This study enrolled 252 patients with PE diagnosed at a respiratory health research institution, and 34 patients were confirmed to have EPE. To our knowledge, this study represents the largest single study group in our country. Patients with EPE accounted for 13.49% (34/252) of all patients with PE. The percentages were similar to those in previous studies, which reported 12.6% [3] and 10% [2], but higher than those in two other studies, which indicated 5-8% [1] and 7.2% [7]. However, Chu FY found that the morbidity of EPE was only 2.9% [6]. The discrepancy may be attributed to different populations, epidemic characteristics, test methods or the timing of pleural fluid collection. The age of patients with EPE is similar to that in previous reports. The ratio of males to females among EPE patients was 1.43:1, which was lower than the 2:1 ratio reported in previous literature [7]. The higher occurrence of PE in males than in females may explain the ratio of males to females among EPE patients.
EPE can be associated with a wide range of underlying conditions, including infections, malignancies, autoimmune diseases, drug reactions, pulmonary embolism, chest trauma and many others [3, 4, 6, 7]. This study indicates that malignant disease was the leading cause of EPE, followed by PPI, IEPE and PPE in sequence. Compared with non-EPE, the prevalence of IPE and PPI was higher in EPE, while TPE was lower. The aetiological distribution of EPE varies among previous reports. In Krenke’s study, malignancy (34.8%), infections (19.3%), unknown causes (14.1%) and posttrauma (8.9%) were the top four aetiologies in EPE [7]. Oba reported that the most common cause of EPE was malignancy (26%), followed by idiopathic (25%) and parapneumonic (13%) effusions, pleural air/blood (13%), tuberculosis (7%), transudate (7%), other (6%) and CVD (collagen vascular disease) (3%) [4]. Wysenbeek’s study showed that the aetiologies of EPE were trauma (39%), congestive heart failure (14%), infection (8.5%) and idiopathic effusion (8.5%) [9]. The differences in results may be explained by the different prevalences of the aetiology of PE at some institutions [10]. Although there was no drug-induced EPE in our study, the list of possible aetiologies has been increasing in recent years, including methimazole, carbimazole, valproic acid, mesalamine, olanzapine and others [11-16]. Adverse drug reactions should be considered in the differential diagnosis following thorough investigation for other potential causes of EPE.
The correlation between EPE and malignancy is still a subject of debate. Our study indicated that malignant disease, accounting for 52.94% of EPE cases, was the most common cause associated with EPE. However, it was once believed that the finding of pleural fluid eosinophilia in an exudative effusion considerably reduced the probability of malignancy and conversely increased the likelihood of an underlying benign disorder [17]. Bower and Wysenbeek reported that air/ blood was the most common cause of EPE [9, 17]. However, the spectrum of EPEs has changed since 1960, and malignancy should no longer be considered uncommon among EPEs [4]. The cumulative incidence of malignancy among EPEs has gradually increased from 7 to 25% over the last 4 decades [4]. Current studies (studies performed in the last two decades) confirmed that malignancy was the leading aetiology of EPE (accounting for 22.7–40.1% of EPEs) [1, 3, 4, 7, 18, 19]. This tendency may be explained by the development of diagnostic technology, improved diagnostic awareness, disparities in the study populations, or varying disease spectra over time [10].
In a recent study, the majority of malignant pleural effusion (MEPE) was associated with lung cancer. According to a literature review, a vast majority of MEPE is related to solid tumours, and only a small group of patients with haematological malignancies develop EPE [1, 2, 6, 18, 20-24]. Lung cancer and metastatic cancer to the lung were the leading causes of MEPE, including solid tumours from other sites and haematological malignancies. The percentage of MEPE with an unknown primary site of cancer accounted for 5-10% of patients with MEPE [7]. Pathological classification included adenocarcinoma, squamous cell carcinoma, and dysgerminoma [20, 22].
It has also been recognized that a high proportion of idiopathic effusions are characterized by EPE [1, 5]. Ferreiro et al. found that the most frequent aetiology of EPE was known, accounting for 36% of EPE [19]. The percentage of IEPE (14.71%) was just secondary to MPE in a recent study. It has been reported that the prevalence of IEPE varies from 0% to 67% [1, 25]. In the last two decades, approximately 3.8%-32.1% of EPE cases were diagnosed as IEPE [4, 22, 26]. Thus, as IEPE appeared to be an important part of EPE with obscure pathogenesis, our previous study advocated that complete medical, surgical and drug-related histories should be obtained and thorough work-up and long-term follow-up should be completed to make differential diagnosis [27].
The percentage of PPI (8.82%) was the third largest group of patients with EPE in our study. Three patients had PPI consisting of of patients with infection of lung fluke Paragonimus westermani, Toxocara spp.. Consumption of raw or undercooked water or food is the main source of parasite infections. Eosinophilia in PPI has been reported in previous studies of EPEs [28-32], but most of these are case reports or small series reports. Interestingly, in a study of EPEs from mainland China, PPIs were responsible for 31.3% of EPE cases [33]. The high incidence may be explained by the high incidence of patients with PPIs and raw food eating habits in certain areas of the country [28]. Most of the patients with PPI had an exposure history [34]. Therefore, one factor is exposure history. Endemicity and local epidemiology should be taken into consideration when exploring the aetiology of EPE.
Our study showed that the percentage of patients with malignant EPE was not related to the percentage of eosinophils in PE. The relationship between the percentage of eosinophils in EPE and malignancy remains controversial. Some studies showed an inverse correlation was between the pleural eosinophil percentage and the likelihood of malignancy in patients with EPE [6]. Kuhn et al. reported that none of the patients were malignant when eosinophils exceeded 50% [2]. Krenke’s analysis revealed that an eosinophil percentage of 40% was the most accurate cut-off level to differentiate between malignant and nonmalignant EPE [7]. Chu et al. also concluded that eosinophil count in pleural effusion was a speculative negative predictor of malignancy in patients with EPE, but the cut-off level of eosinophil was 15% which was relatively lower than other studies [6]. However, it was reported that a patient with MEPE had a pleural eosinophil count of more than 70% [6]. On the other hand, in some studies, eosinophils in the pleural fluid that differentiated malignant from benign pleural effusions were not found [3, 19]. A study indicated that the percentage of eosinophils in the pleural fluid of those individuals with malignant pleural effusion was 26.6%, which was not significantly different from the percentage of those with benign pleural effusion (30.6%) [20].
This was a retrospective study in a single centre, and the number of patients evaluated was small due to the rare prevalence of EPE. Therefore, a larger, multicentre, prospective study is needed to further explore the epidemic characteristics and clinical significance of EPE.