A global call for talaromycosis to be recognised as a neglected tropical disease.

Talaromycosis (penicilliosis) is an invasive mycosis that is endemic in tropical and subtropical Asia. Talaromycosis primarily affects individuals with advanced HIV disease and other immunosuppressive conditions, and the disease disproportionally affects people in low-income and middle-income countries, particularly agricultural workers in rural areas during their most economically productive years. Approximately 17 300 talaromycosis cases and 4900 associated deaths occur annually. Talaromycosis is highly associated with the tropical monsoon season, when flooding and cyclones can exacerbate the poverty-inducing potential of the disease. Talaromycosis can present as localised or disseminated disease, the latter causing cutaneous lesions that are disfiguring and stigmatising. Despite up to a third of diagnosed cases resulting in death, talaromycosis has received little attention and investment from regional and global funders, policy makers, researchers, and industry. Diagnostic and treatment modalities remain extremely insufficient, however control of talaromycosis is feasible with known public health strategies. This Viewpoint is a global call for talaromycosis to be recognised as a neglected tropical disease to alleviate its impact on susceptible populations.

Testing the febrile response of snakes inoculated with Ophidiomyces ophidiicola, the causative agent of snake fungal disease.

Snake Fungal Disease (SFD) negatively impacts wild snake populations in the eastern United States and Europe. Ophidiomyces ophidiicola causes SFD and manifests clinically by the formation of heterophilic granulomas around the mouth and eyes, weight loss, impaired vision, and sometimes death. Field observations have documented early seasonal basking behaviors in severely infected snakes, potentially suggesting induction of a behavioral febrile response to combat the mycosis. This study tested the hypothesis that snakes inoculated with Ophidiomyces ophidiicola would seek elevated basking temperatures to control body temperature and behaviorally induce a febrile response. Eastern ribbon snakes (Thamnophis saurita, n = 29) were experimentally or sham inoculated with O. ophidiicola. Seven days after inoculation, snakes were tested on a thermal gradient and the internal body temperature and substrate temperature of each snake was recorded over time. Quantitative PCR was used when snakes arrived, during pre-inoculation, and post-inoculation to test snakes for the presence of O. ophidiicola. Some snakes arrived with O. ophidiicola and were subsequently inoculated, allowing for an assessment of secondary exposure effects. Snake thermoregulatory behavior was compared between 1) O. ophidiicola inoculated vs. sham inoculated treatments, 2) infected vs. disease negative groups, and 3) disease naïve vs. pre-exposed immune response categories. Neither internal nor substrate temperatures differed among initially prescribed, and qPCR recovered disease states, although infected snakes tended to reach a preferred body temperature faster than disease negative snakes. Snakes experiencing their first exposure (disease naïve) sought higher substrate temperatures than snakes experiencing their second exposure (pre-exposed). Here, we recover no evidence for behaviorally induced fever in snakes with SFD but do elucidate a febrile immune response associated with secondary exposure.

Widespread mortality of trembling aspen (Populus tremuloides) throughout interior Alaskan boreal forests resulting from a novel canker disease.

Over the past several decades, growth declines and mortality of trembling aspen throughout western Canada and the United States have been linked to drought, often interacting with outbreaks of insects and fungal pathogens, resulting in a "sudden aspen decline" throughout much of aspen's range. In 2015, we noticed an aggressive fungal canker causing widespread mortality of aspen throughout interior Alaska and initiated a study to quantify potential drivers for the incidence, virulence, and distribution of the disease. Stand-level infection rates among 88 study sites distributed across 6 Alaska ecoregions ranged from <1 to 69%, with the proportion of trees with canker that were dead averaging 70% across all sites. The disease is most prevalent north of the Alaska Range within the Tanana Kuskokwim ecoregion. Modeling canker probability as a function of ecoregion, stand structure, landscape position, and climate revealed that smaller-diameter trees in older stands with greater aspen basal area have the highest canker incidence and mortality, while younger trees in younger stands appear virtually immune to the disease. Sites with higher summer vapor pressure deficits had significantly higher levels of canker infection and mortality. We believe the combined effects of this novel fungal canker pathogen, drought, and the persistent aspen leaf miner outbreak are triggering feedbacks between carbon starvation and hydraulic failure that are ultimately driving widespread mortality. Warmer early-season temperatures and prolonged late summer drought are leading to larger and more severe wildfires throughout interior Alaska that are favoring a shift from black spruce to forests dominated by Alaska paper birch and aspen. Widespread aspen mortality fostered by this rapidly spreading pathogen has significant implications for successional dynamics, ecosystem function, and feedbacks to disturbance regimes, particularly on sites too dry for Alaska paper birch.

Gastrointestinal manifestations of Talaromyces marneffei infection in an HIV-infected patient rapidly verified by metagenomic next-generation sequencing: a case report.

BACKGROUND: The manifestation of Talaromyces marneffei infection in some HIV-infected patients may be atypical. Cases with gastrointestinal involvement have rarely been reported. It is hard to make a diagnosis when patients are lacking the characteristic rash and positive blood culture. CASE PRESENTATION: Here, we described a patient living with HIV who complained of fever and abdominal pain, and was rapidly diagnosed with Talaromyces marneffei infection by metagenomic next-generation sequencing (mNGS) using formalin-fixation and paraffin-embedded (FFPE) samples of omentum majus tissue. We also reviewed reported related cases. CONCLUSIONS: Talaromyces marneffei is an unusual cause of clinical presentations involving obvious abdominal pain and lower gastrointestinal bleeding, but can be included in the differential diagnosis. As an important diagnostic tool, the significance of mNGS using FFPE samples of lesions provides a more targeted diagnosis.

The potential role of necroptosis in clinical diseases (Review).

As an important type of programmed cell death in addition to apoptosis, necroptosis occurs in a variety of pathophysiological processes, including infections, liver diseases, kidney injury, neurodegenerative diseases, cardiovascular diseases, and human tumors. It can be triggered by a variety of factors, such as tumor necrosis factor receptor and Toll­like receptor families, intracellular DNA and RNA sensors, and interferon, and is mainly mediated by receptor­interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain­like protein. A better understanding of the mechanism of necroptosis may be useful in the development of novel drugs for necroptosis­related diseases. In this review, the focus is on the molecular mechanisms of necroptosis, exploring the role of necroptosis in different pathologies, discussing their potential as a novel therapeutic target for disease therapy, and providing suggestions for further study in this area.

Epidemiology of visceral mycoses in patients with acute leukemia and myelodysplastic syndrome: Analyzing the national autopsy database in Japan.

Visceral mycoses (VM) are a deadly common infection in patients with acute leukemia and myelodysplastic syndrome (MDS). We retrospectively analyzed the data from the centralized "Annual Report of Autopsy Cases in Japan" that archives the national autopsy cases since 1989. Among the total of 175,615 archived autopsy cases, 7183 cases (4.1%) were acute leukemia and MDS patients. While VM was only found in 7756 cases (4.4% in total cases), we found VM had a disproportionally high prevalence among acute leukemia and MDS patients: 1562 VM cases (21.7%) and nearly sixfold higher in prevalence. Aspergillus spp. was the most predominant causative agent (45.0%), and Candida spp. was the second (22.7%) among confirmed single pathogen involved cases. The prevalence of Candida spp. infection decreased about 50% due to the widely use of fluconazole prophylaxis, which may skew toward doubling of the Mucormycetes incidence compared to 30 years ago. Complicated fungal infection (> one pathogen) was 11.0% in acute leukemia and MDS in 2015. It was 14.7 times higher than in other populations. Among 937 patients who received allogeneic hematopoietic cell transplantation (HCT), the prevalence of VM was 28.3% and 23.3% with GVHD. Aspergillus spp. was less prevalent, but Candida spp. was more associated with GVHD. Its prevalence remains stable. Although Aspergillus spp. was the primary causative agent, non-albicans Candida spp. was increasing as a breakthrough infection especially in GVHD cases. Complicated pathogen cases were more common in acute leukemia and MDS.

Iron Assimilation during Emerging Infections Caused by Opportunistic Fungi with emphasis on Mucorales and the Development of Antifungal Resistance.

Iron is a key transition metal required by most microorganisms and is prominently utilised in the transfer of electrons during metabolic reactions. The acquisition of iron is essential and becomes a crucial pathogenic event for opportunistic fungi. Iron is not readily available in the natural environment as it exists in its insoluble ferric form, i.e., in oxides and hydroxides. During infection, the host iron is bound to proteins such as transferrin, ferritin, and haemoglobin. As such, access to iron is one of the major hurdles that fungal pathogens must overcome in an immunocompromised host. Thus, these opportunistic fungi utilise three major iron acquisition systems to overcome this limiting factor for growth and proliferation. To date, numerous iron acquisition pathways have been fully characterised, with key components of these systems having major roles in virulence. Most recently, proteins involved in these pathways have been linked to the development of antifungal resistance. Here, we provide a detailed review of our current knowledge of iron acquisition in opportunistic fungi, and the role iron may have on the development of resistance to antifungals with emphasis on species of the fungal basal lineage order Mucorales, the causative agents of mucormycosis.

Comparative eco-physiology revealed extensive enzymatic curtailment, lipases production and strong conidial resilience of the bat pathogenic fungus Pseudogymnoascus destructans.

The genus Pseudogymnoascus encompasses soil psychrophilic fungi living also in caves. Some are opportunistic pathogens; nevertheless, they do not cause outbreaks. Pseudogymnoascus destructans is the causative agent of the white-nose syndrome, which is decimating cave-hibernating bats. We used comparative eco-physiology to contrast the enzymatic potential and conidial resilience of P. destructans with that of phylogenetically diverse cave fungi, including Pseudogymnoascus spp., dermatophytes and outdoor saprotrophs. Enzymatic potential was assessed by Biolog MicroArray and by growth on labelled substrates and conidial viability was detected by flow cytometry. Pseudogymnoascus destructans was specific by extensive losses of metabolic variability and by ability of lipid degradation. We suppose that lipases are important enzymes allowing fungal hyphae to digest and invade the skin. Pseudogymnoascus destructans prefers nitrogenous substrates occurring in bat skin and lipids. Additionally, P. destructans alkalizes growth medium, which points to another possible virulence mechanism. Temperature above 30 °C substantially decreases conidial viability of cave fungi including P. destructans. Nevertheless, survival of P. destructans conidia prolongs by the temperature regime simulating beginning of the flight season, what suggests that conidia could persist on the body surface of bats and contribute to disease spreading during bats active season.

Streptococcus intermedius masquerading as fungal infective endocarditis.

Infective endocarditis remains an important clinical entity with an incidence of 1.7­10/100 000 person years (Marks et al, 2015). Despite improvements in health care, it still results in significant morbidity and in-hospital mortality approaches 16% (Marks et al, 2015). There are likely multiple causes including late diagnosis, poor response to therapy and the challenges in identifying the causative pathogen and instigating the correct treatment. This is particularly the case for causative organisms that are difficult to culture or identify using routine laboratory methods. An example of this is Streptococcus intermedius, which belongs to the S. milleri group along with other two species (S. anginosus group and S. constellatus). It is a commensal organism that can turn into an opportunistic pathogen (Whiley et al, 1992). It is a rare cause of infective endocarditis and may initially present with abscesses in the liver, spleen or brain which may mimic fungal infection (Woo et al, 2004; Rashid et al, 2007; Tran et al, 2008). Difficulty in identifying this organism has led to the development of molecular testing to aid diagnosis. To the authors' knowledge, there are very few cases in the literature of infective endocarditis caused by S. intermedius that have been confirmed using 16S polymerase chain reaction (Woo et al, 2004). This article describes a patient presenting with S. intermedius infective endocarditis which was diagnosed using this method.

Population-Level Resistance to Chytridiomycosis is Life-Stage Dependent in an Imperiled Anuran.

Amphibian declines caused by chytridiomycosis have been severe, but some susceptible populations have persisted or even recovered. Resistance to the causal agent Batrachochytrium dendrobatidis (Bd) could result from alleles of the adaptive immune system. During metamorphosis, however, immune systems may not be fully functional, implying that an effective immune response to Bd may be life-stage dependent. We evaluated the susceptibility of the relict leopard frog (Rana onca) sourced from two areas where Bd was present or absent, and where the populations appeared to show differences in pathogen resistance. We evaluated whether population-level resistance manifested across life stages using challenge experiments with late-stage tadpoles (Gosner stage 31-38), metamorphs (stage 45-46), and juvenile frogs. We used three different Bd isolates including one from wild R. onca to challenge juvenile frogs and focused on the isolate from R. onca to challenge tadpoles and resulting metamorphs. We found that juveniles from the Bd exposed population were 5.5 times more likely to survive Bd infection and 10 times more likely to clear infections than those from the area without Bd. In contrast, and regardless of the source area, we observed 98% survivorship of tadpoles, but only 19% survivorship of resulting metamorphs following re-exposure. Given the low survivorship of exposed metamorphs in the laboratory, we speculate on how resistance characteristics, whether adaptive or innate, that do not manifest at each life stage could develop in the wild. We suggest that seasonal high temperatures during times when metamorphosis appears common may modulate the effects of the pathogen during this most susceptible life stage.

Severe fungal infections following blunt traumatic injuries: A 5-year multicenter descriptive study.

INTRODUCTION: The aggressive and timely treatment of post-traumatic fungal infections is the most efficacious way to reduce morbidity and mortality. Compared to the military trauma population, studies reporting on fungal infections in civilian trauma are not well described. The purpose of this study was to describe characteristics of civilian trauma patients who developed fungal infections and to identify common risk factors and report any delays between injury and treatment. METHODS: This was a five-year (1/1/2013-3/1/2018) retrospective, descriptive study across six level 1 trauma centers. All consecutively admitted trauma patients (≥18 years) with laboratory-confirmed fungal wound infections were included. Patients with solely candida wound isolates were excluded. Patient demographics, clinical wound and infection characteristics, organisms cultured, treatment modalities, length of stay, in-hospital mortality, and any diagnostic or treatment delays were described. RESULTS: Of the 54,521 trauma patients screened for fungal infection, 12 were identified. All patients suffered major injuries after blunt trauma (abbreviated injury score 3-5) and sustained wound contamination, and in nine patients, the cause of injury was motor vehicle. Six had open wounds/fractures on admission. The geographical region with the highest rate of fungal infection was Texas (n = 7), followed by Kansas (N = 3), then Missouri (N = 2). First symptoms of infection (leukocytosis or fever (n = 10)) presented a median of 6.3 (4.1-9.8) days after injury. Wound management entailed a combination of debridements (n = 8), negative pressure wound therapy (n = 9), amputation (n = 6), and antifungal treatment (n = 10). All fungal isolates identified from the wound site were hyphomycetes. A median of 2.1 (1.8-4.0) days passed from diagnosis to first antifungal treatment, and 3 patients died. CONCLUSIONS: Our study shows the challenges surrounding diagnosis and treatment of fungal infections secondary to trauma. Non-specific fungal infection symptoms, such as leukocytosis and fever, typically presented a week after injury. Vigilance for investigating risk factors and infection symptoms may help clinicians with more timely management of trauma patients with a severe fungal infection.

Clinical pattern of fungal balls in the paranasal sinuses: our experience with 70 patients.

PURPOSE: Many physicians recommend endoscopic sinus surgery (ESS) even when an asymptomatic paranasal sinus (PNS) fungal ball is detected incidentally. The aim of this study was to investigate the natural behavior of PNS fungal balls via sinus imaging techniques. METHODS: A follow-up study of 74 pathologically confirmed fungus balls was conducted in 70 patients who underwent multiple head and neck computed tomography (CT) scans or magnetic resonance imaging (MRI). We investigated the changes in symptoms and lesion size, as well as any new occurrences. RESULTS: Of the 74 fungus balls detected in 70 patients, we observed the renewed formation of a fungal ball in 21 patients, which was not present on initial imaging conducted over a period of 2-162 months. The fungal ball was already present in 53 patients on the initial screening, and the longest follow-up was 197 months (range 1-197 months). Of these 53 lesions, 29 lesions showed an increase in size (29/53, 54.7%), whereas 12 lesions were not associated with any clinical symptoms (12/53, 22.6%). In the 21 newly formed fungal balls, further development was observed in 10 lesions, with 4 lesions showing an increase in size. Thus, size increment occurred in 33 of the 57 fungus balls. CONCLUSIONS: The fungal balls can exist without local tissue invasion for up to 17 years and new formation of the fungal balls was observed even within 2 months, especially when accompanied by initial clinical symptoms of sinusitis.

[The role of microbiota in chronic pharyngitis]. / Rol' mikobioty pri khronicheskim faringite.

This article describes the modern approaches to the diagnostics and treatment of fungoid conditions of the pharynx with special reference to the main methods for the detection of pharyngomycosis and its clinical manifestations based on the results of analysis of the investigations carried out during the period from 2012 till 2016. Among the 3,465 patients presenting with chronic inflammatory pathology of the pharynx who sought medical advice and treatment at the clinical departments of the Institute, 861 ones (25%) were found to have mycotic lesions of the pharynx. Erythematous (atrophic) chronic pharyngitis was the predominant form of the disease documented in 2,059 patients whereas the remaining 1, 406 ones presented with the hypertrophic forms. The fungal infection was diagnosed in 403 (19,5%) patients with erythematous atrophic chronic pharyngitis in comparison with 458 (32,5%) patients suffering from the hypertrophic forms of this pathology including pseudomembranous, hyperplastic (granulomatous), and erosive-ulcerative ones. The principal pathogenic agents responsible for the development of fungal pharyngitis in our patients were fungi of the genus Candida that accounted for 97 - 99% of all the cases of this disease. The currently available modalities for the treatment of pharyngomycosis are described.

[The treatment of laryngomycosis]. / Lechenie laringomikoza.

The objective of the present study was to elaborate the therapeutic algorithm for the treatment of laryngomycosis. We have examined a total of 430 patients suffering from chronic laryngitis including 100 ones (23.2%) having the fungal flora. Mycosis was diagnosed by the microscopic study of the stained preparations with the application of various techniques; moreover, cultivation in elective nutrient media was used. The yeast-like fungi of the genus Candida were identified in 98 (98%) and mold fungi of the genus Aspergillus in the remaining 2 (2%) patients. All these 100 patients were given the antifungal treatment. 98 of them presenting with candidal laryngitis were allocated to three groups. Group A was comprised of 33 patients who received the local treatment alone, group B contained 31 patients given only systemic therapy, and group C included 34 patients undergoing the combined treatment with the use of the medications possessed of both the local and systemic actions. The best clinical results were obtained in the patients of the latter group in which the therapeutic efficiency proved to be as high as 79.4%. It is concluded that all the patients suffering from laryngomycosis are in need of the combined treatment designed to eradicate the causative agent, restore the vocal function, and achieve the stable remission of the chronic inflammatory process in the larynx. The combined treatment with the antimycotic medications exhibiting both the general systemic and local activities during 3 weeks appears to be the optimal therapeutic modality for the management of laryngomycosis. Of special importance is the dynamic follow-up of the treated patients including the control examinations in the course of the treatment (days 7, 14, and 21) to be followed by the mycological study after the termination of therapy and its repetition every 3 months during the subsequent period.

A pathogenic skin fungus and sloughing exacerbate cutaneous water loss in amphibians.

Batrachochytrium dendrobatidis (Bd) is a pathogenic fungus that causes the cutaneous, infectious disease chytridiomycosis and has been implicated in population declines of numerous anuran species worldwide. Proximate cause of death by chytridiomycosis is asystolic cardiac arrest as a consequence of severe disruption to electrolyte balance. Animals heavily infected with Bd also experience a disruption to their skin sloughing regime, indicating that core functions of the skin, such as water retention, may be severely impacted. This study examined how skin sloughing, body size and Bd infection interact to influence water loss rates in five Australian frog species: Litoria caerulea, Limnodynastes peronii, Lechriodus fletcheri, Limnodynastes tasmaniensis and Platyplectrum ornatum Rates of water loss more than doubled during sloughing in L.caerulea During active periods across all species, water loss rates were on average 232% higher in Bd infected frogs than in uninfected frogs. This indicates that dehydration stress may be a significant factor contributing to the morbidity of severely Bd infected anurans, a symptom that is then exacerbated by an increased rate of sloughing. When taking size into account, smaller and/or juvenile anurans may be more at risk from dehydration due to Bd infection, as they lose a greater amount of water and slough more frequently than adults. This may in part explain the higher mortality rates typical for small and juvenile frogs infected with Bd Understanding how Bd affects the core functions of the skin, including rates of water loss, can improve our predictions of disease outcome in amphibians.