Journal of Infection (2016) 72, 615e621 www.elsevierhealth.com/journals/jinf Fungal empyema thoracis in cancer patients Masayuki Nigo a,b, Macarena R. Vial c,d, Jose M. Munita a,b,c, Ying Jiang a, Jeffrey Tarrand e, Carlos A. Jimenez d, Dimitrios P. Kontoyiannis a,* a Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA b Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA c Clı´nica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile d Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Accepted 25 February 2016 Available online 2 March 2016 KEYWORDS Summary Objectives: Fungal empyema thoracis (FET) is a rare life-threatening infection. Fungal empyema; We sought to describe the clinical characteristics of FET in a large academic cancer center. Invasive fungal Methods: We conducted a retrospective chart review of all cancer patients who had a fungal infection; isolate from the pleural fluid culture between 1/2005 and 8/2013. Cancer; Results: A total of 106 fungal isolates were identified in 97 patients. Yeasts accounted for 62% Empyema of the isolates whereas 38% were identified as molds. The most frequent pathogens were Candida spp. (58%) and Aspergillus spp. (12%). All patients with Aspergillus and 83% with Candida met criteria for proven fungal disease. Compared to the Aspergillus group, Candida FET was associated with recent abdominal or thoracic surgical procedures (44% vs. 0%, p Z 0.01). Overall, 6-week mortality was high, with no significant differences between Candida and Aspergillus (31% vs. 45%, respectively [p Z 0.48]). Only 1 out of 11 patients with uncommon molds died at 6 weeks, despite only 2 of them received appropriate antifungal therapy. Conclusions: Development of FET carries a high mortality in cancer patients. A history of a recent surgical procedure is a risk factor for FET due to Candida. Isolation of uncommon molds is likely to represent a contamination of the pleural fluid. ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association. * Corresponding author. Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel.: þ1 713 792 6237; fax: þ1 713 745 6839. E-mail address: [email protected] (D.P. Kontoyiannis). http://dx.doi.org/10.1016/j.jinf.2016.02.014 0163-4453/ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association. 616 M. Nigo et al. Introduction Two independent investigators performed the data extraction using a standardized collection form. All rele- The incidence of fungal infections among cancer patients vant clinical, demographic and microbiological information has increased, likely reflecting a rise in the complexity of was obtained. Patients were classified as having “proven” or “probable” fungal disease based on the revised diag- immunosuppressive therapies and surgical procedures in 6 this population.1 More importantly, despite major advances nostic criteria proposed by the EORTC/MSG. In addition, subjects were grouped into high risk or intermediate-low in modern medicine and the introduction of several effec- 6,7 tive new antifungals, invasive fungal infections (IFI) risk for fungal infections as previously described. Specif- continue to carry an elevated risk of mortality.2 ically, patients were considered to be at high risk if they Fungal empyema thoracis (FET) is a potentially life- had i) high dose corticosteroid use (defined as a cumulative > threatening condition with reported morality rates as high dose of prednisone 0.3 mg/kg/day within 3 weeks prior to as 73%.3 Since its initial description over 60 years ago,4 index culture), ii) severe neutropenia (absolute neutrophil there has been little progress on the diagnosis and manage- counts 500 cell/mL for more than 10 days), iii) hemato- ment of this entity, partly due to its low prevalence. logical malignancy other than lymphoma, or iv) history of Indeed, among 102 cases of pleural empyema collected an allogeneic stem cell transplantation. over a 13-year period, only 8 patients (7%) were diagnosed We evaluated all-cause mortality at 6 weeks after the with FET.5 This lack of data is particularly problematic in index culture and treatment failure, which was defined as subjects with underlying malignancy, given their high risk persistently positive pleural fluid cultures after the fourth for developing severe IFIs. week of antifungal therapy. Additionally, establishing the diagnosis of FET as Descriptive statistics were used to summarize clinical opposed to a fungal contamination poses a clinical conun- and demographic data. Continuous variables were pre- drum that is particularly unsettling in the context of sented as average and standard deviation, when normally severely immunocompromised cancer patients. In 2008, distributed and as median and range otherwise. Categorical the European Organization for Research and Treatment of data was summarized as frequencies and percentages. Cancer/Invasive Fungal Infection Cooperative Group and Wilcoxon rank-sum test was used to compare continuous Infectious Diseases Mycosis Society Group (EORTC/MSG) variables and chi-square or Fisher exact test were used for revised the diagnostic definition for IFI to improve its categorical variables. All tests were two-sided with a consistency and reproducibility.6 However, the diagnostic significance level of 0.05. Data analysis was performed by accuracy of these criteria for unusual sites of infection using SAS version 9.3 software (SAS Institute Inc., Cary, NC). such as the pleura remains to be established. To that end, we sought to describe the clinical charac- Results teristics and outcomes of patients with a fungal isolate recovered from their pleural fluid in a large cancer center. Patient characteristics Patients and methods Out of the 708 positive pleural fluid cultures in the study period, 111 (16%) had at least one fungal isolate identi- After obtaining approval from the institutional review fied. After excluding 5 repeated cultures, a total of 106 board, we retrospectively reviewed the clinical records of fungal isolates recovered from 97 patients were included all patients with a fungal isolate recovered from the pleural in the analysis. The median age of subjects was 63 years e fluid from January 2005 to August 2013. Patients were (range 18 81), 54 of them (56%) were male and a solid identified using the MD Anderson Cancer Center clinical tumor was the underlying malignancy in 66 (69%) cases. microbiology laboratory database. The most frequently reported symptoms were dyspnea We included all adult subjects (>18 years old) with an (78%), followed by cough (44%) and fever (27%). The underlying malignancy. FET was defined as at least one pleural fluid analyses met criteria for an exudate in all fungal isolate recovered from the pleural fluid in the cases and the characteristics of the fluid (i.e. total cell setting of an exudative pleural effusion. If a fungal count, lactate dehydrogenase, total protein, etc.) did not organism was isolated multiple times in the same patient, vary among subjects infected with yeasts or molds (data data were retrieved only for the first index culture. All not shown). pleural fluid samples were inoculated onto Sabouraud A total of 86 (88%) patients met criteria for proven or dextrose Emmons plates, brain-heart infusion agar plus probable IFI, while the remaining 11 cases did not fulfill gentamicin and Mycosel agar containing cycloheximide, criteria for such categories. The proportion of patients and incubated at 35 C for primary growth. Mold isolates classified as having a proven IFI did not differ significantly were transferred to 25 C for morphology development when analyzed by type of fungi (molds vs. yeasts) or risk for and further identification using the cornmeal tween 80 IFI (data not shown). agar slide culture method. Yeasts were identified with Vitek 2 yeast-card and cornmeal tween 80 agar, using Microbiology Dalmau morphology method. Additionally, unidentified molds were sent for amplification and sequencing of the Overall, yeasts accounted for 62% of the isolates recovered fungal ribosomal ITS1 ITS2 targets (performed at the (n Z 66), whereas a mold was identified in the remaining Fungal Testing Laboratory, University of Texas at San 38% (n Z 40). The genera and species of the fungal isolates Antonio, TX). are summarized in Fig. 1. Candida species predominated Fungal empyema thoracis 617 Figure 1 Distribution of 106 fungal isolates from pleural fluid culture in cancer patients. 66 isolates (62%) in corresponded to yeasts and the remaining 40 (38%) to molds. Candida spp. included C. albicans (n Z 20), C. glabrata (18), C. tropicalis (11) and others (5). Aspergillus spp. included A. fumigatus (6), A. terreus (2), and others (4). The group of uncommon molds includes Cla- dosporium spp. (2), Trichoderma spp. (2), Acremonium spp. (1), Cephaloascus spp. (1), Curvularia spp. (1), Phaeoacremonium spp. (1), Paecilomyces spp. (1), and other species (2). among yeasts, with C. albicans being most frequently days of the index culture (44% vs. 0%, p Z 0.01). Further- recovered (n Z 20), followed by C. glabrata (n Z 18) and more, among patients with Candida FET, a prior procedure C. tropicalis (n Z 11). Aspergillus species (n Z 12) ac- was particularly frequent in subjects found to have a counted for the majority of the isolated molds and only pleural fluid positive for C. albicans as compared to other one dimorphic fungus was identified (Coccidioides immitis). Candida spp. (65% vs. 29%, respectively [p Z 0.01]). Overall, a concomitant bacterial organism was recovered Colonization of the respiratory tract with Candida spp. from the pleural fluid of 24 patients, all of which fulfilled (within four weeks of the index culture) was present in 20 criteria for proven IFI.