A case series and literature review of blastomycosis during pregnancy amidst the COVID-19 crisis.

Blastomycosis dermatitidis is a rare fungus known for is classic mimicry of pneumonia, lung cancer, and mycobacterial infections. Whilst it is known best for affecting those in the Ohio and Mississippi River basins, several cases have erupted in the Midwest region. Few case reports have focused on blastomycosis and its sequalae in pregnancy. We present a case series of blastomycosis diagnosed during the second and third trimesters in two women amidst the COVID-19 pandemic. Given immunosuppression, complications and treatment can be challenging for clinicians. This case series and discussion hopes to provide future clinicians with the presentation, diagnosis, management, and treatment of this uncommon infection.

Endemic Systemic Mycoses in Italy: A Systematic Review of Literature and a Practical Update.

Endemic systemic mycoses such as blastomycosis, coccidioidomycosis, histoplasmosis, talaromycosis, paracoccidioidomycosis are emerging as an important cause of morbidity and mortality worldwide. We conducted a systematic review on endemic systemic mycoses reported in Italy from 1914 to nowadays. We found out: 105 cases of histoplasmosis, 15 of paracoccidioidomycosis, 10 of coccidioidomycosis, 10 of blastomycosis and 3 of talaromycosis. Most cases have been reported in returning travelers and expatriates or immigrants. Thirtytwo patients did not have a story of traveling to an endemic area. Fortysix subjects had HIV/AIDS. Immunosuppression was the major risk factor for getting these infections and for severe outcomes. We provided an overview on microbiological characteristics and clinical management principles of systemic endemic mycoses with a focus on the cases reported in Italy.

Intensive Care Unit and Hospital Outcomes of Patients Admitted with Blastomycosis: A 14-Year Retrospective Study.

INTRODUCTION: Blastomycosis is an uncommon; potentially life-threatening granulomatous fungal infection. The aim of this study is to report hospital and intensive care unit (ICU) outcomes of patients admitted with blastomycosis. METHODS: All patients admitted for treatment of blastomycosis at the Mayo Clinic-Rochester, Minnesota between 01/01/2006 and 09/30/2019 were included. Demographics, comorbidities, clinical presentation, ICU admission, and outcomes were reviewed. RESULTS: A total of 84 Patients were identified with 90 unique hospitalizations primarily for blastomycosis. The median age at diagnosis was 49 (IQR 28.1-65, range: 6-85) years and 56 (66.7%) were male. The most frequent comorbidities included hypertension (n = 28, 33.3%); immunosuppressed state (n = 25, 29.8%), and diabetes mellitus (n = 21, 25%). The lungs were the only organ involved in 56 (66.7%) cases and the infection was disseminated in 19 (22.6%) cases. A total of 29 patients (34.5%) underwent ICU admission due to complications of blastomycosis. ICU related events included mechanical ventilation (n = 20, 23.8%), acute respiratory distress syndrome (ARDS) (n = 13, 15.5%), tracheostomy (n = 9, 10.7%), renal replacement therapy (n = 8, 9.5%), and extracorporeal membrane oxygenation (ECMO) (n = 4, 4.8%). A total of 12 patients (14.3%) died in the hospital; all of whom had undergone ICU admission. In-hospital mortality was associated with renal replacement therapy (RRT) (P = 0.0255). CONCLUSION: Blastomycosis is a serious, potentially life-threatening infection that results in significant morbidity and mortality with a 34.5% ICU admission rate. RRT was associated with in-hospital mortality.

Clinical Manifestations and Outcomes in Immunocompetent and Immunocompromised Patients With Blastomycosis.

BACKGROUND: Blastomyces is a dimorphic fungus that infects persons with or without underlying immunocompromise. To date, no study has compared the clinical features and outcomes of blastomycosis between immunocompromised and immunocompetent persons. METHODS: A retrospective study of adult patients with proven blastomycosis from 2004-2016 was conducted at the University of Wisconsin. Epidemiology, clinical features, and outcomes were analyzed among solid-organ transplantation (SOT) recipients, persons with non-SOT immunocompromise (non-SOT IC), and persons with no immunocompromise (NIC). RESULTS: A total of 106 cases met the inclusion criteria including 74 NIC, 19 SOT, and 13 non-SOT IC (malignancy, HIV/AIDS, idiopathic CD4+ lymphopenia). The majority of patients (61.3%) had at least 1 epidemiologic risk factor for acquisition of Blastomyces. Pneumonia was the most common manifestation in all groups; however, immunocompromised patients had higher rates of acute pulmonary disease (P = .03), more severe infection (P = .007), respiratory failure (P = .010), and increased mortality (P = .02). Receipt of SOT primarily accounted for increased severity, respiratory failure, and mortality in immunosuppressed patients. SOT recipients had an 18-fold higher annual incidence of blastomycosis than the general population. The rate of disseminated blastomycosis was similar among NIC, SOT, and non-SOT IC. Relapse rates were low (5.3-7.7%). CONCLUSIONS: Immunosuppression had implications regarding the acuity, severity, and respiratory failure. The rate of dissemination was similar across the immunologic spectrum, which is in sharp contrast to other endemic fungi. This suggests that pathogen-related factors have a greater influence on dissemination for blastomycosis than immune defense.

Blastomycosis in the Capital District of New York State: A Newly Identified Emerging Endemic Area.

BACKGROUND: The Centers for Disease Control and Prevention and New York State Department of Health recently identified the Capital District of New York (CDNY) as an emerging endemic area for blastomycosis. However, no clinical or epidemiological description of blastomycosis in the CDNY has been published. METHODS: We performed a retrospective analysis of blastomycosis cases at Albany Medical Center (AMC) and Albany Stratton Veterans Affairs Medical Center (VAMC) from January 1, 2000, through June 1, 2019. Patients were identified via an institution-approved informatics system at the hospital's microbiology laboratory. RESULTS: We identified 20 patients diagnosed with blastomycosis over the past 2 decades. There was a nearly 9-fold increase in the annual number of cases in 2016-2019 compared with 2000-2015. The majority of patients resided in the CDNY (90%), and 65% lived within the Mohawk River valley. Most cases (85%) were assumed to be malignancies or non-mycotic infections prior to diagnosis, with median time between presentation and diagnosis of 53 days. CONCLUSIONS: Our data support recent reports that blastomycosis is an emerging disease in the CDNY. Most patients were misdiagnosed as malignancy or non-mycotic infection, which led to treatment delays.

Re-drawing the Maps for Endemic Mycoses.

Endemic mycoses such as histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis, and talaromycosis are well-known causes of focal and systemic disease within specific geographic areas of known endemicity. However, over the past few decades, there have been increasingly frequent reports of infections due to endemic fungi in areas previously thought to be "non-endemic." There are numerous potential reasons for this shift such as increased use of immune suppressive medications, improved diagnostic tests, increased disease recognition, and global factors such as migration, increased travel, and climate change. Regardless of the causes, it has become evident that our previous understanding of endemic regions for these fungal diseases needs to evolve. The epidemiology of the newly described Emergomyces is incomplete; our understanding of it continues to evolve. This review will focus on the evidence underlying the established areas of endemicity for these mycoses as well as new data and reports from medical literature that support the re-thinking these geographic boundaries. Updating the endemic fungi maps would inform clinical practice and global surveillance of these diseases.

The endemic mimic: blastomycosis an illness often misdiagnosed.

One of the endemic fungi, Blastomyces dermatitidis, can cause epidemics of infection with multiple persons involved in a point source outbreak but more commonly causes sporadic cases of infection within the areas of endemicity. Blastomycosis can present as an acute pneumonia which is often misdiagnosed as acute pneumococcal pneumonia or the infection may present as a chronic pneumonia along with weight loss, night sweats, hemoptysis, and a lung mass suggesting tuberculosis or carcinoma of the lung. Extrapulmonary infection with B. dermatitidis is protean with many different manifestations. Most commonly, skin or subcutaneous lesions are found with either a verrucous or warty appearance or in an ulcerative form. Cases have been misidentified as keratoacanthoma, pyoderma gangrenosum, carcinoma, or as Weber-Christian panniculitis if there are nodular subcutaneous lesions. Essentially any site or organ can have lesions of disseminated blastomycosis. In our series, cases of laryngeal carcinoma, adrenal insufficiency, thyroid nodules, granulomatous hypercalcemia, abnormal mammograms thought to represent breast carcinoma, otitis media with cranial extension, immune thrombocytopenic purpura, and hemolytic anemia of unknown cause have been misdiagnosed and blastomycosis subsequently identified as the cause. This infection causes manifestations which mimic many other more commonly diagnosed conditions and must always be considered by clinicians practicing in the endemic region.

Blastomycosis diagnosed in a nonhyperendemic area.

INTRODUCTION: Blastomycosis, caused by the dimorphic fungus Blastomyces dermatitidis, is hyperendemic in northern Wisconsin and is unevenly distributed in the rest of the state and contiguous Minnesota. Clinical presentation of this illness has been characterized by localized outbreaks and sporadic cases in endemic areas. METHODS: Using ICD-9 CPT codes, we queried our electronic health record system to identify cases of blastomycosis diagnosed at Gundersen Health System over a 32-year period. Gundersen serves a region outside the hyperendemic area of Wisconsin. Records so identified were reviewed for demographic and clinical features. We attempted to interview patients with a blastomycosis diagnosis from 2002 through 2006. Blastomycosis data also were collected from the states of Wisconsin and Minnesota from 2002 through 2006 and assessed for trends. RESULTS: Thirty-six patients had blastomycosis diagnoses at Gundersen Health System during the study period, as identified by ICD-9 code. Of these, 10 were excluded from further review because they were either miscoded or the code indicated a previous diagnosis. The remaining 26 patients were included in the study. Premorbid conditions included diabetes (38%) and smoking (62%). The mean time from onset of symptoms to the first laboratory specimen positive for B dermatitidis was 51 days. Notably, 73% of these patients were treated initially for bacterial pneumonia. The incidence of blastomycosis in Wisconsin in the review period was 2.0 per 100,000, and the rate in Minnesota was 0.5 per 100,000. Based on the census data in Gundersen Health System's 19-county service area, the incidence of blastomycosis is 0.17 cases per 100,000. CONCLUSION: In this review of blastomycosis cases diagnosed outside the hyperendemic area of northern Wisconsin, diagnosis was often delayed, and 4 patients whose infections might have been treatable died. Although uncommon, blastomycosis needs to be considered in the differential diagnosis in areas outside the hyperendemic area.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

C-type lectin receptors differentially induce th17 cells and vaccine immunity to the endemic mycosis of North America.

Vaccine immunity to the endemic mycoses of North America requires Th17 cells, but the pattern recognition receptors and signaling pathways that drive these protective responses have not been defined. We show that C-type lectin receptors exert divergent contributions to the development of antifungal Th17 cells and vaccine resistance against Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides posadasii. Acquired immunity to B. dermatitidis requires Dectin-2, whereas vaccination against H. capsulatum and C. posadasii infection depends on innate sensing by Dectin-1 and Dectin-2, but not Mincle. Tracking Ag-specific T cells in vivo established that the Card9 signaling pathway acts indispensably and exclusively on differentiation of Th17 cells, while leaving intact their activation, proliferation, survival, and migration. Whereas Card9 signaling is essential, C-type lectin receptors offer distinct and divergent contributions to vaccine immunity against these endemic fungal pathogens. Our work provides new insight into innate immune mechanisms that drive vaccine immunity and Th17 cells.

Fatal disseminated blastomycosis in a free-ranging American black bear (Ursus americanus).

An aged, free-ranging, female, radio-collared American black bear (Ursus americanus) died after an approximately 5 month long period of weight loss. Gross necropsy findings included severe diffuse pyogranulomatous bronchopneumonia, marked granulomatous lymphadenitis of tracheobronchial lymph nodes and multiple intra-abdominal lymph nodes, chronic focal jejunal ulceration, and widespread alopecia. Histopathologic examination revealed abundant fungal organisms morphologically compatible with Blastomyces sp. within pyogranulomatous inflammatory lesions in the lungs, multiple lymph nodes, liver, kidneys, jejunum, and right adrenal gland. In addition, the haircoat had a mild infestation of chewing lice (Trichodectes pinguis euarctidos), and large numbers of rhabditid nematodes consistent with Pelodera sp. were histologically observed within hair follicles.

Endemic systemic mycoses: coccidioidomycosis, histoplasmosis, paracoccidioidomycosis and blastomycosis.

Endemic deep or systemic mycoses are common in specific geographical areas of the world. Coccidioidomycosis is present in semi-desert areas, histoplasmosis and paracoccidioidomycosis in tropical regions and blastomycosis belongs to temperate climates. The two former are widely distributed in the American continent and some tropical regions of the world; the third is limited to Central and South America, and the last to North America and Central and East Africa. These mycoses all have a similar pathogenesis, as the inoculum enters the host through the respiratory tract. Cutaneous manifestations are secondary to lymphatic and hematogenous dissemination. These deep mycoses are exceptional in Europe. Most cases are observed in returning travelers from endemic areas, aid workers, archaeologists, speleologist and immigrants. However, there have been some autochthonous cases of histoplasmosis due to Histoplasma capsulatum var. capsulatum reported in European countries such as Italy and Germany. In this article, we provide up-to-date epidemiological, clinical, diagnostic and therapeutic data on the four most important imported systemic mycoses in Europe.

The differential diagnosis of pulmonary blastomycosis using case vignettes: a Wisconsin Network for Health Research (WiNHR) study.

PURPOSE: Pulmonary blastomycosis is an uncommon but serious fungal infection endemic in Wisconsin. Clinician awareness of the protean presentations of this disease may reduce diagnostic delay. This study addressed the diagnostic accuracy of physicians responding to case vignettes of pulmonary blastomycosis and the primary care differential diagnosis of this disease. METHODS: Eight pulmonary blastomycosis cases were developed from case files. From these, 2 vignettes were randomly selected and mailed to primary care physicians in the Wisconsin Network for Health Research. Respondents were asked to list the 3 most likely diagnoses for each case. RESULTS: Respondents listed Blastomycosis as the most likely diagnosis for 37/227 (16%) case vignettes, and 1 of the 3 most likely diagnoses for 43/227 (19%). When vignettes included patient activity in counties with an annual incidence rate of blastomycosis greater than 2/100,000, compared to counties with lower incidence rates, diagnosis was more accurate (28/61 [46%] vs 15/166 [9%]; P<0.001). Physicians with practice locations in counties with annual blastomycosis incidence rates >2/100,000 listed blastomycosis more commonly than physicians from other counties (16/36 [44%] vs 27/177 [15%]; P<0.001). This difference in accurate diagnosis remained significant in a multivariate model of practice demographics. Based on responses to the vignettes, pneumonia, cancer, non-infectious pulmonary disease, and tuberculosis emerged as the most-frequently noted diagnosis in the differential diagnosis of blastomycosis. CONCLUSION: Blastomycosis was not listed as 1of 3 primary diagnoses in a majority of cases when Wisconsin primary care physicians considered case vignettes of actual pulmonary blastomycosis cases. Diagnosis was more accurate if the patient vignette listed exposure to a higher incidence county, or if the physician practiced in a higher incidence county. In Wisconsin, failure to include blastomycosis in the differential diagnoses of illnesses associated with a wide variety of pulmonary symptoms suspected to represent infectious or non-infectious pulmonary, cardiac, or neoplastic disease, regardless of geographic exposure, could result in excess morbidity or mortality.

Blastomycosis in children and adolescents: a 30-year experience from Manitoba.

Blastomyces dermatitidis, a thermally dimorphic fungus endemic to areas of North America, causes a granulomatous infection which may affect any organ system. Since limited clinical data exist about pediatric blastomycosis, we conducted a retrospective review of medical records of pediatric patients with a laboratory-confirmed diagnosis of blastomycosis treated during a 30-year period at a tertiary care center. Thirty-four pediatric patients with blastomycosis were identified (20 [59%] male), with a mean age at diagnosis of 10 ± 5 years. Two patients were immunocompromised. Pulmonary disease was noted in 27 (79%) patients, and extrapulmonary disease was found in 13 (38%) patients (concurrent pulmonary and extrapulmonary disease, six patients), including five cases of central nervous system (CNS) disease. Delay in diagnosis was greater with extrapulmonary or central nervous system infections as compared with pulmonary blastomycosis. All patients received antifungal chemotherapy, with 19 (56%) patients receiving amphotericin B as initial therapy for 27.5 ± 17 days. Five patients required treatment in the intensive care unit. One patient died of non-Hodgkins lymphoma. Blastomycosis may occur in healthy children, including very young infants. Due to the frequency of extra-pulmonary disease, diagnosis may be difficult and frequently delayed, especially in cases of CNS infection.

Endemic fungal infections in patients receiving tumour necrosis factor-alpha inhibitor therapy.

Tumour necrosis factor (TNF)-alpha inhibitors are widely used agents in the treatment of a variety of inflammatory and granulomatous diseases. It has long been appreciated that these agents confer an increased risk of tuberculosis; however, more recently it has been recognized that patients being treated with TNFalpha inhibitors are also at significant risk for infection with the endemic fungi, in particular Histoplasma capsulatum, and when infected, to develop severe disseminated infection. Patients often present in an atypical manner and the symptoms of the fungal infection can be mistaken for those of the underlying disease. Thus, delay in diagnosis and treatment is common, and mortality has been high. In an attempt to increase awareness of this problem, the US FDA issued a 'black box' warning for clinicians in September 2008 to alert providers of the risks of endemic fungal infections in patients treated with TNFalpha inhibitors. The management of patients who develop endemic fungal infection while receiving TNFalpha inhibitor therapy should include discontinuation of the TNFalpha inhibitor and early use of antifungal agents including polyenes and/or azoles according to the Infectious Diseases Society of America guidelines for treatment of these infections in immunocompromised hosts.

Clinical characteristics and outcomes in patients with pulmonary blastomycosis.

BACKGROUND: Blastomycosis is an uncommon granulomatous infection caused by the thermally dimorphic fungus Blastomyces dermatitidis. The most frequent clinical infections involve the lung, skin, and bone. Pulmonary manifestations range from asymptomatic self-limited infection to severe diffuse pneumonia causing respiratory failure. OBJECTIVES: To establish the clinical characteristics and outcomes of patients with pulmonary blastomycosis diagnosed at hospitals in Manitoba and northwestern Ontario, Canada. METHODS: A retrospective review of medical records was done for 318 patients with blastomycosis in these regions. RESULTS: The majority of patients were Caucasian (198 (62.5%) patients), male (193 (61%) patients), and residents of Ontario (209 (65.7%) patients). Most patients were treated in an inpatient hospital ward (266 (84%) patients) and survived (294 (92%) patients). Pulmonary involvement, either alone or associated with other sites, was present in 296 (93%) of the 318 patients; 22 (7%) patients had no evidence of pulmonary blastomycosis. The majority of patients had localized lung disease (1-3 quadrants on chest radiograph involved; 225 (82%) patients). Of 294 (92%) patients requiring hospitalization, 266 (90%) patients received all inpatient care on a general medical ward; 28 (10%) patients received some care in the intensive care unit (ICU). Factors associated with ICU admission included diffuse pulmonary disease (four quadrants involved on chest radiograph), diabetes, and prior use of antimicrobial therapy. Twenty-four (8%) patients died, and multivariate analysis showed that older age and Aboriginal ethnicity were the significant risk factors for death from blastomycosis. CONCLUSION: Blastomycosis is a cause of serious, potentially life-threatening pulmonary infection in this geographic region.

Seasonal variations in the clinical presentation of pulmonary and extrapulmonary blastomycosis.

Blastomycosis is a granulomatous infection caused by the thermally dimorphic fungus, Blastomyces dermatitidis, for which seasonal variation has been proposed. We conducted a retrospective review of medical records of 324 patients with blastomycosis in Manitoba and northwestern Ontario. The average age of patients at the time of diagnosis was 39+/-20 (range, 0-85) years. Symptoms referable to blastomycosis were first noted in the autumn and winter (September to February) by 63% of the patients. The seasonal distribution of cases was different for localized pulmonary infection than the disseminated disease (P<0.0001). For localized lung disease, the peak incidence of symptom onset occurred in the autumn, and lowest incidence in the spring; one half (50%) of the patients with diffuse lung disease had onset of symptoms in the spring months and a few (11%) cases occurred during the summer. We noted a distinct seasonal variation in the clinical presentation of blastomycosis. The observed pattern suggests that summer environmental exposure and acquisition of the infection results in an early (1-6 months) localized pneumonia in the majority of cases, followed by later (4-9 months) reactivation or slow progression of asymptomatic infection resulting in isolated extrapulmonary or disseminated hematogenous disease in the minority.

Pulmonary blastomycosis.

Blastomycosis is a rare but important fungal infection diagnosed primarily in the south central and midwestern United States but also in the American and Canadian borders of the Great Lakes. Epidemics of infection related to point-source exposure include patients of all ages and both sexes, but endemic cases are usually in young to middle-aged adults, with more men than women reported. Pneumonia is the most common manifestation and the lung is almost always the organ initially infected. The lung manifestations range from illness that mimics acute bacterial pneumonia to chronic, destructive lung disease appearing like tuberculosis or lung cancer. Extrapulmonary disease can occur with or without concomitant lung disease. In descending order, cutaneous, osseous, prostatic, and central nervous system involvements are the most frequent manifestations of extrapulmonary blastomycosis. Amphotericin B is curative, but, because of toxicity, oral azole agents have replaced amphotericin B as therapy for less than overwhelming blastomycosis. Itraconazole is now considered to be the agent of choice with fluconazole, voriconazole, and posaconazole having a role in selected patients. In a patient with life-threatening or central nervous system blastomycosis amphotericin B should be given, at least initially.