Clinical characteristics and outcomes of patients with chronic disseminated candidiasis who need adjuvant corticosteroid therapy

Clinical characteristics and outcomes of patients with chronic disseminated candidiasis who need... Abstract We performed a retrospective study involving 21 patients with chronic disseminate candidiasis (CDC) and 38 patients with candidemia. Neutropenia of >2 weeks’ duration was more common in those with CDC (71%) than in those with candidemia (26%, P < .001), and the azole-resistant rate in patients with CDC (5%) was lower than that in those with candidemia (29%, P = .03). Of the 21 patients with CDC, five (24%) needed adjuvant corticosteroid therapy due to persistent debilitating fever (median, 19 days). Rapid defervescence (median, 5 days) occurred after adjuvant corticosteroid therapy. However, there were no significant differences in 90-day mortality between CDC patients with and without corticosteroid therapy. Further prospective data are needed to define the role of steroids in this setting. candidiasis, adrenal cortex hormones, leukemia, liver abscess, immune recostitution inflammatory syndrome Chronic disseminated candidiasis (CDC) is an uncommon syndrome seen almost exclusively in patients with hematologic malignancies who have been treated with intensive chemotherapy and have just recovered from neutropenia.1,2 A definitive diagnosis of CDC is made by positive cultures for Candida species from blood or biopsy specimens. However, diagnosis often relies on clinical, radiological, and indirect microbiological evidence instead.2–7 CDC appears to share several features with immune reconstitution inflammatory syndrome (IRIS), and the use of corticosteroids may have a role in selected patients.2,8–10 Adjuvant corticosteroid therapy could benefit patients with CDC by hastening improvement of clinical symptoms.11 However, there are limited data regarding the clinical characteristics of patients with CDC who need adjuvant corticosteroid therapy compared to those who do not. Therefore, the purpose of this study was: (1) to compare the clinical characteristics of hematologic malignancy patients with CDC and hematologic malignancy patients with candidemia, and (2) to examine the clinical characteristics of patients with CDC who needed adjuvant corticosteroid therapy and compare them to those who did not. All adult neutropenic patients with proven and probable CDC and/or candidemia in the hematologic unit of a tertiary hospital (Asan Medical Center, Seoul, Korea) between August 2013 and July 2016 were retrospectively enrolled in this study. Patient demographic features, disease status, microbiological and radiological evidence of CDC, antifungal therapy, and outcomes were analyzed. Liver tissue was obtained by ultrasonography-guided percutaneous needle biopsy in some patients at the attending hematologist's discretion. Antifungal and corticosteroid therapies were left to the discretion of the treating physician. Patients were categorized as proven or probable CDC according to the criteria established by the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG).12 Cases were considered to be “proven” if liver biopsy samples stained according to standard laboratory staining methods revealed yeast infection or if liver biopsy specimens gave positive culture results and the liver and/or spleen exhibited clinical/biological or radiologic symptoms consistent with infection. Cases were classified as “probable” if the patients had hematologic malignancies yielding small, peripheral, “target-like” CT images in the liver and/or spleen, and if they had elevated serum alkaline phosphatase levels without any evidence of an alternative diagnosis. Neutropenia was defined as an absolute neutrophil count less than 500 cells/mm3. Febrile illness was defined if the tympanic membrane temperature was equal to or exceeded 38°C over a 24-hour period. Serum galactomannan (GM) antigen levels were measured in all patients with CDC (Platelia Aspergillus enzyme immunoassay; Bio-Rad; Redmond, WA, USA). GM index was considered positive at a serum GM antigen level ≥0.5. Over the study period, 21 patients with CDC and 38 without CDC but who had candidemia were included in this analysis. Of the 21 patients with CDC, nine (43%) were classified as proven CDC and the remaining 12 (57%) as probable CDC. Table 1 presents a comparison of the baseline clinical characteristics and outcomes in patients with CDC versus candidemia. A duration of neutropenia >2 weeks was more common in those with CDC (71%) than in those with candidemia (26%, P < .001). One third of the patients with CDC yielded Candida spp., and the azole-resistant rate in patients with CDC (5%) was lower than that in those with candidemia (29%, P = .03). The most common Candida spp. isolated from CDC patients were C. albicans in more than half of the patients, followed by C. tropicalis and C. glabrata. Mortality was significantly lower among patients with CDC (10%) than among those with candidemia (66%, P < .001). Table 1. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis and candidemia. CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC, chronic disseminated candidiasis; IQR, interquartile range. NOTE. Data are no. (%) of patients unless otherwise indicated; Neutropenia was defined as absolute neutrophil count <500 cells/mm3. View Large Table 1. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis and candidemia. CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC, chronic disseminated candidiasis; IQR, interquartile range. NOTE. Data are no. (%) of patients unless otherwise indicated; Neutropenia was defined as absolute neutrophil count <500 cells/mm3. View Large Of the 21 patients with CDC, five (24%, 95% confidence interval [CI] 8–56) received adjuvant corticosteroid therapy and 16 did not. Table 2 compares the baseline clinical characteristics and outcomes of the two groups. The median duration of fever before corticosteroid therapy was 19 days (interquartile range [IQR] 8–40), and the median duration of defervescence after corticosteroid therapy was 5 days (IQR 2–11). The GM assay yielded negative results in all patients with CDC. Of the five patients given adjuvant corticosteroids, four received two or more sequential antifungal agents, such as fluconazole, echinocandin, and amphotericin B. Of the seven patients with CDC who underwent liver biopsies, six comprising three given steroids and four not given steroids had histologically proven candida infections. Interestingly, granulomatous inflammation was evident in the liver biopsy specimens of two of the three patients receiving steroids and only one of the four patients not given steroids. In addition, the median duration of fever was longer in the patients receiving adjuvant corticosteroid therapy (18 days) than in those not receiving adjuvant corticosteroid therapy (2 days, P = .04). However, there were no significant differences in terms of the duration of antifungal treatment and the overall mortality. Table 2. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis (CDC) who did or did not receive adjuvant steroid therapy. With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 ALP, alkaline phosphatase CDC, chronic disseminated candidiasis; IQR, interquartile range; SD, standard deviation. NOTE. Data are no. (%) of patients unless otherwise indicated. View Large Table 2. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis (CDC) who did or did not receive adjuvant steroid therapy. With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 ALP, alkaline phosphatase CDC, chronic disseminated candidiasis; IQR, interquartile range; SD, standard deviation. NOTE. Data are no. (%) of patients unless otherwise indicated. View Large Limited reports exist on deep-seated candidiasis with/without candidemia, such as CDC, in neutropenic cancer patients. Our finding that neutropenia lasting >2 weeks was more common in those with CDC (71%) than in those with candidemia (26%) is consistent with a previous study.13 Similarly, our observation that mortality was lower in those with CDC (10%) than in those with candidemia (66%, P < .001) is in line with previous studies.8,9,14 A partial explanation for this observation may be that patients with candidemia were more ill than those with CDC because most patients with CDC were not ill enough to die before neutrophil recovery. It is worth noting that the azole-resistance rate in our patients with CDC was lower than that in those with candidemia (5% vs. 29%, respectively), although the small number of cases prevents a firm conclusion. Given that microbiologic documentation and subsequent antifungal susceptibility tests were available only in a small proportion of CDC patients and that about one quarter of CDC patients suffered from persistent fevers in spite of antifungal therapy for fungal IRIS, it is difficult to differentiate between the drug-resistant form of CDC from the fungal IRIS form of CDC in this clinical setting. Therefore, the epidemiological data on the azole-resistant rate in patients with CDC provides us important information in this difficult clinical situation. There is evidence that CDC is a form of IRIS, and that corticosteroids or anti-inflammatory agents may have a useful role in selected CDC patients.2,9,15 Legrand et al. observed that adjuvant steroids improved clinical symptoms and inflammatory responses in ten patients with CDC,9 and Chaussade et al. also reported rapidly improved CDC symptoms in five CDC patients given adjuvant corticosteroids.10 However, these previous studies did not specify the proportion of patients with CDC who needed adjuvant corticosteroids due to debilitating persistent fever or discuss the clinical characteristics that differentiated them from those who did not need adjuvant corticosteroid. We found that about one quarter of CDC patients eventually needed adjuvant corticosteroid therapy. We noted, as did previous studies,9,10 that multiple antifungal drugs were prescribed for those who needed adjuvant corticosteroids, and that there was prolonged fever before adjuvant corticosteroid was initiated. However, other clinical characteristics of those who needed adjuvant corticosteroids and those who did not were similar (Table 2), except for a statistically insignificant trend towards lower age in the adjuvant steroid group. In this context, adjuvant corticosteroid use in patients with CDC is reminiscent of the management of IRIS in AIDS patients. Therefore, antipyretics, such as non-steroidal anti-inflammatory drugs, could be considered in mild forms of CDC, and corticosteroids might be reserved for life-threatening or severe forms of CDC. Further prospective data are needed to define the role of steroids in this setting. It is noteworthy that microbiologic documented cases were more common among those who did not need adjuvant corticosteroids than in those who did, although this difference was not statistically significant (Table 2). Thus, the use of antifungal agents according to antifungal susceptibility results might affect the development of IRIS given that some antifungal agents have immunomodulatory effects.16 The revised (2008) EORTC/MSG diagnostic criteria for CDC require obtaining positive blood cultures for Candida spp. or a specimen from a sterile body site or tissue.17 However, in previous studies, less than 20% of patients with CDC had positive blood cultures,1,2,7 and tissue cultures were positive in only 50% of cases of CDC,2,18 which is consistent with our data. In this study, microbiologic evidence, such as prior candidemia or positive culture results from biopsy specimens, was obtained in less than half of the enrolled patients with CDC (43%). Therefore, we assume that the 2008 EORTC/MSG criteria17 for the diagnosis of CDC are too strict because of insensitivity of the culture-based methods in patients with suspected CDC. Recently, the beta-D-glucan assay has been proposed as a screening test for invasive fungal infection, including deep-seated candidiasis. However, there are limited data on this issue.19 Further studies are needed in this area. In conclusion, patients with CDC, who are common among those suffering from persistent neutropenia, often receive adjuvant corticosteroid therapy after prolonged fever. The prognosis of CDC patients who receive adjuvant corticosteroids appears to be comparable to that of CDC patients who do not receive adjuvant corticosteroids. Acknowledgements We thank Ms. Vanessa Topping from the Scientific Publications Team at Asan Medical Center for her editorial assistance in preparing this manuscript. Funding This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI16C0272). Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper. References 1. Masood A , Sallah S . Chronic disseminated candidiasis in patients with acute leukemia: emphasis on diagnostic definition and treatment . Leuk Res . 2005 ; 29 : 493 – 501 . Google Scholar CrossRef Search ADS PubMed 2. Rammaert B , Desjardins A , Lortholary O . New insights into hepatosplenic candidosis, a manifestation of chronic disseminated candidosis . Mycoses . 2012 ; 55 : e74 – 84 . Google Scholar CrossRef Search ADS PubMed 3. Thaler M , Pastakia B , Shawker TH , O’Leary T , Pizzo PA . Hepatic candidiasis in cancer patients: the evolving picture of the syndrome . Ann Intern Med . 1988 ; 108 : 88 – 100 . Google Scholar CrossRef Search ADS PubMed 4. Haron E , Feld R , Tuffnell P , Patterson B , Hasselback R , Matlow A . Hepatic candidiasis: an increasing problem in immunocompromised patients . 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Clinical characteristics and outcomes of patients with chronic disseminated candidiasis who need adjuvant corticosteroid therapy

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Taylor & Francis
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© The Author(s) 2017. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.
ISSN
1369-3786
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1460-2709
D.O.I.
10.1093/mmy/myx110
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Abstract

Abstract We performed a retrospective study involving 21 patients with chronic disseminate candidiasis (CDC) and 38 patients with candidemia. Neutropenia of >2 weeks’ duration was more common in those with CDC (71%) than in those with candidemia (26%, P < .001), and the azole-resistant rate in patients with CDC (5%) was lower than that in those with candidemia (29%, P = .03). Of the 21 patients with CDC, five (24%) needed adjuvant corticosteroid therapy due to persistent debilitating fever (median, 19 days). Rapid defervescence (median, 5 days) occurred after adjuvant corticosteroid therapy. However, there were no significant differences in 90-day mortality between CDC patients with and without corticosteroid therapy. Further prospective data are needed to define the role of steroids in this setting. candidiasis, adrenal cortex hormones, leukemia, liver abscess, immune recostitution inflammatory syndrome Chronic disseminated candidiasis (CDC) is an uncommon syndrome seen almost exclusively in patients with hematologic malignancies who have been treated with intensive chemotherapy and have just recovered from neutropenia.1,2 A definitive diagnosis of CDC is made by positive cultures for Candida species from blood or biopsy specimens. However, diagnosis often relies on clinical, radiological, and indirect microbiological evidence instead.2–7 CDC appears to share several features with immune reconstitution inflammatory syndrome (IRIS), and the use of corticosteroids may have a role in selected patients.2,8–10 Adjuvant corticosteroid therapy could benefit patients with CDC by hastening improvement of clinical symptoms.11 However, there are limited data regarding the clinical characteristics of patients with CDC who need adjuvant corticosteroid therapy compared to those who do not. Therefore, the purpose of this study was: (1) to compare the clinical characteristics of hematologic malignancy patients with CDC and hematologic malignancy patients with candidemia, and (2) to examine the clinical characteristics of patients with CDC who needed adjuvant corticosteroid therapy and compare them to those who did not. All adult neutropenic patients with proven and probable CDC and/or candidemia in the hematologic unit of a tertiary hospital (Asan Medical Center, Seoul, Korea) between August 2013 and July 2016 were retrospectively enrolled in this study. Patient demographic features, disease status, microbiological and radiological evidence of CDC, antifungal therapy, and outcomes were analyzed. Liver tissue was obtained by ultrasonography-guided percutaneous needle biopsy in some patients at the attending hematologist's discretion. Antifungal and corticosteroid therapies were left to the discretion of the treating physician. Patients were categorized as proven or probable CDC according to the criteria established by the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG).12 Cases were considered to be “proven” if liver biopsy samples stained according to standard laboratory staining methods revealed yeast infection or if liver biopsy specimens gave positive culture results and the liver and/or spleen exhibited clinical/biological or radiologic symptoms consistent with infection. Cases were classified as “probable” if the patients had hematologic malignancies yielding small, peripheral, “target-like” CT images in the liver and/or spleen, and if they had elevated serum alkaline phosphatase levels without any evidence of an alternative diagnosis. Neutropenia was defined as an absolute neutrophil count less than 500 cells/mm3. Febrile illness was defined if the tympanic membrane temperature was equal to or exceeded 38°C over a 24-hour period. Serum galactomannan (GM) antigen levels were measured in all patients with CDC (Platelia Aspergillus enzyme immunoassay; Bio-Rad; Redmond, WA, USA). GM index was considered positive at a serum GM antigen level ≥0.5. Over the study period, 21 patients with CDC and 38 without CDC but who had candidemia were included in this analysis. Of the 21 patients with CDC, nine (43%) were classified as proven CDC and the remaining 12 (57%) as probable CDC. Table 1 presents a comparison of the baseline clinical characteristics and outcomes in patients with CDC versus candidemia. A duration of neutropenia >2 weeks was more common in those with CDC (71%) than in those with candidemia (26%, P < .001). One third of the patients with CDC yielded Candida spp., and the azole-resistant rate in patients with CDC (5%) was lower than that in those with candidemia (29%, P = .03). The most common Candida spp. isolated from CDC patients were C. albicans in more than half of the patients, followed by C. tropicalis and C. glabrata. Mortality was significantly lower among patients with CDC (10%) than among those with candidemia (66%, P < .001). Table 1. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis and candidemia. CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC, chronic disseminated candidiasis; IQR, interquartile range. NOTE. Data are no. (%) of patients unless otherwise indicated; Neutropenia was defined as absolute neutrophil count <500 cells/mm3. View Large Table 1. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis and candidemia. CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC (n = 21) Candidemia (n = 38) P value Age, median years (IQR) 44 (35–63) 55 (44–64) .13 Male sex 9 (43) 16 (42) >.99 Underlying disease  Myeloid neoplasm 13 (62) 18 (47) .42  Lymphoid neoplasm 8 (38) 15 (40) >.99  Aplastic anemia 0 (0) 1 (3) >.99  Hemophagocytic lymphohistiocytosis 0 (0) 4 (11) .28 Prior allogenic stem cell transplantation 3 (14) 11 (29) .34 Duration of neutropenia >2 weeks 15 (71) 10 (26) <.001 Positive serum galactomannan antigen test 0 (0) – Proven candida species (from biopsied specimen or blood culture) 7 (33) 38(100) Azole-susceptible species 6 (28) 27 (71) .03  Candida albicans 4 (19) 3 (8)  Candida tropicalis 2 (10) 21 (55)  Candida parapsilosis 0 (0) 2 (5)  Candida guilliermondii 0 (0) 1 (3) Azole-resistance species 1 (5) 11 (29)  Candida krusei 0 (0) 4 (11)  Candida glabrata 1 (1) 7 (18) Not identified 14 (68) 0 (0) Received prophylactic antifungal agent 17 (81) 17 (45) .002 Median duration of treatment, days (IQR) 120 (75–210) 14 (3–22) .002 First-line antifungal therapy  Fluconazole 17 (81) 4 (11) <.001  Voriconazole 2 (10) 4 (11) .90  Echinocandin 10 (48) 9 (24) .08  Polyenes 4 (19) 19 (50) .03 90-day mortality 2 (10) 25 (66) <.001 CDC, chronic disseminated candidiasis; IQR, interquartile range. NOTE. Data are no. (%) of patients unless otherwise indicated; Neutropenia was defined as absolute neutrophil count <500 cells/mm3. View Large Of the 21 patients with CDC, five (24%, 95% confidence interval [CI] 8–56) received adjuvant corticosteroid therapy and 16 did not. Table 2 compares the baseline clinical characteristics and outcomes of the two groups. The median duration of fever before corticosteroid therapy was 19 days (interquartile range [IQR] 8–40), and the median duration of defervescence after corticosteroid therapy was 5 days (IQR 2–11). The GM assay yielded negative results in all patients with CDC. Of the five patients given adjuvant corticosteroids, four received two or more sequential antifungal agents, such as fluconazole, echinocandin, and amphotericin B. Of the seven patients with CDC who underwent liver biopsies, six comprising three given steroids and four not given steroids had histologically proven candida infections. Interestingly, granulomatous inflammation was evident in the liver biopsy specimens of two of the three patients receiving steroids and only one of the four patients not given steroids. In addition, the median duration of fever was longer in the patients receiving adjuvant corticosteroid therapy (18 days) than in those not receiving adjuvant corticosteroid therapy (2 days, P = .04). However, there were no significant differences in terms of the duration of antifungal treatment and the overall mortality. Table 2. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis (CDC) who did or did not receive adjuvant steroid therapy. With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 ALP, alkaline phosphatase CDC, chronic disseminated candidiasis; IQR, interquartile range; SD, standard deviation. NOTE. Data are no. (%) of patients unless otherwise indicated. View Large Table 2. Clinical characteristics and treatment outcomes in patients with chronic disseminated candidiasis (CDC) who did or did not receive adjuvant steroid therapy. With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 With steroid therapy (n = 5) Without steroid therapy (n = 16) P value Age, mean years ± SD 38 ± 10 51 ± 15 .13 Male gender 2 (40) 10 (63) .61 Median time from diagnosis of underlying disease to CDC, months (IQR) 6 (2–21) 4 (3–9) >.99 Median time from chemotherapy to CDC, days (IQR) 55 (20–61) 22 (10–27) .04 Hematopoietic stem cell transplant recipient 2 (40) 1 (6) .13 Anti-fungal prophylaxis 5 (100) 12 (75) .30 Clinical symptoms and signs  Fever 4 (80) 11 (69) .55  Hepatomegaly 1 (20) 3 (19) .70  Splenomegaly 2 (40) 3 (19) .34  Abdominal pain 1 (20) 4 (25) .66  Skin lesion 0 1 (6) .76 Median duration of fever, days (IQR) 18 (3–41) 2 (0–8) .04  Median duration of fever before steroid therapy, days (IQR) 19 (8–40)  Median duration of fever after steroid therapy, days (IQR) 5 (2-11) Alkaline phosphatase, mean IU/l ± SD 432 ± 275 399 ± 296 .56 Median duration of neutropenia before CDC, days (IQR) 30 (16–30) 17 (9–30) .65 Positive serum galactomannan antigen test 0 0 CDC location  Liver 5 (100) 15 (93) .76  Spleen 3 (60) 11 (68) .56  Kidney 0 2 (13) .57  Lung 2 (40) 3 (18) .34  Central nerve system 1 (20) 0 (0) .24 Biopsy proven CDC (Positive/ biopsied specimens) 3/3 (100) 3/4 (75) Granuloma (positive/ biopsied specimens) 2/3 (66) 1/4 (25) Microbiologic documented cases 0 5 (31) .28  Prior candidemia 0 4 (25) .50  Positive candida species from biopsied specimens 0 1  Candida albicans 0 2  Candida tropicalis 0 2  Candida glabrata 0 1 First-line antifungal therapy  Fluconazole 3 (60) 14 (87) .23  Voriconazole 0 2 (13) >.99  Echinocandin 4 (80) 6 (36) .15  Polyenes 2 (40) 2 (13) .23 Multiple antifungal therapy (two or more antifungal drugs) 4 (80) 8 (50) .34 Median duration of treatment, months (IQR) 7 (4-22) 6 (2-8) .14 90-day mortality 1 (20) 1 (6) .43 ALP, alkaline phosphatase CDC, chronic disseminated candidiasis; IQR, interquartile range; SD, standard deviation. NOTE. Data are no. (%) of patients unless otherwise indicated. View Large Limited reports exist on deep-seated candidiasis with/without candidemia, such as CDC, in neutropenic cancer patients. Our finding that neutropenia lasting >2 weeks was more common in those with CDC (71%) than in those with candidemia (26%) is consistent with a previous study.13 Similarly, our observation that mortality was lower in those with CDC (10%) than in those with candidemia (66%, P < .001) is in line with previous studies.8,9,14 A partial explanation for this observation may be that patients with candidemia were more ill than those with CDC because most patients with CDC were not ill enough to die before neutrophil recovery. It is worth noting that the azole-resistance rate in our patients with CDC was lower than that in those with candidemia (5% vs. 29%, respectively), although the small number of cases prevents a firm conclusion. Given that microbiologic documentation and subsequent antifungal susceptibility tests were available only in a small proportion of CDC patients and that about one quarter of CDC patients suffered from persistent fevers in spite of antifungal therapy for fungal IRIS, it is difficult to differentiate between the drug-resistant form of CDC from the fungal IRIS form of CDC in this clinical setting. Therefore, the epidemiological data on the azole-resistant rate in patients with CDC provides us important information in this difficult clinical situation. There is evidence that CDC is a form of IRIS, and that corticosteroids or anti-inflammatory agents may have a useful role in selected CDC patients.2,9,15 Legrand et al. observed that adjuvant steroids improved clinical symptoms and inflammatory responses in ten patients with CDC,9 and Chaussade et al. also reported rapidly improved CDC symptoms in five CDC patients given adjuvant corticosteroids.10 However, these previous studies did not specify the proportion of patients with CDC who needed adjuvant corticosteroids due to debilitating persistent fever or discuss the clinical characteristics that differentiated them from those who did not need adjuvant corticosteroid. We found that about one quarter of CDC patients eventually needed adjuvant corticosteroid therapy. We noted, as did previous studies,9,10 that multiple antifungal drugs were prescribed for those who needed adjuvant corticosteroids, and that there was prolonged fever before adjuvant corticosteroid was initiated. However, other clinical characteristics of those who needed adjuvant corticosteroids and those who did not were similar (Table 2), except for a statistically insignificant trend towards lower age in the adjuvant steroid group. In this context, adjuvant corticosteroid use in patients with CDC is reminiscent of the management of IRIS in AIDS patients. Therefore, antipyretics, such as non-steroidal anti-inflammatory drugs, could be considered in mild forms of CDC, and corticosteroids might be reserved for life-threatening or severe forms of CDC. Further prospective data are needed to define the role of steroids in this setting. It is noteworthy that microbiologic documented cases were more common among those who did not need adjuvant corticosteroids than in those who did, although this difference was not statistically significant (Table 2). Thus, the use of antifungal agents according to antifungal susceptibility results might affect the development of IRIS given that some antifungal agents have immunomodulatory effects.16 The revised (2008) EORTC/MSG diagnostic criteria for CDC require obtaining positive blood cultures for Candida spp. or a specimen from a sterile body site or tissue.17 However, in previous studies, less than 20% of patients with CDC had positive blood cultures,1,2,7 and tissue cultures were positive in only 50% of cases of CDC,2,18 which is consistent with our data. In this study, microbiologic evidence, such as prior candidemia or positive culture results from biopsy specimens, was obtained in less than half of the enrolled patients with CDC (43%). Therefore, we assume that the 2008 EORTC/MSG criteria17 for the diagnosis of CDC are too strict because of insensitivity of the culture-based methods in patients with suspected CDC. Recently, the beta-D-glucan assay has been proposed as a screening test for invasive fungal infection, including deep-seated candidiasis. However, there are limited data on this issue.19 Further studies are needed in this area. In conclusion, patients with CDC, who are common among those suffering from persistent neutropenia, often receive adjuvant corticosteroid therapy after prolonged fever. The prognosis of CDC patients who receive adjuvant corticosteroids appears to be comparable to that of CDC patients who do not receive adjuvant corticosteroids. Acknowledgements We thank Ms. Vanessa Topping from the Scientific Publications Team at Asan Medical Center for her editorial assistance in preparing this manuscript. Funding This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI16C0272). 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Medical MycologyOxford University Press

Published: Aug 1, 2018

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