.1 As these entities differ in prognosis and response to therapy, an accurate diagnosis is required. Idiopathic pulmonary fibrosis (IPF) with the histopathologic finding of usual interstitial pneumonia (UIP) is the most common type of IIP.2 The diagnosis of IPF is based on clinical findings, typical features of IPF observed on high-resolution CT (HRCT), and exclusion of other diseases. In the absence of typical clinical and radiographic features of IPF or if there is uncertainty about the diagnosis, surgical lung biopsy (SLB) is needed for the definitive diagnosis of UIP/IPF.2
Recently, the role of SLB has been considered acceptable since the advent of video-assisted thoracoscopic surgery (VATS). SLB for interstitial lung disease is relatively safe, and its overall mortality rate for a variety of indications is less than 1%, and morbidity is approximately 10% to 20%.3 Elements that indicate high risk include mechanical ventilation, marked impairment of lung function (forced expiratory volume in one second<1 L), coagulopathy, immunosuppression, pulmonary hypertension, severe hypoxia, and rapid deterioration of underlying lung disease.4 Kreider et al5 demonstrated that the risk of postoperative complications seemed to be greatest in those dependent on oxygen and those who have pulmonary hypertension. In addition, a recent report showed a high mortality rate (21.7%) in patients with IPF after SLB, and noted that patients with IPF may be at a higher risk for death after SLB than those with other interstitial illnesses.6 The most frequent cause of death in these patients is acute respiratory failure and examination of biopsy specimens has shown diffuse alveolar damage superimposed on IPF.5,7 These findings could be considered to represent acute exacerbation of IPF after SLB. Although IPF has been described as a gradually progressive disease, acute exacerbation is increasingly recognized as a relatively common and highly morbid clinical event in patients with IPF.8 Although the pathogenesis of acute exacerbation of IPF remains unclear and acute exacerbation seems to occur at any time during the course of the disease, several reports have suggested that SLB may be a risk factor.5,6,9,10
Therefore, we retrospectively reviewed the status of performing VATS biopsy during a 13-year period (1994 to 2006) and analyzed its complications, in particular, risk of acute exacerbation of IPF.
PATIENTS AND METHODS
The study subjects comprised patients who underwent biopsy by VATS for a definite diagnosis of diffuse parenchymal lung disease in the 13 years from January 1994 to December 2006 at our hospital. The diagnoses of IPF, nonspecific interstitial pneumonia (NSIP), and cryptogenic organizing pneumonia (COP) were made according to the ATS/ERS consensus classification1 after review and reclassification of pathologic specimens and results of HRCT. Information on patient background, operations, perioperative care, and details of sample collection, postoperative complications, and histologic diagnosis were collected from patient charts and operation/anesthesia records, and examined retrospectively. Pulmonary function tests (forced vital capacity, FVC); percentage of predicted FVC (%FVC); forced expiratory volume in one second (FEV1.0); percentage of predicted carbon monoxide diffusing capacity (%DLco); blood gas analysis (PaO2); and serum markers for interstitial pneumonia [KL-6, surfactant protein (SP)-A and SP-D] were retrospectively evaluated. Serum KL-6 was measured by a sandwich ECLIA for routine laboratory use (Picolumi KL-6, Sanko, Tokyo, Japan). SP-A was measured by enzyme-linked immunosorbent assay using monoclonal antibodies to human SP-A (SP-A test, Kokusai, Tokyo, Japan) and SP-D was measured by enzyme-linked immunosorbent assay using monoclonal antibodies to human SP-D (SP-D EIA kit, Yamasa, Tokyo, Japan). A pulmonary function test, arterial blood gas analysis, and serum markers were obtained within a month before VATS for all the patients. As postoperative complications, data on persistent fever (7 days or longer) including pneumonia, prolonged duration of oxygen inhalation (10 days or longer), and extended periods of drainage tube placement (7 days or longer) were examined. In addition, acute exacerbation after VATS was declared according to the following criteria proposed by the Japanese Respiratory Society: (1) diagnosis of IPF, (2) worsening of dyspnea within a month, (3) new infiltrates on chest HRCT, (4) worsening gas exchange as determined by a decline of 10 mm Hg in PaO2, and (5) exclusion of pulmonary infection, pneumothorax, malignancy, pulmonary thromboembolism, and heart failure.11 Contraindications for VATS in our hospital were (1) an acute exacerbation before VATS and (2) need for mechanical ventilation before VATS. This study was approved by the Institutional Review Board at Jichi Medical University Hospital.
All values were given as mean±SD. A χ2 statistical test or Fisher exact test was used for categorical data. Unpaired Student t test for parametric data and the Mann-Whitney test for nonparametric data were used for continuous data. A P value of less than 0.05 was considered statistically significant. All data were analyzed using SPSS version 11.0.
There were 113 patients who underwent biopsy by VATS during the 13 years of the study period. Sample collection by VATS was carried out from the right in 81%, and 2 or more samples were collected in 91% of the patients. The most frequent biopsy pattern was 1 sample each from the upper and lower lobes. An earlier lung resection and severe pleural adhesion were the main causes for the collection of only 1 sample. The final diagnoses in these cases are shown in Table 1. IIPs were the most frequent diagnosis, being found in 52 cases; among these, IPF was most frequently observed (34 cases), followed by NSIP and COP in that order.
Number of VATS Performed in Each Year Studied
The proportion of VATS for the diagnosis of IPF peaked in 1995 and decreased thereafter (Fig. 1) . VATS was carried out to differentiate IPF from other types of diffuse parenchymal lung disease in cases that did not have the typical clinical course or image findings of IPF. Several cases were histologically diagnosed as having IPF by VATS every year.
Demographic and Clinical Characteristics of Patients With Interstitial Pneumonia
Patients with IPF were significantly older and more likely to be male than those with the other types of interstitial pneumonia (Table 2). Before VATS, IPF cases had average values of 82.0% FVC and 44.0% DLco. %DLco in patients with IPF was significantly lower than that in patients with chronic hypersensitivity pneumonitis. However, there were no other significant differences with regard to other demographic data.
Perioperative Status of VATS
Average operation time was 56 minutes, and was 60 minutes or longer in 7% of cases examined (Table 3). Anesthesia was given for an average of 141 minutes and for 180 minutes or longer in 15% of patients. The average duration of drainage was 4.6 days; 18.1% of patients required drainage for 7 days or longer (Table 4). Postoperative duration of oxygen inhalation was 5.6 days on average and 10 days or longer in 14.9% of patients (Table 4). Transition to long-term oxygen therapy was observed in 3 cases. Operation time in IPF patients was significantly shorter than that in non-IPF patients, but there were no other significant differences in these parameters between the groups.
Complications of VATS
Postoperative complications included early-period death by postoperative acute exacerbation, persistent fever including pneumonia, prolonged duration of oxygen inhalation, and extension of drainage periods (Table 4). Complications were more frequently found in IPF cases than in patients with other IIPs and all deaths were observed in IPF cases. Acute exacerbation after VATS occurred in 2 IPF cases and was fatal in both of these patients (mortality rate in all cases, 1.8%; mortality rate in interstitial pneumonia cases, 2.1%; mortality rate in IPF cases, 5.9%). The 2 patients who died from post-VATS acute exacerbation were identified before 2000 when ATS/ERS published the clinical diagnostic criteria for IPF. Both patients (55- and 65-year-old men) had a history of heavy smoking and gradually worsening exertional dyspnea of 6 months' duration. A HRCT scan revealed honeycombing primarily in the lung bases in both patients, presenting with typical IPF, which could have been clinically and radiographically diagnosed at this time. One case was diagnosed as acute exacerbation based on the Japanese Respiratory Society diagnostic criteria because VATS was followed by the appearance of bilateral diffuse ground-glass shadows as revealed by the CT scan in 10 days. The patient was placed on a ventilator and was treated with 3 courses of intravenous corticosteroid pulse therapy using methylprednisolone but died from complicated pneumothorax 57 days after VATS. The other case was diagnosed as acute exacerbation at 3 days of VATS. This patient was also treated with mechanical ventilation as well as 5 courses of similar corticosteroid pulse therapy and immunosuppressive therapy using cyclosporine-A, but died 74 days after VATS. Neither of the patients was decided to have respiratory infection based on bacteriologic examination of bronchial aspirates.
Comparison of Parameters Between 32 IPF Cases that did not Develop Acute Exacerbation and 2 Fatal IPF Cases had Acute Exacerbation After VATS
As there were only 2 fatalities, it was difficult to find a statistically significant marker (Fig. 2). Nevertheless, all cases had ventilation restriction and diffusion disturbance, and in both fatalities the %FVC and %DLco were below 55 and 40, respectively. Serum markers for interstitial pneumonia, KL-6 and SP-D, were both elevated. There was no difference in operation and anesthesia time between the 2 groups, but 100% oxygen was inhaled for 80 minutes or longer during the operation and drainage periods after the operation were as long as 10 days or longer in the 2 patients who died. Both the deaths that were caused by acute exacerbation after VATS occurred before 2000. Since then no acute exacerbation after VATS has been observed. All patients undergoing VATS in 2000 or later had a %FVC value of 55 or higher and %DLco of 40 or higher. Among all the cases that were examined, with one exception, 100% oxygen was inhaled for less than 60 minutes and drainage duration was 7 days or less.
In this study, the proportion of IPF cases among all VATS cases decreased around 2000. However, VATS continues to be performed in our department to differentiate IPF in cases without a clinical picture or CT scan findings typical of IPF. As a result, several cases of IPF continue to be diagnosed every year in our department. An accurate diagnosis of IPF is important, given the prognostic differences among the various IIPs. In 2000, the ATS suggested an iterative approach to diagnosis that incorporated all the available data in reaching a final diagnosis.2 HRCT scanning is particularly helpful in diagnosing certain specific diffuse parenchymal lung diseases, including IPF. Hunninghake et al12 noted that lower lobe honeycombing and upper lung irregular lines were predictive of an HRCT diagnosis of UIP. The high degree of consistency of HRCT in showing the typical features of UIP has resulted in widespread acceptance of this technique in international guidelines. Studies have shown that clinical criteria and HRCT scans provide an accurate diagnosis in up to three-quarters of cases of interstitial lung diseases or suspected IPF.13–15 Although the diagnosis of IPF may be assured without the need for an SLB in an appropriate clinical setting, caution should be exercised when features are atypical. At present, even by HRCT, it is hard to distinctly differentiate atypical IPF from fibrotic NSIP. Flaherty et al16 reported that a radiologic diagnosis of probable or definite NSIP was confirmed pathologically in only 41% of cases; in the remainder of the cases, histologic findings after SLB indicated UIP. Given the diagnostic limitations of HRCT imaging and the prognostic importance of a UIP diagnosis, lung biopsy continues to play an important role in the evaluation of a patient with interstitial pneumonia. Therefore, it is expected that atypical IPF cases will be increasingly diagnosed by VATS. In the near future, it is important to elucidate the clinical manifestations of atypical IPF cases as well as clarify their differences from typical IPF cases so that the necessity of SLB in atypical IPF cases can be reconsidered.
In this study, postoperative complications were early-period death by postoperative acute exacerbation, persistent fever including that from pneumonia, prolonged duration of oxygen inhalation, and extension of chest tube drainage periods. Complications were frequently found in IPF cases and all deaths in this series of patients were in IPF cases (mortality rate in all cases, 1.8%; mortality rate in IPF cases, 5.9%). Recent reports suggest that operative mortality and morbidity are limited in IPF patients who undergo SLB as part of diagnostic evaluation.7,17 Mortality rate was as low as 1.5% in patients who did not require mechanical ventilation and were not immunocompromised when they underwent VATS.17 Rena et al18 reported that postoperative complications after VATS were rare, with 2 patients experiencing prolonged air leakage for more than 5 days. Elements that indicate high risk include mechanical ventilation, marked impairment of lung function, coagulopathy, immunosuppression, pulmonary hypertension, severe hypoxia, and a rapid deterioration of underlying lung disease. Utz et al6 showed that patients with UIP of the idiopathic type who present with atypical features may be at higher risk for death after SLB than patients presenting with more typical features or patients with other interstitial illnesses.
In this study, histologically diagnosed UIP, impaired lung function (%FVC, <55; %DLco, <40), elevated KL-6 and SP-D, which are serum markers for interstitial pneumonia; long inhalation of 100% oxygen during surgery; and prolongation of postoperative drainage periods were considered to be risk factors for acute exacerbation after VATS. Acute exacerbation of IPF seems to occur at any time during the course of the disease with no clear association with age or smoking history.8 Martinez et al19 showed that patients with a lower FVC had more total and respiratory hospitalizations during subsequent follow-up. Earlier reports suggested that SLB may be a risk factor of acute exacerbation of IPF,9,10 although distinguishing these cases from postsurgical acute respiratory distress syndrome is difficult.8 Kreider et al5 also showed that biopsy may rarely trigger acute exacerbation of UIP. To our knowledge, however, there are no gold-standard predictors of acute exacerbation of IPF by SLB. Utz et al6 examined UIP cases that had acute exacerbation after SLB and reported that it occurred in cases with low %DLco. Park et al20 also reported that lower DLco (<50% predicted) was associated with death after SLB. In our data, the serum markers for interstitial pneumonia, KL-6 and SP-D, were both elevated in 2 patients with acute exacerbation of IPF after VATS. KL-6, a high MW mucin-like glycoprotein, has been reported to be a sensitive marker for interstitial lung diseases, such as IPF, and collagen vascular diseases associated with interstitial pneumonia.21 A higher level of serum KL-6 is associated with active interstitial pneumonia, and KL-6 is supposed to reflect the number of regenerating type 2 epithelial cells. Yokoyama et al22 suggested that circulating KL-6 predicts the outcome of rapidly progressive IPF. In contrast, the hydrophilic SP-A and SP-D, which belong to the collection subgroup of the C-type lectin superfamily, also proved to be useful markers in patients with IPF. Takahashi et al23 showed that serum levels of SP-A and SP-D were correlated with the extent of ground-glass opacities seen on HRCT. High levels of KL-6 and SP-D in sera of the IPF patient have been shown to be predictive of poor survival.24,25 Therefore, monitoring the circulating levels of these 2 biomarkers before SLB may be useful predictors of acute exacerbation of IPF after VATS. In our study, acute exacerbation after VATS was found only in IPF cases. However, as acute exacerbation was found not only in IPF cases and acute exacerbation of NSIP has been reported,26 its mechanism largely remains to be clarified. Kondoh et al27 showed that acute exacerbation after SLB occurred in patients with NSIP and COP.
In our department, given the experience of patients having fatal acute exacerbation before 2000, VATS has not been performed since that time in cases with restricted ventilation and reduced diffusion (%VC, <55; %DLco, <40). In addition, when serum markers for IPF are elevated and high activity of IPF is diagnosed, indications for VATS should be evaluated carefully and the period of intraoperative inhalation of 100% oxygen should be shortened as much as possible. Our data are also considered to provide important information for risk evaluation and perioperative care in surgical resection of lung cancer associated with IPF, a condition in which acute exacerbation after surgery has been observed and which sometimes has a poor prognosis.
In conclusion, given the potential risks and a better definition of the diagnostic accuracy of a diagnosis by HRCT scan, VATS is not required in all patients with suspected IPF. In any case, since there has been no large-scale prospective study to evaluate the risk of VATS in patients with interstitial pneumonia, factors involved in the occurrence of complications including acute exacerbation should be elucidated and indication and contraindication criteria of VATS for interstitial pneumonia patients should be established.
1. American Thoracic Society/European Respiratory Society. International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2002;165:277–304.
2. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:646–664.
3. Mckenna RJ Jr. Thoracoscopic evaluation and treatment of pulmonary disease. Surg Clin North Am. 2000;80:1543–1553.
4. Riley DJ. Risk of surgical lung biopsy in idiopathic interstitial pneumonias. Chest. 2005;127:1485–1486.
5. Kreider ME, Hansen-Flaschen J, Ahmad NN, et al. Complications of video-assisted thoracoscopic lung biopsy
in patients with interstitial lung disease. Ann Thorac Surg. 2007;83:1140–1145.
6. Utz JP, Ryu JH, Douglas WW, et al. High short-term mortality following lung biopsy for usual interstitial pneumonia. Eur Respir J. 2001;17:175–179.
7. Tiitto L, Heiskanen U, Bloigu R, et al. Thoracoscopic lung biopsy is a safe procedure in diagnosing usual interstitial pneumonia. Chest. 2005;128:2375–2380.
8. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176:636–643.
9. Kumar P, Goldstraw P, Yamada K, et al. Pulmonary fibrosis and lung cancer: risk and benefit analysis of pulmonary resection. J Thorac Cardiovasc Surg. 2003;125:1321–1327.
10. Yüksel M, Özyurtkan MO, Bostanci K, et al. Acute exacerbation of interstitial fibrosis after pulmonary resection. Ann Thorac Surg. 2006;82:336–338.
11. Japanese Respiratory Society. Idiopathic Interstitial Pneumonias. Diagnosis and Treatment. Nankaido, Tokyo: 2004.
12. Hunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest. 2003;124:1215–1223.
13. Peckham RM, Shorr AF, Helman DL Jr. Potential limitations of clinical criteria for the diagnosis of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis. Respiration. 2004;71:165–169.
14. Raghu G, Mageto YN, Lockhart D, et al. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease. Chest. 1999;116:1168–1174.
15. Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001;164:193–196.
16. Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58:143–148.
17. Lettieri CJ, Veerappan GR, Helman DL, et al. Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest. 2005;127:1600–1605.
18. Rena O, Casadio C, Leo F, et al. Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease. Eur J Cardiothorac Surg. 1999;16:624–627.
19. Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–967.
20. Park JH, Kim DK, Kim DS, et al. Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia. Eur J Cardiothorac Surg. 2007;31:1115–1119.
21. Kohno N, Kyoizumi S, Awaya Y, et al. New serum indicator of interstitial pneumonitis activity: sialylated carbohydrate antigen KL-6. Chest. 1989;96:68–73.
22. Yokoyama A, Kohno N, Hamada H, et al. Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158:1680–1684.
23. Takahashi H, Fujishima T, Koba H, et al. Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent. Am J Respir Crit Care Med. 2000;162:1109–1114.
24. Yokoyama A, Kondo K, Nakajima M, et al. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology. 2006;11:164–168.
25. Greene KE, King TE Jr, Kuroki Y, et al. Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis. Eur Respir J. 2002;19:439–446.
26. Park I-N, Kim DS, Shim TS, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest. 2007;132:214–220.
27. Kondoh Y, Taniguchi H, Kitaichi M, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med. 2006;100:1753–1759.