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W2317555001 abstract "Introduction Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis cause the vast majority of endemic mycoses (EM) in North America (52). Infections with these fungi have been described sporadically in case reports and case series of cancer patients, mainly those having hematologic malignancies (7,22,34,51,58,60,61). In addition, a recent population-based surveillance study reported that 9.3% of patients having coccidioidomycosis and 12.2% of patients having histoplasmosis had an underlying malignancy (55). However, no large studies of EM in cancer centers have been reported recently. Although the pathogenesis and presentation of EM in cancer patients have not been fully described, all EM appear to share common risk factors (for example, T-cell dysfunction, prior therapy using systemic steroids), have similar clinical presentations, and are treated using similar agents (such as amphotericin B, itraconazole) (22,34,51). However, several questions regarding these patients remain unanswered. For example, are the clinical progression and prognosis of EM in these patients different from those in other hosts? Furthermore, do each of the EM have the same propensity for dissemination in patients having cancer? Also, which endemic mycosis has the worst prognosis in this patient population? Finally, what is the duration of therapy for EM in patients having cancer? To answer these questions, we reviewed our experience over the past 13 years with patients having cancer who developed EM at The University of Texas M. D. Anderson Cancer Center, Houston, Texas, a tertiary-care oncology center located in a state in which histoplasmosis and coccidioidomycosis are endemic (23,51,72). Patients and Methods Cases of endemic mycosis in hospitalized patients were identified by reviewing histopathology and microbiology culture reports, including autopsy reports, at M. D. Anderson Cancer Center from October 1988 through March 2001. The patients’ age, gender, race, underlying malignancy (hematologic malignancy, solid tumor, and use of bone marrow transplantation [BMT]), and history of prior EM were collected from their records. Also, the presence of diabetes mellitus, graft-versus-host disease, chronic pulmonary disease, or end-stage renal disease; performance of splenectomy or thymectomy; and history of smoking or intravenous drug abuse, all of which are conditions potentially associated with EM, were recorded. Patients having known human immunodeficiency virus 1–2 infection or acquired immunodeficiency syndrome (AIDS) were excluded. Additionally, history of either residence in or visiting an area in which EM are endemic was abstracted. The use of steroids, chemotherapy, and antifungals 4 weeks before the onset of endemic mycosis was also assessed, and the presence of either concomitant or prior infection (within 4 weeks before the onset of endemic mycosis) was recorded. Finally, information about the clinical and radiologic presentation of EM was collected. The diagnosis of histoplasmosis was established if a patient had a compatible illness and at least 1 of the following: 1) a culture from any site positive for H. capsulatum due to the appearance of colonial morphology and 2) a biopsy sample showing the characteristic intracellular yeast form of H. capsulatum (34). The diagnosis of coccidioidomycosis was established if a patient had a compatible illness and at least 1 of the following: 1) a culture from any site positive for C. immitis due to the appearance of typical colonial morphology and characteristic arthrospores and 2) a biopsy showing typical spherules containing endospores of C. immitis (22). Blastomycosis was diagnosed if a patient had a compatible illness and at least 1 of the following: 1) a culture from any site positive for B. dermatitidis and 2) in the absence of a positive culture, a biopsy sample showing the morphologic finding of a broad-based budding yeast with thick, doublerefractile cell walls and cultures negative for other morphologically similar yeasts, such as Candida and Cryptococcus species (51). Neutropenia was defined as <500 neutrophils/mm3, lymphopenia was defined as <1,000 lymphocytes/mm3, and monocytopenia was defined as <80 monocytes/mm3. Serologic evidence of EM included complement fixation titers of at least 1:8 with the yeast or mycelial antigens or detection of precipitating antibodies using immunodiffusion. Breakthrough endemic mycosis was defined as infection occurring in a patient receiving systemic antifungals for any reason for at least 7 days before the onset of the infection. Response to antifungal therapy was defined as the resolution or improvement of all signs, symptoms, microbiologic findings, and radiographic changes of infection. Failure of antifungal therapy was defined as deterioration of the patient’s condition as judged according to clinical and radiographic features that resulted in death. Finally, endemic mycosis was considered a contributory cause of death at autopsy if there was histopathologic involvement of a major organ and antemortem evidence of severe dysfunction of the affected organ. Results General characteristics of EM We found that 42 patients had either a culture or histopathology positive for EM; of these, 16 were excluded from our analysis (15 had EM mimicking lung cancer but no underlying malignancy, while 1 had AIDS). Hence, 26 cancer patients having definite EM were identified (incidence of 30/100,000 admissions). Histoplasmosis was the most common of the EM (14 patients, 54%), followed by coccidioidomycosis (10 patients, 38%) and blastomycosis (2 patients, 8%). The characteristics of these patients are shown in Table 1. The majority of the patients were white (81%) and had either lived in or traveled to regions in which EM were endemic (73%).TABLE 1: Summary of 26 cancer patients who had EMSixteen patients (62%) had an underlying solid tumor, while only 10 patients (38%) had an underlying hematologic malignancy, which was lymphoid in half of them. In 3 patients, EM followed BMT; median time to the onset of EM following BMT was 360 days (range, 41–546 d). Other comorbidities were seen in 23% of patients (chronic pulmonary disease in 3 patients and diabetes mellitus, end-stage renal disease, and splenectomy in 1 patient each). At the onset of endemic mycosis, many patients (12 [46%]) had lymphopenia; 4 (15%) had monocytopenia, while 4 others had neutropenia. Chemotherapy was administered within 1 month before the onset of EM in only 8 patients (31%). In particular, fludarabine was given to 2 of 5 patients having non-Hodgkin lymphoma or chronic lymphocytic leukemia. In addition, systemic steroids were administered within 1 month before the diagnosis of EM in 8 patients (31%) (median total dose, 1,594 mg of a prednisone equivalent; range, 300–9,760 mg). Two patients (8%) had received immunosuppressive drugs (tacrolimus and hydroxyurea, respectively). Finally, radiation therapy was administered to 11 patients (42%), 5 of whom received it during the last month before the onset of EM. Prior or concomitant infections were seen in 11 patients (42%). Five of these patients (45%) had infections associated with impaired T-cell immunity (infection with atypical mycobacteriae in 4 patients, Pneumocystis carinii in 2 patients, and Salmonella group G, invasive mold, herpesvirus, and respiratory syncytial virus in 1 patient each). The lung was the most common site affected by EM (18 patients, 69%), principally in the setting of coccidioidomycosis. Metastatic lung disease was a common initial diagnostic impression in these patients. Also, disseminated disease was observed in 5 patients (19%), mainly due to histoplasmosis. Disseminated EM appeared to be more common in cancer patients with underlying lymphopenia than in those without lymphopenia (p = 0.09 according to the Fisher exact test). The diagnosis of endemic mycosis was made antemortem in 21 patients (81%). EM were diagnosed using histopathology in 20 patients (77%) and microbiology in 18 patients (69%). As shown in Table 2, the yield of invasive diagnostic procedures in patients who had pulmonary EM was good. Antifungal treatment was heterogeneous, as treatment failure was seen in only 3 patients (12%). Only histoplasmosis resulted in death (see Table 3). Breakthrough EM, which occurred despite the use of systemic fluconazole therapy (daily dose, 200–400 mg), were found in 4 patients (15%; 3 patients having histoplasmosis and 1 having blastomycosis).TABLE 2: Yield of diagnostic procedures in 18 cancer patients who had pulmonary EMTABLE 3: Characteristics of 14 cancer patients who had histoplasmosisHistoplasmosis As stated above, histoplasmosis was the most common of the EM, identified in 14 patients (Table 3). Illustrative cases Case 1 (Table 5, Patient 1): A 68-year-old man from northwest Texas had anaplastic seminoma that was treated using irradiation. At the end of treatment, he developed fever, weight loss, oral ulcers, and a mildly indurated, painful perianal ulcer that remained for 18 weeks. He was found to have anemia but not neutropenia, lymphopenia, or monocytopenia. A few calcified granulomas, a small amount of calcification in the left psoas muscle, bilateral adrenal masses, and splenomegaly were noted on a chest X-ray and abdominal computed tomography scan. Biopsy analysis of bone marrow, right adrenal, and perianal tissue samples showed granulomatous inflammation with numerous cytoplasmic yeastlike organisms compatible with H. capsulatum. A culture positive for H. capsulatum was obtained from perianal tissue. The patient received intravenous amphotericin B (0.4 mg/kg per day) for 90 days followed by oral fluconazole (400 mg/day) for 146 days, which resulted in slow improvement of his condition, including resolution of the lung lesions and ulcers. Twenty-one months after the primary infection with H. capsulatum and while receiving chronic steroids, the patient’s perianal ulcer recurred. A new culture positive for H. capsulatum was obtained from a sample of the ulcer tissue. The patient then underwent long-term therapy using oral ketoconazole (400 mg/day). He had stable disease upon therapy with a decrease in the size of adrenal masses without complete resolution. The patient died 5 years following the diagnosis of histoplasmosis; the cause of death was unclear.TABLE 5: Summary of cancer patients who had EM (n 26)TABLE 5: Continued Summary of cancer patients who had EM (n 26)Comment: This case illustrates the potential for a relapse of histoplasmosis in the setting of continuous immunosuppression. Case 2 (Table 5, Patient 2): A 65-year-old man who lived in Porto Alegre, Brazil, had chronic lymphocytic leukemia that was in remission. He received chemotherapy consisting of fludarabine in December 1995. One month after receiving chemotherapy, he developed fever, sweats, weight loss, splenomegaly, and single supraclavicular lymph node involvement. Also, he was anemic but did not have neutropenia, lymphopenia, or monocytopenia. Mediastinal lymphadenopathy was observed on a chest X-ray and assumed to be related to a malignancy. Biopsy analysis of the involved lymph node showed necrotizing granuloma along with yeast compatible with H. capsulatum, which grew in the lymph node culture. Oral itraconazole (400 mg/day) was given for 295 days, which produced a complete response. He did not have a relapse after receiving further courses of chemotherapy. Two years after completing the itraconazole regimen, he died of massive intracranial bleeding; an autopsy was not performed. Comment: This case illustrates that histoplasmosis can have an atypical presentation, such as isolated lymphadenitis, in cancer patients. The characteristics of patients having histoplasmosis are presented in Table 3. A hematologic malignancy, most often of the lymphoid type, was present in most of the patients (57%). Forty-three percent of the patients received chemotherapy and steroids, respectively, at least 1 month before the onset of infection. Breakthrough histoplasmosis occurred in 3 patients (21%), all of whom were receiving systemic therapy using fluconazole (daily dose, 200–400 mg) at the time. Histoplasmosis was the most common of the EM associated with prior or concomitant episodes of another infection (7 patients, 50%). Pulmonary histoplasmosis: Histoplasmosis limited to the lungs and/or pleura was seen in 7 patients (50%); of these cases, only 3 were symptomatic. Among the 3 patients having symptomatic pulmonary histoplasmosis, the clinical presentation was nonspecific and included fever, dyspnea, and a productive cough; none had hemoptysis. A systemic sepsis-like condition was observed in 2 patients, and acute respiratory distress syndrome (ARDS) was observed in 1. The median duration of symptoms was 4 weeks (range, 1–18 weeks). Radiographic analysis of the 7 patients having pulmonary histoplasmosis revealed disease patterns, such as solitary nodules (4 patients) and confluent infiltrates, bilateral cavitary lesions, and focal consolidation (1 patient each). Disseminated histoplasmosis: Four patients had disseminated histoplasmosis, diagnosed antemortem in only 2 cases. Of these 4 cases, 3 were symptomatic. The median duration of the symptoms was 7 weeks (range, 2–18 weeks). The lone asymptomatic patient had a subclinical disseminated infection that was diagnosed upon autopsy and manifested as hepatosplenic calcified lesions containing morphologically demonstrable organisms in the absence of an active inflammatory response. Only 2 of the 4 patients underwent autopsy. The organs most commonly affected by disseminated histoplasmosis were the bone marrow, spleen, lungs, liver, gut, adrenal, and psoas muscle. Other atypical presentations of histoplasmosis: Histoplasmosis presented in 3 patients in other than pulmonary or disseminated form: 2 had isolated fungemia (non-catheter related in both patients), while the third had lymphadenitis. Diagnosis of histoplasmosis: The diagnosis of histoplasmosis was antemortem in 9 patients (64%). In 10 patients (71%), the diagnosis was documented microbiologically. Six of the 7 patients (86%) who had pulmonary histoplasmosis had cultures positive for H. capsulatum, obtained using the following procedures: bronchoalveolar lavage (BAL; 3 patients), open lung biopsy (2 patients), and endobronchial biopsy (1 patient). Also, 3 of the 4 patients (75%) with disseminated histoplasmosis and all of the patients with other presentations of histoplasmosis (blood culture in 2 patients, lymph node biopsy in 1) had cultures yielding H. capsulatum. Histopathology yielded the diagnosis of histoplasmosis in 10 patients (71%). Six of the 7 patients (86%) who had pulmonary histoplasmosis had a positive Gomori methenamine silver (GMS) stain of smears obtained using the following procedures: open lung biopsy (3 patients) and BAL alone, lung tissue analysis (autopsy), and endobronchial biopsy (1 patient each). Also, all 4 patients with disseminated histoplasmosis and 1 patient with lymphadenitis had histopathologic evidence of histoplasmosis. In 1 patient, serologic tests for H. capsulatum were performed at the time of illness, with negative results. Therapy and outcome: Information about the use of antifungal therapy was available for 13 patients. Eight of them received antifungal therapy; of the 5 who did not, the infection was diagnosed postmortem in 3 patients, and an asymptomatic histoplasmoma was surgically resolved in the remaining 2. The antifungal therapy used was heterogeneous (amphotericin B plus fluconazole in 3 patients, amphotericin B and itraconazole monotherapy in 2 patients each, and fluconazole alone in 1 patient). The median duration of antifungal therapy was 28 days (range, 3–295 days). Antifungal therapy failure was reported for 3 patients (38%): 1 patient who was receiving amphotericin B alone (1 mg/kg per day) for 3 days, 1 receiving fluconazole alone (400 mg/day) for 7 days, and 1 receiving amphotericin B (1 mg/kg per day) plus fluconazole (400 mg/day) for 46 days. The 3 untreated patients mentioned above died of different causes unrelated to histoplasmosis; the diagnosis of histoplasmosis in these patients was incidental. Also, histoplasmosis was determined to have contributed to death in all 3 patients who experienced treatment failure, producing a mortality rate of 30% (only 10 case records contained information about cause of death). The median duration from the onset of histoplasmosis to death was 23 days (range, 10–43 days). Two of these 3 patients had hematologic malignancy, lymphopenia, and concurrent infections. In addition, 2 patients underwent an autopsy, both of whom were found to have bilateral pulmonary histoplasmosis. The only patient who died and did not undergo an autopsy had fungemia due to H. capsulatum. Coccidioidomycosis Coccidioidomycosis was the second most common of the EM, identified in 10 patients (Table 4).TABLE 4: Characteristics of 10 cancer patients who had coccidioidomycosisIllustrative cases Case 3 (Table 5, Patient 15): A 27-year-old woman had stage IV breast cancer. She had a history of disseminated coccidioidomycosis involving lung and bone before the diagnosis of her malignancy and while pregnant. Her infection followed a visit to the Mojave Desert in California. She received amphotericin B for 30 days followed by fluconazole for 30 days, which did not produce a response. The antifungal therapy regimen was then switched to amphotericin B administered intravenously for 30 days followed by oral itraconazole (600 mg/day) given for 23 months, which produced complete resolution of the infection. The patient’s breast cancer was diagnosed when she was receiving itraconazole therapy. Chemotherapy using cyclophosphamide, methotrexate, and 5-fluorouracil was started without evidence of coccidioidomycosis reactivation. Twenty-six months after her first episode of coccidioidomycosis and while she was receiving chemotherapy (tamoxifen) but not antifungal therapy (for the previous 3 months), the patient developed fever, nausea, and hip pain. Evidence of bone lesions in the pelvis and thorax was found on X-rays; it was assumed that she had a metastasis to the bone, so she was referred to M. D. Anderson Cancer Center. However, due to the fact that she had a slight increase in serologic titers (1:4 of complement-fixing antibody) for C. immitis, relapsed coccidioidomycosis was also considered. A bone biopsy exhibited that the lesions were bony metastases but failed to show any fungal organisms. Itraconazole (600 mg/day) was then given for 6 months followed by a dose of 400 mg/day given as secondary prophylaxis; the patient’s subsequent serology was negative (1:2 of complement-fixing antibody). The patient died 2 years later due to liver failure secondary to metastatic breast cancer. An autopsy was not performed. Comment: This case illustrates the difficulties in diagnosing disseminated coccidioidomycosis in the setting of a metastatic solid tumor. Case 4 (Table 5, Patient 20): A 77-year-old woman who lived in Tucson, Arizona, had uterine cancer. She developed fever and erythema multiforme that lasted for 2 weeks without any laboratory abnormalities. A solitary nodule 2 cm in diameter in her left lung was observed on a chest X-ray, which was thought to represent metastatic cancer. However, open lung biopsy analysis of the nodule was diagnostic for C. immitis. Antifungal therapy was not given, as the nodule was treated surgically. The patient improved clinically without any evidence of coccidioidomycosis during 7 years of follow-up. Comment: This case shows that 1) the presentation of coccidioidoma may mimic metastatic cancer, and 2) coccidioidoma may have a benign course in cancer patients after a complete resection. Characteristics of patients with coccidioidomycosis: Solid tumors were present in 9 of the 10 patients (90%) with C. immitis infection; coccidioidomycosis antedated the onset of the underlying disease in 2 of these patients. Overall, 20% of the patients had received either chemotherapy or steroids within 1 month before the onset of infection, respectively. Three of the 9 patients described above had prior or concomitant infections (caused by a Gram-negative rod, Mycobacterium avium complex, and Aspergillus flavus, respectively). None of the patients had breakthrough coccidioidomycosis. Isolated pulmonary involvement was seen in 9 patients (90%); 5 of these cases (56%) were symptomatic. In these 5 patients, the clinical presentation was nonspecific and included fever, a productive cough, dyspnea, and chest pain. One patient had erythema multiforme. None of the patients had hemoptysis, sepsis, or acute respiratory distress. The median duration of symptoms before diagnosis was 1 week (range, 1–2 wk). Radiography revealed several patterns of pulmonary involvement, such as solitary nodules (7 patients) and focal consolidation alone and combined with pleural effusion (1 patient each). Because most of the patients had an underlying solid tumor, the pulmonary abnormalities were thought to represent metastasis. Only 1 patient had disseminated coccidioidomycosis, which involved lung and bone (Case 3). Diagnosis: In all patients with coccidioidomycosis, the disease was diagnosed antemortem. The diagnosis was microbiologically documented in 7 patients (70%). Six of 9 patients (67%) who had pulmonary coccidioidomycosis had cultures positive for C. immitis. All of these cultures were obtained using open lung biopsy. Histopathology yielded the diagnosis of coccidioidomycosis in 9 patients (90%). Eight of the 9 patients (89%) who had pulmonary coccidioidomycosis underwent an open lung biopsy, with GMS and periodic acid-Schiff stains used to detect the characteristic spherules of C. immitis. Information about serologic tests for C. immitis infection was available for 3 patients; of these patients, only 1 had a positive result (1:128) at the time of diagnosis. Therapy and outcome: Information about the use of antifungal therapy for coccidioidomycosis was available for all 10 patients. Only 4 of these patients (40%) received antifungal therapy; the remaining 6 all had an isolated pulmonary coccidioidoma that was treated surgically and did not relapse. The antifungal regimens used were of amphotericin B lipid complex (ABLC) (5 mg/kg per day) plus oral fluconazole (400 mg/day), ABLC (5 mg/kg per day) plus oral itraconazole (400 mg/day), oral itraconazole alone (600 mg/day), and oral ketoconazole alone (6 mg/kg per day) in 1 patient each. The median duration of antifungal therapy in these patients was 210 days (range, 150–690 d). Four patients died during follow-up (median duration, 34 mo); coccidioidomycosis did not contribute to death in any of the cases. Blastomycosis Blastomycosis was the least common of the EM, identified in only 2 patients. Illustrative case Case 5 (Table 5, Patient 25): A 49-year-old man had chronic myelogenous leukemia in remission after undergoing allogeneic BMT. He had a history of traveling to Honduras and suffered from bronchiolitis obliterans organizing pneumonia and chronic graft-versus-host disease of the skin. He was receiving penicillin, trimethoprim/sulfamethoxazole, fluconazole (200 mg/day), and tacrolimus. He sought medical evaluation for worsening dyspnea, a dry cough, and fever that had lasted for 3 weeks; a physical examination showed bilateral wheezing as well. The initial chest X-ray revealed small nodules in both lungs, so a presumptive diagnosis of invasive aspergillosis was made. The patient’s status continued to worsen with the occurrence of sepsis and increasing interstitial changes in the lingula and right middle lobe. B. dermatitidis grew in a BAL culture, but the result of using a serum antibody against B. dermatitidis (complement fixation) was negative. The patient received oral itraconazole (suspension, 400 mg/day) followed by liposomal amphotericin B (5 mg/kg per day) over 136 days (total amphotericin B dose, 27,825 mg). He was also found to have a concomitant infection with Mycobacterium chelonae and respiratory syncytial virus. One day before the diagnosis of blastomycosis, he began receiving chronic high-dose steroids (total dose, 4,970 mg of a prednisone equivalent) and was subsequently found to have iatrogenic Cushing syndrome and diabetes mellitus. He had a complete response to antifungal therapy, which was confirmed by a BAL culture negative for B. dermatitidis. The patient did not have a relapse in the 6 months after he developed blastomycosis. He died of fungal superinfection with Scedosporium apiospermum; an autopsy was not performed. Comment: The presentation of blastomycosis in this case mimicked that of other more common opportunistic pulmonary fungal infections seen in the setting of BMT. This case shows that 1) breakthrough blastomycosis can occur despite the use of fluconazole therapy, 2) responses to antifungal therapy can be seen despite the severe presentation of blastomycosis in a patient having profound chronic immunosuppression, and 3) subsequent administration of high-dose steroids does not always result in dissemination of blastomycosis. The age of the 2 patients with blastomycosis was 49 and 36 years, respectively. One patient had chronic myelogenous leukemia, while the other had rectal cancer. Both patients traveled to regions in which blastomycosis is endemic. Neither patient received chemotherapy at least 1 month before the onset of infection. However, 1 patient underwent BMT and was receiving chronic immunosuppressive therapy using tacrolimus. Breakthrough blastomycosis occurred in 1 patient in the setting of systemic therapy using fluconazole (200 mg/day). Pulmonary involvement was the only presentation seen in these 2 patients, but only 1 patient had symptoms (worsening dyspnea, a dry cough, and fever that lasted for 3 weeks before diagnosis). Radiography revealed bilateral nodules with mild interstitial changes in 1 patient and a solitary cavitating nodule in the other. The diagnosis of blastomycosis was microbiologically documented in 1 patient (BAL culture), while histopathology yielded the diagnosis in the other patient (GMS and periodic acid-Schiff stains of smears obtained using open lung biopsy). Serologic tests for B. dermatitidis were performed at the time of diagnosis; the result was negative in both cases (< 1:8). Both patients received antifungal therapy. The regimens consisted of oral itraconazole (400 mg/day) followed by liposomal amphotericin B (5 mg/kg per day) in 1 patient and oral itraconazole alone (200 mg/day) in the other. The median duration of antifungal therapy was 158 days (range, 136–180 d), and therapy failure was not detected. One patient received steroids simultaneously with antifungal therapy (total dose, 4,970 mg of a prednisone equivalent). No relapses occurred. One patient died during follow-up; however, blastomycosis did not appear to contribute to death. A summary of all patients who developed each type of EM is shown in Table 5. Discussion To our knowledge, this is the largest comparative series of EM in patients having cancer at a single institution located in an area in which EM are endemic. The true incidence of EM in cancer patients is unknown (17). However, EM were uncommon in our institution during the study period (incidence of 30/100,000 admissions). Two of the most common predisposing factors for fungal infections in cancer patients are neutropenia and impaired T-cell immunity (10). Impaired T-cell immunity is a common predisposing factor for infections caused by endemic fungi, as well (58). Several studies describing patients having malignancy and EM reported a predominance of non-Hodgkin lymphoma, Hodgkin disease, and acute or chronic lymphocytic leukemia (1,7,12,18,22,27,28,33,34,37,43,45,48,54,56,69,75). However, a predominance of solid tumors was observed in our series, which is in accordance with the results of a previous study (55). This predominance of solid tumors in our study may reflect the fact that patients at highest risk for fungal infections, such as those having hematologic malignancies, have routinely received fluconazole and itraconazole either empirically or prophylactically. Similarly, a recent study (39) at our institution that evaluated cancer patients with cryptococcosis, a fungal infection that is classically associated with lymphoid malignancies (10), showed that solid tumors were frequent underlying malignancies. The present study indicates that neutropenia is not typically associated with EM. On the other hand, lymphopenia was observed in almost half of the patients with EM, mainly those with histoplasmosis. The association of lymphopenia with disseminated EM observed in this study highlights the importance of cell-mediated immune responses for the prevention of dissemination. Although EM have rarely been reported in BMT recipients (44,76), these infections should remain in the differential diagnosis of infections in this patient population along with the more common fungal infections, such as candidiasis and mold infections (44). In our patient population, the presentation of EM was nonspecific and typically mimicked other more common chronic bacterial, mycobacterial, and fungal pulmonary infections (such as invasive pulmonary aspergillosis). The most common site affected by EM was the lungs (69%). This is not surprising, because it is well known that infections due to endemic fungi are usually acquired via inhalation of conidia from environmental sources (52). EM confined to the lungs are commonly seen in immunocompetent hosts (14,25,36,40,41,70). The predominance of the pulmonary form of EM in our series could be related to the fact that the majority of our patients had an underlying solid tumor and were not severely immunocompromised. Not all of the EM involving the lungs were symptomatic; in fact, histoplasmoma and coccidioidoma were the most common presentations. Because the majority of our patients had solid tumors, metastatic lung cancer was also highly considered in the differential diagnosis, as EM have been reported to mimic lung malignancy (20,40,39,59). It is important to mention that a clinical picture compatible with lung metastasis in a patient having a known malignancy should always persuade the clinician to attempt to establish a definite diagnosis, especially considering that the diagnostic yield of invasive pulmonary procedures in this series was found to be very good (see Table 2). Endemic fungi have been reported to have a propensity for causing disseminated infection in cancer patients, especially those with a hematologic malignancy (11,27,58,66). However, only 5 of our patients (19%) had disseminated EM, only 2 of whom (40%) had an underlying hematologic malignancy. Therefore, the exact role of the type of underlying malignancy as well as prior immunosuppression remain unclear as a predisposing factor for evolution to more severe systemic manifestations of EM. On the other hand, lymphopenia has been described in association with disseminated disease (22). In our study, because lymphopenia was present in all patients with disseminated EM, it could be a marker for patients at highest risk for dissemination of EM. Finally, we found that the diagnosis of EM in cancer patients rests on microbiologic and histopathologic findings. The role of serologic tests appears dubious in this population, as has been described previously (34). Histoplasmosis Although histoplasmosis was the most common of the EM in our study, H. capsulatum remains a very uncommon cause of fungal pneumonia in cancer patients upon autopsy (38,39,49). Specifically, in an abnormal host, H. capsulatum can act as an opportunistic pathogen (9). We found that the lung was the most common organ involved with histoplasmosis, mainly as histoplasmoma. Bilateral pulmonary histoplasmosis was also observed and appeared to have a poor outcome. Histoplasmosis was also the most common of the EM associated with dissemination, as 4 of the patients (29%) with histoplasmosis developed disseminated disease. This contrasts with the incidence of dissemination seen in immunocompetent patients, which was less than 7% in previous studies (26,73,74). Disseminated histoplasmosis is encountered mainly in patients having profound deficiency of cellular immunity (such as AIDS) or those who are very young or old (4,9,24,53,63,68,70,71). However, only a minority of the patients in our series having disseminated histoplasmosis had a hematologic malignancy or underwent BMT. It is noteworthy that all of the patients with disseminated histoplasmosis had been receiving fludarabine and steroids. Use of fludarabine, which is a purine analogue that has a rapid and profound lympholytic action, may result in severe immunosuppression (3). This drug has been associated with severe opportunistic infections, especially when used in combination with steroids (3,67). Furthermore, in our study, all of the patients with disseminated histoplasmosis were lymphopenic, which is in accordance with other studies of disseminated histoplasmosis in cancer patients (7,34). In particular, 1 of these patients had subclinical disease; such a presentation has rarely been reported in cancer patients (37). In our study, the most common mucocutaneous manifestations of histoplasmosis were oral and rectal ulcers (21); plaques, pustules, and nodules were not observed (6,32). The radiologic appearance of histoplasmosis did not have a specific pattern, as has been described previously (19). Common pulmonary radiographic presentations of histoplasmosis, such as a miliary pattern (47), were not observed in the present study. The antifungal therapy for histoplasmosis used in this study, like that for all of the EM, was heterogeneous. However, consideration must be given to the fact that breakthrough histoplasmosis was observed in the setting of fluconazole prophylaxis. We believe that antifungal prophylaxis using drugs other than fluconazole (for example, itraconazole) should be considered for cancer patients at high risk for severe histoplasmosis, such as those who live in areas where histoplasmosis is endemic. In the present study, only cancer patients with histoplasmosis experienced antifungal therapy failure and died of the disease (n = 3). We found that 2 of these 3 patients were older than 50 years, had lymphopenia, and had previously used immunosuppressive drugs. Also they had concurrent infections and developed bilateral pulmonary diseases along with ARDS. The reported mortality rates associated with untreated disseminated histoplasmosis have ranged from 83% to 93% (9). Previous studies have shown a relationship between the use of appropriate, timely antifungal therapy and a good outcome in cancer patients having disseminated or hematogenous histoplasmosis (30,34,35,42). Severe bilateral pulmonary involvement and hyperacute disease appear to be associated with a poor outcome. A question we must ask is, compared with the other EM, what accounted for the poorer outcome of histoplasmosis in our series? First, a hematologic malignancy, most often of the lymphoid type, was present in 57% of the patients having histoplasmosis, which contrasted with the incidence in patients having coccidioidomycosis or blastomycosis. Second, of all the EM, histoplasmosis was the type most commonly associated with prior or concomitant infections, which is a marker of profound immunosuppression (45). Seventy-six percent of the patients having histoplasmosis who died had concurrent infections and lymphopenia. Finally, 1 patient who had disseminated histoplasmosis had a relapse while receiving steroids in the absence of secondary prophylaxis for histoplasmosis. Relapse of histoplasmosis has been described in cancer patients, even more so when steroid use is not tapered (10,30). However, not all cancer patients having histoplasmosis who receive steroids or chemotherapy subsequent to antifungal therapy have a relapse (64). Hence, the risk factors for relapse have not been fully elucidated. Coccidioidomycosis Coccidioidomycosis may be an early or late complication in patients with cancer, even in areas where this disease is not endemic (15,65). We found that coccidioidomycosis commonly occurred as pulmonary disease in cancer patients, with asymptomatic coccidioidoma being the most common presentation. None of the patients had aggressive pulmonary disease or ARDS (60,65). Disseminated coccidioidomycosis has been associated with hematologic malignancy and prior use of chemotherapy or steroids (5,13,22,61). However, the only patient in our study who developed disseminated coccidioidomycosis had a solid tumor; also, coccidioidomycosis developed while the patient was receiving chemotherapy (Case 3), as was previously reported (61). It has been reported that if a patient’s immunity is altered, C. immitis has the potential to disseminate (46). Notwithstanding that finding, in our study, none of the patients who had coccidioidoma that was treated either medically or surgically developed dissemination, even after receiving immunosuppressive chemotherapy or steroids. The utility of using serology to detect coccidioidomycosis (22) was difficult to evaluate in our study because of the small number of patients in which serologic tests were performed. However, the patient who had disseminated coccidioidomycosis had a blunted complement-fixing antibody response (62). In immunocompromised patients, including those who have cancer, coccidioidomycosis limited to the chest has a favorable prognosis similar to that of limited disease in nonimmunocompromised hosts (17,22,61). In the absence of significant immunosuppression, it is believed that antifungal therapy is not necessary if the lesion is completely resected (25). We observed that resection alone seemed to have a curative role in the subset of cancer patients having surgically treated coccidioidoma. Finally, in contrast to prior reports (2,5,22,57,66), we had no fatal cases of pulmonary or disseminated coccidioidomycosis. On the other hand, the patient (Case 3) with coccidioidomycosis who had a relapse had a history of coccidioidal infection while she was pregnant in the absence of cancer. It has been reported that patients with prior exposure to or latent coccidioidomycosis may develop disseminated infection, which may even be fatal, when their host defenses are suppressed (23,46). Blastomycosis B. dermatitidis has been reported infrequently in cancer patients, although it is regarded as a potentially opportunistic pathogen (29,31,48,51,54). As has been reported in other studies (54), 1 of our 2 patients who had blastomycosis had a malignancy associated with a T-cell defect. Also, 1 of these patients was receiving chronic immunosuppressive therapy using tacrolimus before developing this disease. To our knowledge, we report here (Case 5) the third case of blastomycosis complicating BMT (16,76). Both patients having blastomycosis had pulmonary infection (1 had diffuse interstitial disease, while the other had a solitary cavitating nodule), the clinical presentation of which was similar to that seen in normal hosts (8,20,41,48,54). In our patients, serologic tests for B. dermatitidis were not useful, as has been described previously (14). Of note, extrapulmonary disease was not observed in our study, although dissemination has been reported in almost one-third of immunosuppressed patients in prior reports (51,54). In contrast to histoplasmosis and coccidioidomycosis, though, it is controversial whether cancer patients harbor an excessive risk of dissemination of blastomycosis (17,51,75). In our study, 1 patient received chronic high-dose steroids concomitantly with antifungal therapy, but progressive pulmonary disease, dissemination, or relapse did not occur afterward. In addition, a lack of tapering of immunosuppression has been reported to intensify the infection and increase the risk of relapse (8,20,31). Neither of the patients in our study died of blastomycosis (14). A favorable outcome should be expected in cancer patients having blastomycosis (17), which contrasts with the expected outcome in AIDS patients (50). In conclusion, a predominance of EM in patients with solid tumors was observed. Hence, EM should be considered in the differential diagnosis of a variety of pulmonary manifestations in cancer patients, such as presumed metastatic lung cancer and chronic or subacute pneumonia. Breakthrough EM could occur in the setting of fluconazole prophylaxis. Lymphopenia appears to be related to the development of disseminated EM. Finally, histoplasmosis has the worst prognosis of all the EM. Summary Infections caused by endemic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis) have been described sporadically in cancer patients. We reviewed the records of 26 cancer patients who developed endemic mycoses (EM) at our institution from 1988 to 2001. Solid tumors were the most common underlying malignancy. In 3 patients, EM complicated bone marrow transplantation. Histoplasmosis was the most common of the EM (14 patients). Lymphopenia was observed in 12 patients (46%), and 8 patients (31%) received either steroids or chemotherapy before the onset of endemic mycosis. Breakthrough EM occurred in 4 patients in the setting of fluconazole prophylaxis. Pulmonary disease was seen in 18 patients having EM (69%), consisting mainly of coccidioidomycosis (9 patients). Disseminated disease was observed in 5 patients (19%), consisting mainly of histoplasmosis. The antifungal therapy used in these patients was heterogeneous, and therapy failure was seen in 3 of 25 patients (12%) for whom data are available. In addition, only patients having histoplasmosis had a fatal outcome due to the infection (3 patients [30%]). We found that EM are infrequent in cancer patients, lymphopenia appears to be related to the development of disseminated EM, and histoplasmosis has the worst prognosis of the EM we evaluated. Acknowledgments We thank Dr. J. Tarrand and Dr. M. Luna for their assistance in identifying cases." @default.
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W2317555001 date "2002-05-01" @default.
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W2317555001 title "Endemic Mycoses in a Cancer Hospital" @default.
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