Eur J Cardiothorac Surg 2006;30:657-662
© 2006 Elsevier Science NL
Acute interstitial pneumonia following surgery for primary lung cancer
Masashi Muraokaa,*,
Tsutomu Tagawaa,
Shinji Akaminea,
Tadayuki Okaa,
Tomoshi Tsuchiyaa,
Masato Arakia,
Tomayoshi Hayashib,
Takeshi Nagayasua
a Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
b Division of Pathology, Nagasaki University Hospital, Nagasaki, Japan
Received 21 April 2006;
received in revised form 4 June 2006;
accepted 26 June 2006.
* Corresponding author. Address: Department of Chest Surgery, Oita Prefectural Hospital, 476 Ohaza-Bunyou, Oita 870-8511, Japan. Tel.: +81 97 546 7111; fax: +81 97 546 0725. (Email: mmuraoka{at}oitakenbyo.jp).
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Abstract
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Objective: Although acute interstitial pneumonia is a life-threatening complication following surgery for lung cancer, the cause and risk factors for acute interstitial pneumonia remain unknown. We conducted this study to determine the characteristics of acute interstitial pneumonia after pulmonary resection and to identify the risk factors for this disease. Methods: We experienced 16 (2.0%) cases of acute interstitial pneumonia among 822 patients who underwent pulmonary resection for primary lung cancer over a period of 12 years. We performed a retrospective analysis of these patients, comprising the patients’ background, the operative procedure, the radiographic characteristics and the prognosis. Results: In all patients, the shadow appeared within 1 week after the operation. Twelve patients required mechanical ventilatory support due to the development of respiratory failure. The site of the tumor (right side), preoperative radiation or chemotherapy, pneumonectomy, blood transfusion, and intraoperative complication were independent risk factors for the incidence of acute interstitial pneumonia (P
= 0.001, 0.0484, 0.0012, 0.0002, 0.0003, respectively) in the multivariate analysis. Nine of the 16 patients died due to respiratory failure, resulting in a mortality rate of 56.3%. The maximum amount of lactate dehydrogenase (LDH) in the operative death patients was significantly higher than that in the survivors (472 ± 138 IU/l vs 257 ± 79 IU/l, respectively, P
= 0.0031). Conclusions: We concluded that in order to reduce the incidence of acute interstitial pneumonia, it is necessary to perform careful postoperative management for patients who are male, have right lung disease, have undergone preoperative chemo or radiation therapy, or have undergone pneumonectomy.
Key Words: Acute respiratory distress syndrome (ARDS) • Lung cancer surgery • Outcomes (operative mortality)
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1. Introduction
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With advances in the techniques for managing preoperative and postoperative care, mortality and morbidity have been decreasing in thoracic surgery [1]. However, on rare occasions patients develop postoperative acute interstitial pneumonia (AIP) that is of unknown cause and that often progresses to respiratory failure during the early postoperative course. These patients did not exhibit any indication for preoperative interstitial pneumonia or pulmonary fibrosis [2]. Kutlu et al. [3] recently reported that the frequency of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after pulmonary resection was 3.9%, and caused 72.5% of the total mortality after pulmonary resection. ALI/ARDS might include a variety of life-threatening diseases, such as noncardiogenic pulmonary edema including postpneumonectomy pulmonary edema (PPE), AIP, etc. Diffuse pulmonary infection, including some bacterial, viral, or pneumocystis were risk factors for ARDS [4]. Although postoperative ALI/ARDS is widely recognized as a cause of acute respiratory failure by many thoracic surgeons, only a few reports [5] examining the cause and clinical features of postoperative AIP are available.
We conducted this study to determine the characteristics of AIP after pulmonary resection for lung cancer and to identify the risk factors for this disease.
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2. Patients and methods
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Between January 1992 and May 2003, 822 patients with lung cancer at the Nagasaki University Hospital underwent pulmonary resection. During this period, we experienced 16 cases (2.0%) of AIP after pulmonary resection for the treatment of lung cancer (AIP group). The clinical characteristics of the patients are shown in Table 1
. Fifteen patients were male (94%) and one was female (6%), and their median age was 65 years (range, 48–79 years).
We used the new international consensus statement of idiopathic interstitial pneumonias (IIPs) to diagnose AIP [6]. The clinical symptoms and signs generally include fever, cough, and shortness of breath, all of which present acutely (days to weeks from the onset of symptoms). Diffuse, bilateral airspace opacification is seen on chest radiograph, and computed tomography (CT) can demonstrate bilateral, patchy, symmetrical areas of ground glass attenuation. Bilateral areas of airspace consolidation may also be present, and a predominantly subpleural distribution may be observed. Most patients have moderate to severe hypoxia and develop respiratory failure. Patients with chronic interstitial pneumonia or idiopathic pulmonary fibrosis before surgery were excluded from this study.
We analyzed the background of the patients, operative procedures, laboratory data including the white blood cell count (WBC), C-reactive protein (CRP), the serum lactate dehydrogenase (LDH) on the 1st, 2nd, 3rd, 5th, 7th, 10th, and 14th postoperative days (POD), and the treatment of AIP in 16 patients. KL-6 was measured in three recent patients. Chest radiograph was routinely taken on the 1st, 2nd, and 3rd POD and on the day after chest tube removal. Additional chest radiographs were taken, depending upon the patients’ clinical state, as opposed to including all symptoms and signs. If infiltrates were revealed on chest radiograph, which would suggest ARDS, acute pulmonary embolism (APE) or AIP, high-resolution CT (HRCT) scan was performed for the differential diagnosis of these lung diseases. Cultures of sputum and bronchoalveolar lavage were performed via bronchoscopy at least twice to exclude infection in the AIP group. Polymerase chain reaction (PCR) for cytomegalovirus (CMV) and serum antibodies for CMV, influenza, herpes simplex, varicella, EB virus, etc. were performed after the appearance of radiographic abnormalities in this series.
To determine the risk factors for postoperative AIP, we performed a retrospective analysis of 16 patients who developed AIP compared to 806 patients who underwent pulmonary resection for primary lung cancer during the same period and did not develop AIP (control group). If intraoperative major vascular injury in pulmonary artery or vein, which needed additional procedures including the vascular reconstruction or extended pulmonary resection, would be occurred, these cases were considered as the intraoperative complications. And if the intended surgery had to be altered due to some intraoperative situation or unexpected disease progression, they were counted into the complications. The need for blood transfusion was decided by the each anesthesiologist considering the amount of blood loss and the hemodynamics of the each patient.
The institutional review board approved this study, and informed consent was obtained from the patients or their families in the AIP group prior to their inclusion in this investigation. Statistical analysis of the data was performed using StatView version 5.0 software (SAS Institute Inc., Cary, NC, USA). The Student's t-test and the Fisher's exact test were used for the univariate analysis. In the multivariate analysis, any variables with a P value of less than 0.2 in the univariate analysis, which tend to be associated with the incidence of AIP, were included. In all tests, the level of statistical significance was set at 5% (P
< 0.05).
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3. Results
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The overall frequency of AIP was 2.0% (16/822) in this series. Abnormal radiographs were observed in 42 patients during this period: pneumonia in 19 patients, atelectasis in 16, pulmonary embolism in 3, heart failure with pulmonary edema in 2, deterioration of pulmonary fibrosis and acute empyema in 1 each. One other patient developed respiratory failure after a complication of bronchopleural fistula, which was diagnosed as ARDS based on radiographic and clinical findings.
The preoperative co-morbidities of the 16 patients are also shown in Table 1. Thirteen of these patients (81%) exhibited a co-morbid condition. Two patients had synchronous carcinomas in other organs; one had gastric cancer and the other had esophageal and gastric cancer. Radical surgery was performed on these two patients at the same time as the pulmonary resection for lung cancer. Two additional patients had metachronous carcinomas in the tongue and pharynx, and radiotherapy was performed after surgery at doses of 45 and 60 Gy, respectively. One patient underwent induction chemotherapy with two courses of cisplatin (80 mg/m2, day 1), vinorelbine (25 mg/m2, day 1 and 8), and mitomycin C (8 mg/m2, day 1), 4 weeks prior to the resection, due to advanced local lung disease with mediastinal lymph node involvement (C-T3N2M0). Although this patient had a partial response to chemotherapy, he underwent a right pneumonectomy for complete resection of the hilar tumor.
There were nine patients with a performance status (PS) of 0 and 6 with PS 1, and 1 with PS 2. The preoperative pulmonary function of the 16 patients were as follows (mean ± standard deviation): vital capacity (VC) was 3340 ± 780 ml, %VC was 105 ± 18%, forced expiratory volume in 1.0 s (FEV1) was 2290 ± 670 ml, FEV1% was 69.7 ± 10.6%, percent diffusing capacity of carbon monoxide (%DLCO) was 87.3 ± 28.6%, PaO2 was 85.9 ± 10.5 Torr, and PaCO2 was 39.4 ± 4.2 Torr. Seven of the 16 patients had borderline obstructive pulmonary dysfunction. However, we determined that these patients were able to undergo surgery because their predicted postoperative (postop) FEV1 after surgery was >600 ml/m2, when calculated according to the method formulated by Nakahara et al. [7] or using the preoperative quantitative perfusion or ventilation scan. Brinkman's smoking index (calculated by multiplying the number of cigarettes per day by the number of years the patient had smoked) ranged from 0 to 1800 (931 ± 469 = 46.6 ± 23.5 packs-year).
Lobectomies were performed in 11 patients. Bilobectomies and pneumonectomies were performed in two and three patients, respectively, in the AIP group. In three patients, the intended surgery had to be altered intraoperatively; pneumonectomies in two and a combined resection of the chest wall in one, due to an injury of the main pulmonary artery or progression of the disease that was more advanced than anticipated. Another two patients suffered from intraoperative vascular injury. These five patients were considered as cases of intraoperative complication. Complete resection was performed in all patients except for one, who had microscopic residual tumor in the bronchial stump after right middle and lower lobectomy. Systematic mediastinal lymph node dissections were performed in 12 patients (75%) and hilar node dissection with mediastinal lymph node sampling was performed in 4 patients (25%). Of the 822 patients treated during this period, none who underwent limited resection, including segmentectomy or partial resection of the lung (173 patients), developed AIP.
The histological type and stage of lung cancer of the 16 patients are shown in Table 1. In the resected specimens, there was no preoperative evidence of fibrosis or interstitial pneumonia. Details of the surgical procedures and postoperative laboratory data are shown in Table 2
.
In the patients of AIP group, airspace consolidation or a ground glass attenuation on chest radiograph usually occurred within 1 week after the operation; the infiltrates appeared within 3 days after the operation in 10 patients (62%), in 3 patients (19%) the infiltrates were detected on the 4th or 5th POD, and on the 6th or 7th POD in another 3 patients (19%). A radiographic abnormality was sequentially revealed on the other side of the resected lung in 12 patients, or in the bilateral lung in 2, and on the same side in 2. These infiltrates of the all patients developed to the bilateral lung in a few days. None of the patients exhibited bacterial infection in the airway at the onset of the infiltrates. Viral infections were excluded by PCR and the lack of serum antibodies. Hypoxia and dyspnea appeared on the same day as the appearance of the infiltrates. The infiltrates spread to all areas of the lung field in all 16 patients, developing into respiratory failure requiring admission to the intensive care unit (ICU). The period of ICU stay was 23.3 ± 17.7 days.
Twelve patients (75%) required mechanical ventilatory support for 15.8 ± 10.8 days. Steroid pulse therapy with intravenous methylprednisolone ranged from 500 to 1000 mg per body for 3 days was initiated in 14 patients from the day on which the infiltrates appeared, and continued in 9 patients for two or three courses at 1-week intervals. The other two patients who did not receive methylprednisolone therapy were initially suspected of suffering from a pulmonary embolism or a mixture of aspiration pneumonia and infection, but were diagnosed with AIP retrospectively, based on the course of their illness, HRCT findings, and the pathological findings at autopsy. Percutaneous cardiopulmonary support (PCPS) was introduced for severe hypoxia in two patients, but these patients died on the 13th and 22nd POD, respectively. Recently, we administered Sivelestat sodium hydrate (ELASPOL®) to two patients who suffered from AIP after pulmonary resection, beginning just after tracheal intubation, due to severe hypoxia. These two patients recovered from respiratory failure.
We analyzed the risk factors associated with AIP. In the univariate analysis (Table 3
), age (elderly patients 
70 years old) and gender (male) tend to be associated with a higher incidence of AIP than the patients under 70 years old or those who were female; however, this difference was not significant (P
= 0.1287 and 0.0515, respectively). Although 16 of the 464 patients with right-sided tumors had AIP, none of the 358 patients with left-sided tumors developed this complication. Therefore, the site of the tumor (right side) was a significant risk factor for AIP (P
= 0.0001). The co-morbidity of synchronous or metachronous cancer was not a risk factor for AIP (P
= 0.5178), whereas preoperative radiation or chemotherapy was a significant risk factor (P
= 0.0410). The patients who underwent pneumonectomy suffered from AIP more frequently than the patients who underwent other operations (14% vs 1.6%, respectively, P
= 0.0065). Mediastinal lymph node dissection was not a risk factor for AIP (P
= 0.2089). The patients who required a blood transfusion due to intraoperative hemorrhage developed AIP more frequently than patients who did not require a blood transfusion (10% vs 1.4%, respectively, P
= 0.0018). Intraoperative complications in five patients were a risk factor for AIP (P
= 0.0021). In multivariate analysis, the tumor site (right side), preoperative radiation or chemotherapy, pneumonectomy, blood transfusion and intraoperative complications were all independently associated with an increased incidence of AIP (Table 4
).
Nine of the 16 patients died within 30 days after surgery due to the development of respiratory failure with multi-organ failure, resulting in a mortality rate of 56.3%. We also analyzed the patients who died postoperatively (n
= 9) and compared them to the survivors (n
= 7) in Table 5
. The serum LDH levels were significantly higher in the nonsurvivors compared to the survivors (472 ± 138 IU/l vs 257 ± 79 IU/l at the maximum point, respectively, P
= 0.0031). However, none of the parameters, including the serum LDH, increased before the appearance of infiltrates on chest radiograph. Therefore, using biochemical parameters we were not able to predict the onset, prior to the onset of symptoms and the appearance of the infiltrates on chest radiograph.
We did not perform a lung biopsy, but autopsies were available for five patients. These lung specimens showed diffuse alveolar damage (DAD), which suggested the end-stage of respiratory failure due to AIP.
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4. Discussion
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Recently the American Thoracic Society (ATS) and European Respiratory Society (ERS) proposed a new international consensus statement for idiopathic interstitial pneumonias, in which they categorized AIP as a rare fulminant form of lung injury that presents acutely, usually in a previously healthy individual [6]. They insisted that the diagnosis of AIP requires the presence of the clinical syndrome of idiopathic ARDS and pathological confirmation of organizing DAD. We diagnosed 16 patients with AIP, based on their clinical course and the radiographic findings, but could not confirm the pathological findings except for in the 5 patients who were autopsied. Ichikado et al. [9] and Johkoh et al. [8] insisted that a combination of ground glass attenuation, air space consolidation, traction bronchiectasis, and architectural distortion is observed on HRCT in the majority of patients with AIP, which correlated well with the pathology. Therefore, we determined that our patients were highly likely to have AIP according to their HRCT findings, although we were not able to obtain pathological confirmation in all cases. Indeed, it was very difficult to determine the diagnosis of the patients as AIP distinct from ARDS, based on the rigorous medical definition, because these patients were considered to be suffering from ARDS or ALI in the broad clinical sense. However, there was no risk factor in our patients except for pulmonary resection, whereas ARDS usually has some risk factors, including diffuse pulmonary infection, toxic inhalation, lung contusion, etc. [4]. According to these clinical features, HRCT findings in 16 patients, and pathology in several cases, we defined the patients in the AIP group as postoperative AIP.
We experienced AIP only in those patients who underwent pulmonary resection in the right side. Some reviewers experienced AIP after pulmonary resection only in the patients who had advanced lung cancer in the right lung and required aggressive lymphadenectomy. These facts suggest that the cause of AIP after surgery may be related to lymphatic flow between the lung and mediastinum [10]. Furthermore, another group has insisted that they did not experience AIP after pulmonary resection for benign disease that did not require lymph node dissection, although two patients suffered from AIP after surgery for lung cancer [2]. Another surgeon expressed doubt that lymphadenectomy for advanced lung cancer was the cause of AIP. However, in our multivariate analysis, mediastinal lymph node dissection was not an independent risk factor for the incidence of AIP.
Yano et al. [11] reported that the need for pneumonectomy was a predominant risk factor for life-threatening morbidity. Pneumonectomy is one of the most invasive operations among all the types of pulmonary resection, which remove almost half of the lung. To determine the indication for pneumonectomy, we usually perform a pulmonary arterial occlusion test and evaluate residual pulmonary function using the quantitative perfusion or ventilation scan prior to this operation [12]. However, we were not able to perform these examinations in two patients in this series because the operation methods were converted to a pneumonectomy during the procedure due to intraoperative findings. In our study, we experienced 3 cases (14%) of AIP after pneumonectomy among 22 patients who underwent pneumonectomy for lung cancer within the same period. Pneumonectomy was a significant risk factor for AIP compared to the other operations, and intraoperative complication was also one of the risk factors for AIP after pulmonary resection.
WBC, CRP, and LDH increased upto two or three times above the upper limit of their respective normal ranges, but we were not able to find any parameters that enabled us to predict the incidence of AIP; including KL-6, which is a serum marker for IIPs [13]. We were only able to measure KL-6 in three cases in this series. However, KL-6 may eventually become a useful biomarker in the diagnosis of AIP that is distinct from the usual ARDS. LDH is also a well-known biochemical marker of the activity in interstitial pneumonia [14,15], and the maximum LDH in the operative death patients was significantly higher than that in the survivors in this study. However, the increase of LDH was gradual and occurred during the late phase of AIP, which might suggest an irreversible change in the lung. Therefore, LDH might not be a predictor of the prognosis of AIP during the early stage of the disease.
In 1986, Katzenstein et al. [16] reported eight cases of AIP, and suggested that AIP differs clinically from chronic interstitial pneumonias by a sudden onset and rapid course. These investigators reported that 5 of the 8 patients (63%) died of respiratory failure from 23 days to 2 months after the onset of AIP. In the new international consensus statement of IIPs proposed by ATS and ERS, the mortality from AIP is over 60%, with the majority of patients dying within 6 months of presentation. The mortality for AIP in our study (56%) was almost the same as those described previously [6,16], which ranged from 56% to 63%.
Some researchers presumed that there was a relationship between the incidence of AIP and viral infection [5,17]. Okamoto et al. [18] reported that they experienced AIP and an exacerbation of IP in patients with poorly differentiated squamous cell carcinoma. However, the AIP patients in our study did not exhibit any elevation of antibodies to viruses or any deviation of the proportion of the histological types of carcinoma (Table 1). Although the cause of AIP remains controversial, we were able to determine several risk factors for the incidence of AIP in this study.
Several investigations have reported the exacerbation of IP following surgery for lung cancer in preoperative IP patients, and have described several risk factors for this deterioration [18,19]. For these patients, steroids or a neutrophil elastase inhibitor can be used to prevent the exacerbation of IP. Following the same concept, steroid therapy during the early stage of AIP is recommended to aid recovery [18]. It is very important for the prevention of AIP to predict the incidence of AIP in patients who do not exhibit IP preoperatively. It was described in the consensus statement that the main treatment is supportive care after the diagnosis of AIP [6]. Treatments using immunosuppressive agents, including cyclosporine [20], cyclophosphamide [21], and tacrolimus [22], for chronic interstitial lung disease have been reported previously by many institutions. However, we did not use these agents due to concern about the side effects, including infection during the perioperative period.
Sivelestat sodium hydrate, which is a specific neutrophil elastase inhibitor, may protect endothelial cells against neutrophil-mediated injury by inactivating the extracellular elastase secreted by neutrophils, and also by acting directly on neutrophils to suppress the production and secretion of activated elastase [23]. We used this drug with steroid pulse therapy for AIP at the start of the ventilatory support in two cases, both of whom recovered from respiratory failure due to AIP. Since the current study refers to the practical treatment of a small number of patients, randomized trials of this agent will need to be conducted in order to evaluate the efficacy for AIP in the near future.
AIP is a life-threatening complication of pulmonary resection for lung cancer. However, the cause of postoperative AIP remains controversial. Careful postoperative management must be performed, especially within 1 week after surgery, for patients who are male, have the disease in their right lung, have had preoperative chemo or radiation therapy, or have undergone a pneumonectomy. If it is impossible to avoid the conversion to extended surgery or if an intraoperative complication occurs that requires blood transfusion, the administration of steroids and specific neutrophil elastase inhibitors immediately after surgery can be considered to prevent AIP.
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Abstract
1. Introduction
