Skin innate immune response against fungal infections and the potential role of trained immunity.

Fungal skin infections are distributed worldwide and can be associated with economic and social traits. The immune response related to skin cells is complex and its understanding is essential to the comprehension of each cell's role and the discovery of treatment alternatives. The first studies of trained immunity (TI) described the ability of monocytes, macrophages and natural killer (NK) cells to develop a memory-like response. However, the duration of TI does not reflect the shorter lifespan of these cells. These conclusions supported later studies showing that TI can be observed in stem and haematopoietic cells and, more recently, also in non-immune skin cells such as fibroblasts, highlighting the importance of resident cells in response to skin disorders. Besides, the participation of less studied proinflammatory cytokines in the skin immune response, such as IL-36γ, shed light into a new possibility of inflammatory pathway blockade by drugs. In this review, we will discuss the skin immune response associated with fungal infections, the role of TI in skin and clinical evidence supporting opportunities and challenges of TI and other inflammatory responses in the pathogenesis of fungal skin infections.

Case report: First case of fungemia caused by Papiliotrema laurentii in a patient with SARS-CoV-2 infection

ABSTRACT Previously considered saprobe and non-pathogenic, the fungus Papiliotrema laurentii (formerly known as Cryptococcus laurentii), is rarely associated with human infection. Nevertheless, there has been an increase in reported infections by non-neoformans cryptococci. After a literature search on the Cochrane Library, LILACS, SciELO, MEDLINE, PubMed, and PMC (PubMed Central) databases, we conclude that this is the first case report of fungemia and probable meningitis caused by Papiliotrema laurentii in a previously immunocompetent host with associated COVID-19.

Invasive Aspergillosis in Patients with Acute Leukemia: Comparison Between Acute Myeloid and Acute Lymphoid Leukemia.

BACKGROUND: The epidemiology of invasive aspergillosis (IA) in patients with acute lymphoid leukemia (ALL) has not been well characterized. OBJECTIVES: To identify potential peculiarities in the natural history, treatment response and outcome of IA diagnosed in patients with ALL and AML. METHODS: This is a retrospective cohort study conducted in seven tertiary-care hospitals between 2009 and 2017 of all consecutive episodes of IA occurring in adult patients with acute leukemia. Demographic characteristics, underlying disease and recent treatment, antifungal prophylaxis, neutropenia, receipt of corticosteroids, clinical and radiological findings, mycological results, antifungal therapy, and 6-week and 12-week survival were recorded. RESULTS: We identified 77 cases of IA in 54 patients with AML and 23 patients with ALL. The majority of patients developed IA in the context of induction chemotherapy for newly diagnosed (48.0%) or relapsed (41.6%) leukemia, with no differences between ALL and AML. Lung involvement was more frequent in AML (96.3% vs. 82.6%, p = 0.06) and rhinosinusitis was more common in ALL (43.5% vs. 24.1%, p = 0.09). Galactomannan was the microbiologic documentation of IA in 76.6%, with similar patterns of positivity in AML and ALL. The 6-week survival of IA in patients with AML and ALL was 63.0% and 56.5%, respectively (p = 0.60). CONCLUSIONS: The epidemiology, clinical presentation, diagnosis and outcome of IA in ALL patients are similar to patients with AML.

Case report: Mycetoma caused by Gordonia soli

ABSTRACT Mycetoma is a neglected tropical disease caused by fungi (eumycetoma) or bacteria (actinomycetoma), with high morbidity. Gordonia spp. are gram-positive bacteria that have previously been reported to cause mycetoma. Here, we report a case of Gordonia soli (initially misidentified as Nocardia spp.) as the etiological agent of actinomycetoma in a 64-year-old patient. After a literature search in the Cochrane Library, LILACS, SciELO, MEDLINE, PubMed, and PubMed Central databases, we concluded that this is the first case report of mycetoma caused by Gordonia soli. The current case highlights the importance of microbiological diagnosis of mycetoma and the challenges in its management.

Spread of Sporothrix spp. through respiratory droplets from infected cats: A potential route of transmission.

Cases of cat-transmitted sporotrichosis in Brazil have increased in recent years. We collected respiratory secretions expelled while sneezing from 28 cats diagnosed with sporotrichosis. We identified the presence of Sporothrix spp. in respiratory droplets expelled in the sneeze of infected cats. The results raise concerns about a new transmission route for cat-transmitted sporotrichosis. Physicians who diagnose and treat human cases of sporotrichosis should be aware of this potential new transmission method to improve clinical suspicion. Approximately half of patients with granulomatous conjunctival sporotrichosis did not report experiencing traumatic injury from cats.

Cat-transmitted sporotrichosis is a zoonosis in geographic expansion from Brazil to other Latin American countries and is considered a public health problem. Data suggest that transmission can occur through the sneeze of an infected cat. The One Health approach is necessary to control the disease.

The global burden of chromoblastomycosis.

BACKGROUND: Chromoblastomycosis (CBM), represents one of the primary implantation mycoses caused by melanized fungi widely found in nature. It is characterized as a Neglected Tropical Disease (NTD) and mainly affects populations living in poverty with significant morbidity, including stigma and discrimination. METHODS AND FINDINGS: In order to estimate the global burden of CBM, we retrospectively reviewed the published literature from 1914 to 2020. Over the 106-year period, a total of 7,740 patients with CBM were identified on all continents except Antarctica. Most of the cases were reported from South America (2,619 cases), followed by Africa (1,875 cases), Central America and Mexico (1,628 cases), Asia (1,390 cases), Oceania (168 cases), Europe (35 cases), and USA and Canada (25 cases). We described 4,022 (81.7%) male and 896 (18.3%) female patients, with the median age of 52.5 years. The average time between the onset of the first lesion and CBM diagnosis was 9.2 years (range between 1 month to 50 years). The main sites involved were the lower limbs (56.7%), followed by the upper limbs (19.9%), head and neck (2.9%), and trunk (2.4%). Itching and pain were reported by 21.5% and 11%, respectively. Malignant transformation was described in 22 cases. A total of 3,817 fungal isolates were cultured, being 3,089 (80.9%) Fonsecaea spp., 552 (14.5%) Cladophialophora spp., and 56 Phialophora spp. (1.5%). CONCLUSIONS AND SIGNIFICANCE: This review represents our current knowledge on the burden of CBM world-wide. The global incidence remains unclear and local epidemiological studies are required to improve these data, especially in Africa, Asia, and Latin America. The recognition of CBM as NTD emphasizes the need for public health efforts to promote support for all local governments interested in developing specific policies and actions for preventing, diagnosing and assisting patients.

Clinical and epidemiological aspects of Candidemia in eight medical centers in the state of Parana, Brazil: Parana Candidemia Network.

OBJECTIVES: Candida spp. has been reported as one of the common agents of nosocomial bloodstream infections and is associated with a high mortality. Therefore, this study evaluated the clinical findings, local epidemiology, and microbiological aspects of candidemia in eight tertiary medical centers in the state of Parana, South of Brazil. METHODS: In this study, we reported 100 episodes of candidemia in patients admitted to eight different hospitals in five cities of the state of Parana, Brazil, using data collected locally (2016 and 2017) and tabulated online. RESULTS: The incidence was found to be 2.7 / 1000 patients / day and 1.2 / 1000 admissions. C. albicans was responsible for 49% of all candidemia episodes. Cancer and surgery were the two most common underlying conditions associated with candidemia. The mortality rate within 30 days was 48%, and removal of the central venous catheter (p = 0.029) as well as empirical or prophylactic exposure to antifungals were both related to improved survival (p = 0.033). CONCLUSIONS: This study highlights the high burden and mortality rates of candidemia in hospitals from Parana as well as the need to enhance antifungal stewardship program in the enrolled medical centers.

Epidemiology of invasive fungal disease in haematologic patients.

Invasive fungal disease (IFD) is frequent in patients with haematologic malignancies and in recipients of haematopoietic cell transplantation (HCT). An epidemiologic study conducted in Brazil reported a high incidence of IFD in haematologic patients, and invasive fusariosis was the leading IFD. A limitation of that study was that galactomannan was not available for at least half of the study period. In order to characterise the epidemiology and burden of IFD in three cohorts, HCT, acute myeloid leukaemia (AML) or myelodysplasia (MDS), and acute lymphoid leukaemia (ALL), we conducted a prospective multicentre cohort study in four haematologic Brazilian centres. From August 2015 to July 2016, all patients receiving induction chemotherapy for newly diagnosed or relapsed AML, MDS or ALL, and all HCT recipients receiving conditioning regimen were followed during the period of neutropenia following chemotherapy or the conditioning regimen. During a 1-year period, 192 patients were enrolled: 122 HCT recipients (71 allogeneic, 51 autologous), 46 with AML, and 24 with ALL. The global incidence of IFD was 13.0% (25 cases, 11 proven and 14 probable). Invasive aspergillosis (14 cases) was the leading IFD, followed by candidemia (6 cases) and fusariosis (3 cases). The incidence of IFD was 26.1% in AML/MDS, 16.7% in ALL, 11.3% in allogeneic HCT, and 2.0% in autologous HCT. The burden of IFD in haematologic patients in Brazil is high, with a higher frequency in AML and ALL. Invasive aspergillosis is the leading IFD, followed by invasive candidiasis and fusariosis.

Nodular Human Lagochilascariasis Lesion in Hunter, Brazil.

Lagochilascariasis is a rare helminthic infection caused by Lagochilascaris minor nematodes and found in Latin America; most cases are reported in the Amazon region. We report on a case observed in a hunter in southern Brazil and describe scanning electron microscopy results for L. minor adult forms.

Top 10 evidence-based recommendations from the Brazilian Society of Infectious Diseases for the Choosing Wisely Project.

The Choosing Wisely Initiative aims to collect statements from medical societies all over the world on medical interventions that result in no benefit to patients, with the potential to cause harm. In this article we present the views of the Diagnostic Laboratory Group at the Brazilian Society of Infectious Diseases (SBI). Ten experts from SBI were asked to list 10 diagnostic tests that were perceived as unnecessary in the field of infectious diseases. After voting for the more relevant topics, a questionnaire was sent to all SBI members, in order to select for the most important items. A total of 482 votes were obtained, and the top 10 results are shown in this manuscript. The Choosing Wisely statements of SBI should facilitate clinical practice by optimizing the use of diagnostic resources in the field of infectious diseases.

The Diagnosis of Fungal Neglected Tropical Diseases (Fungal NTDs) and the Role of Investigation and Laboratory Tests: An Expert Consensus Report.

The diagnosis of fungal Neglected Tropical Diseases (NTD) is primarily based on initial visual recognition of a suspected case followed by confirmatory laboratory testing, which is often limited to specialized facilities. Although molecular and serodiagnostic tools have advanced, a substantial gap remains between the desirable and the practical in endemic settings. To explore this issue further, we conducted a survey of subject matter experts on the optimal diagnostic methods sufficient to initiate treatment in well-equipped versus basic healthcare settings, as well as optimal sampling methods, for three fungal NTDs: mycetoma, chromoblastomycosis, and sporotrichosis. A survey of 23 centres found consensus on the key role of semi-invasive sampling methods such as biopsy diagnosis as compared with swabs or impression smears, and on the importance of histopathology, direct microscopy, and culture for mycetoma and chromoblastomycosis confirmation in well-equipped laboratories. In basic healthcare settings, direct microscopy combined with clinical signs were reported to be the most useful diagnostic indicators to prompt referral for treatment. The survey identified that the diagnosis of sporotrichosis is the most problematic with poor sensitivity across the most widely available laboratory tests except fungal culture, highlighting the need to improve mycological diagnostic capacity and to develop innovative diagnostic solutions. Fungal microscopy and culture are now recognized as WHO essential diagnostic tests and better training in their application will help improve the situation. For mycetoma and sporotrichosis, in particular, advances in identifying specific marker antigens or genomic sequences may pave the way for new laboratory-based or point-of-care tests, although this is a formidable task given the large number of different organisms that can cause fungal NTDs.

Molecular Characterization and Antifungal Susceptibility of Clinical Fusarium Species From Brazil.

Fusarium is widely distributed in the environment and is involved with plant and animal diseases. In humans, several species and species complexes (SC) are related to fusariosis, i.e., F. solani SC, F. oxysporum SC, F. fujikuroi SC, F. dimerum, F. chlamydosporum, F. incarnatum-equiseti, and F. sporotrichoides. We aimed to investigate the susceptibility of Fusarium clinical isolates to antifungals and azole fungicides and identify the species. Forty-three clinical Fusarium isolates were identified by sequencing translation elongation factor 1-alpha (TEF1α) gene. Antifungal susceptibility testing was performed to the antifungals amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole, and the azole fungicides difenoconazole, tebuconazole, and propiconazole. The isolates were recovered from patients with median age of 36 years (range 2-78 years) of which 21 were female. Disseminated fusariosis was the most frequent clinical form (n = 16, 37.2%) and acute lymphoblastic leukemia (n = 7; 16.3%) was the most commonly underlying condition. A few species described in Fusarium solani SC have recently been renamed in the genus Neocosmospora, but consistent naming is yet not possible. Fusarium keratoplasticum FSSC 2 (n = 12) was the prevalent species, followed by F. petroliphilum FSSC 1 (n = 10), N. gamsii FSSC 7 (n = 5), N. suttoniana FSSC 20 (n = 3), F. solani sensu stricto FSSC 5 (n = 2), Fusarium sp. FSSC 25 (n = 2), Fusarium sp. FSSC 35 (n = 1), Fusarium sp. FSSC18 (n = 1), F. falciforme FSSC 3+4 (n = 1), F. pseudensiforme (n = 1), and F. solani f. xanthoxyli (n = 1). Amphotericin B had activity against most isolates although MICs ranged from 0.5 to 32 µg mL-1. Fusarium keratoplasticum showed high MIC values (8->32 µg mL-1) for itraconazole, voriconazole, posaconazole, and isavuconazole. Among agricultural fungicides, difenoconazole had the lowest activity against FSSC with MICs of >32 µg mL-1 for all isolates.

Sporotrichosis In Immunocompromised Hosts.

Sporotrichosis is a global implantation or subcutaneous mycosis caused by several members of the genus Sporothrix, a thermo-dimorphic fungus. This disease may also depict an endemic profile, especially in tropical to subtropical zones around the world. Interestingly, sporotrichosis is an anthropozoonotic disease that may be transmitted to humans by plants or by animals, especially cats. It may be associated with rather isolated or clustered cases but also with outbreaks in different periods and geographic regions. Usually, sporotrichosis affects immunocompetent hosts, presenting a chronic to subacute evolution course. Less frequently, sporotrichosis may be acquired by inhalation, leading to disseminated clinical forms. Both modes of infection may occur in immunocompromised patients, especially associated with human immunodeficiency virus (HIV) infection, but also diabetes mellitus, chronic alcoholism, steroids, anti-TNF treatment, hematologic cancer and transplanted patients. Similar to other endemic mycoses caused by dimorphic fungi, sporotrichosis in immunocompromised hosts may be associated with rather more severe clinical courses, larger fungal burden and longer periods of systemic antifungal therapy. A prolonged outbreak of cat-transmitted sporotrichosis is in progress in Brazil and potentially crossing the border to neighboring countries. This huge outbreak involves thousands of human and cats, including immunocompromised subjects affected by HIV and FIV (feline immunodeficiency virus), respectively. We reviewed the main epidemiologic, clinical, diagnostic and therapeutic aspects of sporotrichosis in immunocompromised hosts.

Breakthrough candidemia after the introduction of broad spectrum antifungal agents: A 5-year retrospective study.

Candidemia is the main invasive fungal disease among hospitalized patients. Several breakthrough candidemia (BrC) cases have been reported, but few studies evaluate the epidemiology, risk factors, molecular characterization, antifungal susceptibility profile and outcome of those patients, especially in developing countries and including patients using broad spectrum antifungals. We conducted a retrospective study from 2011 to 2016, including patients aged 12 years or older with candidemia. Epidemiological characteristics and risk factors for candidemia were evaluated and compared with patients with BrC using univariate and multivariate analysis. Sequential Candida isolates from BrC were identified by internal transcribed spacer sequencing, genotyped with amplified fragment length polymorphism fingerprinting (AFLP), and tested for antifungal susceptibility. From 148 candidemia episodes, 27 breakthrough episodes (18%) were identified, with neutropenia and mucositis being independent risk factors for BrC. Candida non-albicans was more frequent in the BrC group (P < .001). AFLP showed high correlation with conventional methods of identification among breakthrough isolates and a high genetic similarity among isolates from the same patient was observed. C. albicans was the most susceptible species with low MIC values for all antifungal agents tested. In contrast, we found isolates of C. glabrata, C. parapsilosis and C. tropicalis resistant to triazoles and echinocandins. In conclusion, BrC occurred mainly in severely immunosuppressed patients, with neutropenia and mucositis. Mortality did not differ between the groups. Candida non-albicans species were more recovered from BrC, with C. albicans being the most susceptible to antifungals.

Differential In Vitro Cytokine Induction by the Species of Cryptococcus gattii Complex.

Cryptococcal species vary in capsule and cell size, thermotolerance, geographic distribution, and affected populations. Cryptococcus gattii sensu stricto and C. deuterogattii affect mainly immunocompetent hosts; however, C. bacillisporus, C. decagattii, and C. tetragattii cause infections mainly in immunocompromised hosts. This study aimed to compare the capacities of different species of the C. gattii species complex to induce cytokines and antimicrobial molecules in human peripheral blood mononuclear cells (PBMCs). Cryptococcus bacillisporus and C. deuterogattii induced the lowest levels of tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6 among the five species of the C. gattii complex. Cryptococcus deuterogattii induced higher levels of IL-22 than those induced by C. tetragattii and the environmental species C. flavescens In addition, C. bacillisporus and C. gattii sensu stricto proliferated inside human monocyte-derived macrophages after 24 h of infection. All Cryptococcus species were able to generate reactive oxygen species (ROS) in human PBMCs, with C. bacillisporus and C. deuterogattii being more efficient than the other species. In conclusion, C. bacillisporus and C. deuterogattii induce lower levels of the proinflammatory cytokines TNF-α, IL-1ß, and IL-6 and higher ROS levels than those induced by the other species. Species of the Cryptococcus gattii complex have different abilities to induce cytokine and ROS production by human PBMCs.

Brazilian guidelines for the clinical management of paracoccidioidomycosis.

Paracoccidioidomycosis is a systemic fungal disease occurring in Latin America that is associated with rural environments and agricultural activities. However, the incidence and prevalence of paracoccidiodomycosis is underestimated because of the lack of compulsory notification. If paracoccidiodomycosis is not diagnosed and treated early and adequately, the endemic fungal infection could result in serious sequelae. While the Paracoccidioides brasiliensis ( P. brasiliensis ) complex has been known to be the causal agent of paracoccidiodomycosis, a new species, Paracoccidioides lutzii ( P. lutzii ), has been reported in Rondônia, where the disease has reached epidemic levels, and in the Central West and Pará. Accurate diagnoses and availability of antigens that are reactive with the patients' sera remain significant challenges. Therefore, the present guidelines aims to update the first Brazilian consensus on paracoccidioidomycosis by providing evidence-based recommendations for bedside patient management. This consensus summarizes etiological, ecoepidemiological, molecular epidemiological, and immunopathological data, with emphasis on clinical, microbiological, and serological diagnosis and management of clinical forms and sequelae, as well as in patients with comorbidities and immunosuppression. The consensus also includes discussion of outpatient treatments, severe disease forms, disease prevalence among special populations and resource-poor settings, a brief review of prevention and control measures, current challenges and recommendations.

Geographic distribution of patients affected by Cryptococcus neoformans/Cryptococcus gattii species complexes meningitis, pigeon and tree populations in Southern Brazil.

Cryptococcal meningitis is mainly caused by members of the C. neoformans/C. gattii species complexes. The ecological niches of Cryptococcus species have extensively been studied, but its epidemiological relationship with meningitis cases is still unknown. In this study, we estimate the relationship between cryptococcal meningitis cases and tree and pigeon populations, the classical niches of members of C. neoformans/C. gattii sensu lato. We analysed the records of every patient whose cerebrospinal fluid culture yielded Cryptococcus spp. during the last 30 years at Clinical Hospital of Curitiba. Data about Curitiba's pigeon and tree distribution were obtained from Curitiba's Secretaries of Zoonosis and Environment archives. We used ArcGis9 software to plot the distribution of the pigeon and tree populations in this city as well as cryptococcal meningitis cases, distinguishing them according to the causal agent in C. neoformans or C. gattii s.l. In total, 489 cryptococcal cultures were documented, with 140 corresponding to patients eligible for this study (134 affected by C. neoformans s.l. and 6 by C. gattii s.l.). The map showed a relationship between C. neoformans s.l. patients and pigeon population. C. gattii s.l. patients were associated with neither tree nor pigeon populations, but lived close to large unbuilt, unforested areas.

Chromoblastomycosis.

Chromoblastomycosis (CBM), also known as chromomycosis, is one of the most prevalent implantation fungal infections, being the most common of the gamut of mycoses caused by melanized or brown-pigmented fungi. CBM is mainly a tropical or subtropical disease that may affect individuals with certain risk factors around the world. The following characteristics are associated with this disease: (i) traumatic inoculation by implantation from an environmental source, leading to an initial cutaneous lesion at the inoculation site; (ii) chronic and progressive cutaneous and subcutaneous tissular involvement associated with fibrotic and granulomatous reactions associated with microabscesses and often with tissue proliferation; (iii) a nonprotective T helper type 2 (Th2) immune response with ineffective humoral involvement; and (iv) the presence of muriform (sclerotic) cells embedded in the affected tissue. CBM lesions are clinically polymorphic and are commonly misdiagnosed as various other infectious and noninfectious diseases. In its more severe clinical forms, CBM may cause an incapacity for labor due to fibrotic sequelae and also due to a series of clinical complications, and if not recognized at an early stage, this disease can be refractory to antifungal therapy.

Discontinuation of empirical antifungal therapy in ICU patients using 1,3-ß-d-glucan.

BACKGROUND: Empirical antifungal therapy in high-risk ICU patients is an attractive strategy, but overuse of antifungal agents is a potential problem. OBJECTIVES: We evaluated if ICU patients at high risk to develop candidaemia identified by a prediction rule could discontinue empirical antifungal therapy on the basis of repeatedly negative 1-3-ß-d-glucan (BDG) tests. METHODS: We conducted a multicentre cohort study in 85 ICU patients receiving antibiotics or with central venous catheter plus two additional factors (dialysis, parenteral nutrition, surgery, pancreatitis or receipt of corticosteroids or other immunosuppressive agents) plus either fever, hypothermia, hypotension, acidosis, elevated C-reactive protein or leucocytosis. Blood cultures (days 1 and 2) and BDG (days 1-3, baseline period) were performed and anidulafungin was given. On day 4, patients with negative blood cultures and BDG discontinued antifungal therapy. Registered in ClinicalTrials.gov (NCT01734525). RESULTS: The incidence of candidaemia was 8.2% in patients selected versus 0.5% in patients without entry criteria (16.9 times higher). Sixty-four patients (75.3%) had baseline positive BDG, including 7 with candidaemia. All 21 patients with baseline negative BDG discontinued anidulafungin on day 4. None developed candidaemia until day 30. CONCLUSIONS: Early discontinuation of empirical echinocandin therapy in high-risk ICU patients based on consecutive negative BDG tests may be a reasonable strategy, with great potential to reduce the overuse of echinocandins in ICU patients. Prospective studies with a higher number of patients are needed.

Susceptibility and molecular characterization of Candida species from patients with vulvovaginitis

Abstract Vulvovaginal candidiasis affects women of reproductive age, which represents approximately 15–25% of vaginitis cases. The present study aimed to isolate and characterize yeast from the patients irrespective of the presentation of clinical symptoms. The isolates were subjected to in vitro susceptibility profile and characterization by molecular markers, which intended to assess the distribution of species. A total of 40 isolates were obtained and identified through the CHROMagar, API20aux and by ITS and D1/D2 regions sequencing of DNAr gene. Candida albicans strains were genotyped by the ABC system and the isolates were divided into two genotypic groups. The identity of the C. albicans, C. glabrata, C. guilliermondii, C. kefyr and Saccharomyces cerevisiae isolates was confirmed by the multilocus analysis. The strains of Candida, isolated from patients with complications, were found to be resistant to nystatin but sensitive to fluconazole, amphotericin B and ketoconazole, as observed by in vitro sensitivity profile. The isolates from asymptomatic patients, i.e., the colonized group, showed a dose-dependent sensitivity to the anti-fungal agents, fluconazole and amphotericin B. However, the isolates of C. albicans that belong to distinct genotypic groups showed the same in vitro susceptibility profile.