Journal of Infection (2016) 72, 615e621

www.elsevierhealth.com/journals/jinf

Fungal 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 . 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 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 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. The number of patients found to (37%) patients developing Candida FET. In contrast, only 2 have a bacterial co-pathogen was not significantly different out of the 11 (18%) subjects diagnosed with Aspergillus among fungal pathogens (Table 1) and the most frequently FET had prior colonization of the airway with the same co-cultured were alpha-streptococci, Entero- fungal organism. In terms of lung imaging, abnormal paren- coccus faecalis, coagulase negative staphylococci and Es- chymal findings were more frequently reported in patients cherichia coli. infected with Aspergillus spp. (data not shown). Most patients infected with Candida (42/54, 78%) or Aspergillus (8/11, 73%) received systemic antifungals. Candida spp. vs. Aspergillus spp. Among the 42 patients infected with Candida in which anti- fungals were prescribed, 30 received monotherapy, and the Table 1 summarizes the characteristics of patients found to most frequently used drugs were azoles (n Z 20) followed have FET due to Candida spp. or Aspergillus spp. All 11 pa- by echinocandins (n Z 9). Combination therapy with tients in whom Aspergillus was isolated fulfilled criteria for more than one antifungal (most frequently dual therapy proven IFI, whereas 45 out of the 54 patients (83%) in which with fluconazole plus an echinocandin) was used in the re- Candida was isolated met these criteria. Of the remaining 9 maining 12 patients. patients, 1 met criteria for probable fungal disease and 8 Among the 8 patients treated for Aspergillus FET, only were categorized as indeterminate as per EORTC criteria two of them received monotherapy (liposomal amphoteri- because the fluid sample was obtained from a pleural drain cin B in both). Of the remaining 6 patients, 5 were managed placed >24 h prior. Subjects infected with Candida were with a triple combination therapy with liposomal amphoter- older than those with Aspergillus (65 vs. 52 year, icin B plus voriconazole plus an echinocandin, and one p Z 0.04), had a lower risk for IFIs (19% vs. 64%, received dual therapy (voriconazole plus amphotericin B). p Z 0.01) and were more likely to have a history of an inva- Finally, local instillation of an antifungal to the pleural sive procedure (abdominal or thoracic surgery) within 30 space (amphotericin B) was used in one occasion in a 618 M. Nigo et al.

Table 1 Comparison of patients with FET caused by Candida spp. vs. Aspergillus spp. Candida spp. (N Z 54), N (%) Aspergillus spp. (N Z 11), N (%) p Value Gender, male 38 (70) 5 (46) 0.11 Age, median (range) 65 (23e81) 52 (19e74) 0.04 Race White 43 (80) 8 (73) 0.61 Non-white 11 (20) 3 (27) High risk 10 (19) 7 (64) 0.01 Solid tumor malignancy 41 (76) 5 (46) 0.67 Lung cancer/mesothelioma 12 (22) 1 (9) 0.44 Esophageal cancer 8 (15) 0 (0) 0.33 Gastric cancer 5 (9) 0 (0) 0.58 Liver/pancreatic cancer 5 (9) 0 (0) 0.58 Other 11 (20) 4 (36) Hematologic malignancy 13 (24) 6 (55) 0.67 Leukemia 7 (13) 5 (45) 0.22 Post HSCT 2 (4) 2 (18) 0.13 Other 6 (11) 1 (9) Immunosuppression Neutropenia 4 (7) 2 (18) 0.27 Diabetes 9 (17) 2 (18) 1.00 Chemotherapy/corticosteroid 12 (22) 3 (27) 0.71 Other 4 (7) 4 (37) Invasive procedure last 30 days 24 (44) 0 (0) 0.01 Microbiology Concomitant fungal isolate 7 (13) 1 (9) 1 Concomitant bacterial isolate 22 (41) 2 (18) 0.19 Fungemia 2 (4) 0 (0) Diagnostic classificationa 0.45 Proven invasive fungal infection 45 (83) 11 (100) Probable fungal infection 1 (2) 0 (0) Indeterminate 8 (12) 0 (0) or 35 (65) 3 (27) 0.04 Chest tube placement 28 (52) 2 (18) Decortication 7 (13) 1 (9) Systemic antifungal therapy 42 (78) 8 (73) 0.71 Amphotericin B 5 (12) 6 (75) Azole 29 (69) 5 (63) Echinocandin 15 (36) 6 (75) Treatment failureb 3 (5) 1 (9) 0.53 Mortality at 6 weeks 17 (31) 5 (45) 0.48 HSCT, hematopoietic stem cell transplant. a Based on EORTC/EMS diagnostic definition. b Defined as persistently positive pleural fluid cultures after the fourth week of antifungal therapy.

patient infected with C. glabrata that also received sys- 31% in patients infected with Candida and 45% in the Asper- temic voriconazole. No treatment was given in 12 subjects gillus group (p Z 0.48) (Table 1). Among subjects that did found to have Candida and in 3 found to have Aspergillus not receive antifungal therapy, only 1 out of the 12 patients spp. in the pleural fluid. (8%) in the Candida group died. In contrast, the 6-week Regarding other management interventions for FET, the mortality rate among untreated patients found to have proportion of patients who underwent drainage of the Aspergillus was 2 out of 3 (66%). empyema (through surgical decortication or insertion of a chest tube) was significantly lower in patients infected with Molds other than Aspergillus spp. Aspergillus as compared to those with Candida FET (27% vs. 65%, respectively [p Z 0.04]). A mold other than Aspergillus was recovered from the The overall 6-week mortality among patients diagnosed pleural fluid of 26 patients, 4 of which had pathogenic fungi with FET due to Candida or Aspergillus spp. was 34%. The 6- known to cause IFI in severely immunocompromised (two week mortality rate was also similar among groups, with cases Fusarium spp. and two of Mucorales). Among the Fungal empyema thoracis 619 remaining 22, 11 were found to have Penicillium spp., a with better fungal detection techniques.8e10 As expected, fungal species generally regarded as a laboratory contami- Candida and Aspergillus spp., the most common opportu- nant and were excluded from the analysis. The clinical and nistic fungal pathogens, were the predominant microorgan- demographic characteristics of the remaining 11 patients in isms in our series. C. albicans was the most frequent whom an uncommon mold was isolated from the pleural species among yeasts, however the incidence of C. glabrata fluid are summarized in Table 2. was also high, an observation that is consistent with reports Out of the 11 patients with uncommon molds that were showing an overall increase in the rates of invasive infec- analyzed, 10 met technically the criteria for proven and tions due to this pathogen.11,12 one for probable IFI. In spite of this, isolation of an Although we found no significant differences regarding uncommon mold was regarded as a contaminant in all the type of underlying malignancies between patients cases (as per clinical records) and no specific antifungal infected with Candida or Aspergillus, it is notable that therapy was prescribed in 9 of the 11 patients. Interest- more than 50% of the cancer patients with Candida FET ingly, the mortality rate of this group was low, with only 1 had an underlying solid tumor involving the lung or the up- patient deceased at 6-weeks of follow-up. Of note, the per gastrointestinal tract (see Table 1). In contrast, only cause of death of that single case was attributed to his one case of such malignancies was reported in subjects underlying malignancy and not to an uncontrolled fungal found to have Aspergillus in the pleural fluid. Additionally, infection. patients diagnosed with Candida FET (and in particular C. albicans infections) were much more likely to have had a recent abdominal or thoracic surgical procedure than those Discussion infected with Aspergillus. Thus, these observations suggest that the type of malignancy and the history of a recent sur- Clinicians dealing with cancer patients found to have a gical intervention are important risk factors for the devel- fungal isolate recovered from the pleural fluid face a opment of FET due to Candida. The reasons to explain puzzling situation. To the best of our knowledge, we this association are unclear, but Lin et al. previously re- present the largest series of FET among cancer patients to ported that contiguous spread to the pleural space was as date. an important risk factor for the development of Candida In our cohort, the proportion of fungal isolates recov- FET13 and this mechanism could have played an important ered among all positive pleural fluid cultures was 16% (111/ role in some of our patients (e.g. subjects with solid tumors 708), which is higher than prior reports.5 The reasons for involving the upper gastrointestinal tract). Additionally, this finding are unclear, but they are likely related to the cryptic fungemia during an invasive procedure with second- increased incidence of IFIs in cancer patients, coupled ary seeding of the pleural space is also a plausible explana- tion for this association. Lastly, patients diagnosed with Candida FET frequently had prior colonization of the respi- Table 2 Uncommon molds. ratory tract with the same organism, which is a known risk Number factor for invasive candidiasis in postsurgical patients and (N Z 11) (%) in the intensive care setting.14 Gender, male 5 (45) A large proportion of the patients infected with Candida Age, median (range) 63 (26e79) or Aspergillus received systemic antifungals, however data Race on the concentration of antifungal agents in the pleural White 8 (73) fluid are limited. Some studies suggest that voriconazole Non-White 3 (27) achieves therapeutic concentrations in the pleural 15,16 High risk 3 (27) space, whereas the concentration of echinocandins in 17 Hematologic malignancy 4 (36) the pleural fluid is marginal. In our series, Candida infec- Leukemia 1 (9) tions were usually managed with monotherapy, most HSCT 1 (9) frequently with azoles, whereas patients with Aspergillus Other 3 (27) FET usually received a combination of multiple antifungals. Solid tumor malignancy 7 (64) The use of intrapleural instillation of an antifungal, strat- Lung cancer/mesothelioma 1 (9) egy used in only one of our patients, has been sporadically GI cancer 0 (0) reported as an effective adjunctive therapy for FET due to 3,18,19 Liver/pancreatic cancer 2 (18) Mucorales, Aspergillus or Candida spp. Data to sup- Other 4 (36) port one particular therapeutic strategy over the others Immunodeficiency are lacking and further studies are needed. Severe neutropenia 0 (0) Overall, the 6-week all cause mortality of patients with Chemotherapy/corticosteroid 7 (64) FET due to Candida or Aspergillus spp. in our series was Invasive procedure last 30 days 2 (18) 34%, which is substantially lower than the 73% and 62% pre- 3,13 Microbiology viously reported. The reasons for this difference are un- Concomitant fungal or bacterial isolate 1 (9) clear, but they could be related to the timing of the Chest tube or decortication 7 (64) assessment of mortality (in our case it was assessed at 6 13 Systemic antifungal therapy 2 (18) weeks after the index culture, whereas Li et al. measured Death at 6 weeks 1 (10) in-hospital mortality and this information was not disclosed by Ko and colleagues3). Additionally, the difference in mor- HSCT, hematopoietic stem cell transplant; GI, gastrointestinal. tality could also be explained due to advances in the 620 M. 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