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Introduction: Fungal PCR has undergone considerable standardization and together with the availability of commercial assays, external quality assessment schemes and extensive performance validation data, is ready for widespread use for the screening and diagnosis of invasive fungal disease (IFD).Areas Covered: Drawing on the experience and knowledge of the leads of the various working parties of the Fungal PCR initiative, this review will address general considerations concerning the use of molecular tests for the diagnosis of IFD, before focussing specifically on the technical and clinical aspects of molecular testing for the main causes of IFD and recent technological developments.Expert Opinion: For infections caused by Aspergillus, Candida and Pneumocystis jirovecii, PCR testing is recommended, combination with serological testing will likely enhance the diagnosis of these diseases. For other IFD (e.g. Mucormycosis) molecular diagnostics, represent the only non-classical mycological approach towards diagnoses and continued performance validation and standardization has improved confidence in such testing. The emergence of antifungal resistance can be diagnosed, in part, through molecular testing. Next-generation sequencing has the potential to significantly improve our understanding of fungal phylogeny, epidemiology, pathogenesis, mycobiome/microbiome and interactions with the host, while identifying novel and existing mechanisms of antifungal resistance and novel diagnostic/therapeutic targets.

Emergence might be associated with increasing immunocompromised conditions and gastroesophageal diseases., Rare fungal pathogens are emerging as agents of invasive fungal infections. We analyzed 13 cases of fungal infections caused by Kazachstania (Arxiozyma) spp. in Strasbourg University Hospital, Strasbourg, France. Among the cases, 4 patients had proven fungal disease (3 cases of invasive fungal disease and 1 mucocutaneous infection) and 9 were colonized by Kazachstania (Arxiozyma) spp. Candida albicans was also isolated from 11 of the 13 patients. None of the patients with proven invasive fungal disease met host criteria, but most had underlying diseases. All strains were identified as K. telluris by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and 3 were confirmed as K. bovina by internal transcribed spacer sequencing. For all tested strains, the MICs for fluconazole were >2 μg/mL. Emergence of this rare fungal infection might be explained by the increasing number of patients with immunocompromised conditions and gastroesophageal diseases.

OBJECTIVE: The need for pediatric antifungal stewardship programs has been driven by an increasing consumption of antifungals for prophylactic and empirical use. Drivers and rational of antifungal prescribing need to be identified to optimize prescription behaviors. METHODS: A prospective modified weekly Point Prevalence Survey capturing antifungal prescriptions for children (> 90 days to < 18 years of age) in 12 centers in England during 26 consecutive weeks was performed. Demographic, diagnostic and treatment information was collected for each patient. Data were entered into an online REDCap database. RESULTS: One thousand two hundred fifty-eight prescriptions were included for 656 pediatric patients, 44.9% were girls, with a median age of 6.4 years (interquartile range, 2.5-11.3). Most common underlying condition was malignancy (55.5%). Four hundred nineteen (63.9%) received antifungals for prophylaxis, and 237 (36.1%) for treatment. Among patients receiving antifungal prophylaxis, 40.2% did not belong to a high-risk group. In those receiving antifungal treatment, 45.9%, 29.4%, 5.1% and 19.6% had a diagnosis of suspected, possible, probable of proven invasive fungal disease (IFD), respectively. Proven IFD was diagnosed in 78 patients, 84.6% (n = 66) suffered from invasive candidiasis and 15.4% (n = 12) from an invasive mold infection. Liposomal amphotericin B was the most commonly prescribed antifungal for both prophylaxis (36.6%) and empiric and preemptive treatment (47.9%). Throughout the duration of the study, 72 (11.0%) patients received combination antifungal therapy. CONCLUSIONS: Antifungal use in pediatric patients is dominated by liposomal amphotericin B and often without evidence for the presence of IFD. A significant proportion of prophylactic and empiric antifungal use was seen in pediatric patients not at high risk for IFD.

Serum 1,3-β-d-glucan(BDG) is a broad fungal biomarker for invasive fungal disease (IFD). More data is still required to support the Fujifilm Wako assay as a valuable alternative to the widely used Fungitell assay. We included archived serum samples from 157 individuals (97 cases; 33-IA, 64-IC, and 60 controls) for the comparative performance evaluation of the Fungitell assay and the Fujifilm Wako assay for IFD diagnosis. The BDG value was significantly higher in patients with IFD vs. controls (70.79 pg/mL vs. 3.03 pg/mL, p: 0.0002). An area under the curve (AUC) for the IFD, IC, and IA diagnosis was 0.895, 0.910, and 0.866, respectively, for the Fujifilm Wako assay. Based on the highest Youden’s index (0.667), a cutoff of 5 pg/mL was selected as the optimum for the Fujifilm Wako assay with good sensitivity (79.4%), specificity (88.3%) and agreement (84.7%, Cohen’s k:0.691) with the Fungitell assay. The mean run-time of the Fujifilm Wako assay was 70.12 min, and real-time observation allowed earlier time to result in Fujifilm Wako vs. Fungitell assay (37 vs. 120 min, p: < 0.0001). Thus, our findings support the diagnostic value of the Fujifilm Wako assay for the diagnosis of IFD. However, there is still a need to validate diagnostic protocols to optimize their use in multi-centre studies with different patient groups.

Invasive fungal disease (IFD) causes severe morbidity and mortality, and the number of IFD cases is increasing. Exposure to opportunistic fungal pathogens is inevitable, but not all patients with underlying diseases increasing susceptibility to IFD, develop it. IFD diagnosis currently uses fungal biomarkers and clinical risk/presentation to stratify high-risk patients and classifies them into possible, probable, and proven IFD. However, the fungal species responsible for IFD are highly diverse and present numerous diagnostic challenges, which culminates in the empirical anti-fungal treatment of patients at risk of IFD. Recent studies have focussed on host-derived biomarkers that may mediate IFD risk and can be used to predict, and even identify IFD. The identification of novel host genetic variants, host gene expression changes, and host protein expression (cytokines and chemokines) associated with increased risk of IFD has enhanced our understanding of why only some patients at risk of IFD actually develop disease. Furthermore, these host biomarkers when incorporated into predictive models alongside conventional diagnostic techniques enhance predictive and diagnostic results. Once validated in larger studies, host biomarkers associated with IFD may optimize the clinical management of populations at risk of IFD. This review will summarise the latest developments in the identification of host biomarkers for IFD, their use in predictive modelling and their potential application/usefulness for informing clinical decisions.

The COVID-19 pandemic has placed a huge strain on global healthcare and been a significant cause of increased morbidity and mortality, particularly in at-risk populations. This disease attacks the respiratory systems and causes significant immune dysregulation in affected patients creating a perfect opportunity for the development of invasive fungal disease (IFD). COVID-19 infection can instill a significant, poorly regulated pro-inflammatory response. Clinically induced immunosuppression or pro-inflammatory damage to mucosa facilitate the development of IFD and Aspergillus, Mucorales, and Candida infections have been regularly reported throughout the COVID-19 pandemic. Corticosteroids and immune modulators are used in the treatment of COVID-19. Corticosteroid use is also a risk factor for IFD, but not the only reason for IFD in COVID -19 patients. Specific dysregulation of the immune system through functional exhaustion of Natural killer (NK) cells and T cells has been observed in COVID-19 through the expression of the exhaustion markers NK-G2A and PD-1. Reduced fungicidal activity of neutrophils from COVID-19 patients indicates that immune dysfunction/imbalance are important risk factors for IFD. The COVID-19 pandemic has significantly increased the at-risk population for IFD. Even if the incidence of IFD is relatively low, the size of this new at-risk population will result in a substantial increase in the overall, annual number of IFD cases. It is important to understand how and why certain patients with COVID-19 developed increased susceptibility to IFD, as this will improve our understanding of risk of IFD in the face of future pandemics but also in a clinical era of increased clinical immuno-suppression/modulation.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency due to defective leukocyte NADPH responsible for recurrent infections and aberrant inflammation. Mutations in the CYBB gene are responsible for the X-linked CGD and account for approximately 70% of the cases. CGD is diagnosed during childhood in males. Female carriers may have biased X-inactivation and may present with clinical manifestations depending on the level of residual NADPH oxidase activity. We report the case of a previously asymptomatic female carrier who was diagnosed at age 67 with a skin infection with the rare fungus Paecilomyces lilacinus as the first manifestation of CGD. Dihydrorhodamine 123 (DHR) activity was below 10%. Next-generation sequencing (NGS) revealed mutations in DNMT3A, ASXL1, and STAG2 suggesting that clonal hematopoiesis could be responsible for a progressive loss of NADPH oxidase activity and the late onset of X-linked CGD in this patient. Long-term follow-up of asymptomatic carrier women seems to be essential after 50 years old.

Mucormycosis, formerly known as zygomycosis, is a potentially fatal invasive fungal disease (IFD) caused by fungi in the Mucorales order and the zygomycetes class. Mucormycosis is a rare but deadly fungal infection that generally affects those who have weakened immune systems. The infection has the potential to spread throughout the body. Death is a possibility with this type of severe infection. It’s important to get treatment. If left untreated, mucormycosis can be fatal. Zygomycosis has a high mortality of 70–100%. The prevalence of mucormycosis in India is approximately 80 times that of developed countries, with 0.14 cases per 1000 population. The main aim and purpose of this review related to overview and history, causative agents, epidemiology, etiopathogenesis, transmission, types, clinical features, recent advances in diagnosis and treatment of Mucormycosis. A systematic literature search was conducted in the electronic databases of PubMed, Google Scholar and relevant sources. It will be helpful for those who work in the medicine field to explore their knowledge about mucormycosis.

The predisposing factors of invasive fungal disease in COVID 19 infection are still debatable because of the limited human understanding of the virus with the current literature. In this study, we have tried to correlate the various predisposing factors influencing the clinical profile and treatment outcomes in patients with covid associated mucormycosis (CAM). It is a retrospective analysis of cases of CAM during the second wave of COVID 19 infection, which was managed in the department of Otorhinolaryngology from Dec 1, 2020, to June 10, 2021. The detailed clinical, radiological and management of patients with CAM were collected, recorded, evaluated and correlated with the predisposing factors. Of the total, 46 patients, 44(95.65%) were diabetic and 41 patients had a previous history of steroid intake. When clinical parameters were compared between blood sugar 200 mg/dl, the old and newly diagnosed diabetes mellitus in patients with CAM, there was no significant differences in any of the above clinical parameters (p > 0.05), except the hospital stay (p = 0,004). Steroid intake in patients with coexisting DM associated with CAM is considered the most important factor for the development of the CAM. There was are no significant difference in any of the clinical/treatment outcomes in patients with CAM with respect to the initial blood sugar, except for the hospital stay. A large sample size with a long-term follow-up period may be needed for a better understanding of common predisposing factors for the development of CAM.

This review examined the literature on the diagnosis of invasive fungal disease (IFD) in patients undergoing solid organ transplants (SOT) to describe the diagnostic options available for this cohort. The tools available for the diagnosis of IFD in SOT patients are similar to those for patients undergoing stem cell transplants. These include (1) direct visualisation by radiography or histopathology, (2) antigenic tests using ELISA or lateral flow devices for fungal antigens, and (3) PCR-based assays that are commercially available for the two primary IFD affecting SOT patients, aspergillosis and candidiasis. Testing recipients and donors for IFD susceptibility may lead to improved prediction of IFD in SOT. The organ being transplanted has a strong bearing on the risk of IFD and the fungi that will cause disease. No single methodology can yield a definitive diagnosis so combinations of diagnostic tests targeted to the specific patient can indicate the probability of IFD.

Purpose of review This review will comment on the current knowledge for the diagnosis of the main causes of COVID-19-associated invasive fungal disease (IFD); it will discuss the optimal strategies and limitations and wherever available, will describe international recommendations. Recent findings A range of secondary IFDs complicating COVID-19 infection have been described and while COVID-19-associated pulmonary aspergillosis was predicted, the presentation of significant numbers of COVID-19-associated candidosis and COVID-19-associated mucormycosis was somewhat unexpected. Given the range of IFDs and prolonged duration of risk, diagnostic strategies need to involve multiple tests for detecting and differentiating various causes of IFD. Although performance data for a range of tests to diagnose COVID-19-associated pulmonary aspergillosis is emerging, the performance of tests to diagnose other IFD is unknown or based on pre-COVID performance data. Summary Because of the vast numbers of COVID-19 infections, IFD in COVID-19 critical-care patients represents a significant burden of disease, even if incidences are less than 5%. Optimal diagnosis of COVID-19-associated IFD requires a strategic approach. The pandemic has highlighted the potential impact of IFD outside of the typical high-risk clinical cohorts, given the ever-increasing population at risk of IFD and enhanced surveillance of fungal infections is required.

Mucormycosis is an opportunistic, invasive fungal disease, which is most commonly found in patients with preexisting morbidity such as diabetes mellitus and prolonged steroidal therapy. During this COVID-19 pandemic, diabetic patient’s food and their lifestyle, as well as their access to medicine and regular medical care becomes disrupted. This could result in metabolic decompensation, resulting in hyperglycemia, and causes secondary bacterial and fungal infections such as Rhinocerebral mucormycosis and Staphylococcus sepsis. The most common cause of this condition is the extraction of maxillary posterior tooth, which accounts for more than 80% of all cases. In this article, five cases of mucormycosis have been documented after dental extractions in maxilla. Importance of understanding this disease, early diagnosis and appropriate aggressive treatment is emphasized in this article for a successful outcome modality associated with the surgeries are explained.

The multiple forms of pulmonary aspergillosis caused by Aspergillus species are the most common respiratory mycoses. Although invasive, the analysis of diagnostic biomarkers in bronchoalveolar lavage fluid (BALF) is a clinical standard for diagnosing these conditions. The BALF samples from 22 patients with proven or probable aspergillosis were assayed for human pentraxin 3 (Ptx3), fungal ferricrocin (Fc), and triacetylfusarinine C (TafC) in a retrospective study. The infected group included patients with invasive pulmonary aspergillosis (IPA) and chronic aspergillosis (CPA). The BALF data were compared to a control cohort of 67 patients with invasive pulmonary mucormycosis (IPM), non-Aspergillus colonization, or bacterial infections. The median Ptx3 concentrations in patients with and without aspergillosis were 4545.5 and 242.0 pg/mL, respectively (95% CI, p < 0.05). The optimum Ptx3 cutoff for IPA was 2545 pg/mL, giving a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100, 98, 95, and 100%, respectively. The median Ptx3 concentration for IPM was high at 4326 pg/mL. Pentraxin 3 assay alone can distinguish IPA from CPA and invasive fungal disease from colonization. Combining Ptx3 and TafC assays enabled the diagnostic discrimination of IPM and IPA, giving a specificity and PPV of 100%.

Chalinee Monsereenusorn,1 Thitiyaporn Sricharoen,2 Piya Rujkijyanont,1 Detchvijitr Suwanpakdee,3 Apichat Photia,1 Nawachai Lertvivatpong,1 Chanchai Traivaree1 1Division of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, Thailand; 2Buayai Hospital, Nakhon Ratchasima, Thailand; 3Division of Infectious Disease, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, ThailandCorrespondence: Chalinee MonsereenusornDivision of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, 315 Ratchawithi Road, Ratchathewi, Bangkok, 10400, ThailandEmail chalinee_monsereenusorn@pedpmk.orgBackground: The most common complication among pediatric oncology patients is febrile neutropenia (FN). Invasive fungal disease (IFD) is suspected when fever persists > 4– 7 days after empirical antibiotics. Its clinical characteristics and predictive factors associated with IFD among pediatric oncology patients with FN were thus explored.Methods: Pediatric oncology patients with FN between January 1, 2012 and December 31, 2016 were enrolled in this study. Clinical characteristics, including laboratory investigations, treatment modalities, and final outcomes of IFD were retrospectively reviewed and analyzed.Results: In all, 73 patients with 180 episodes of confirmed diagnosis of FN were studied. Median age at diagnosis was 6.2 years, with equal sex distribution. The most common diagnosis was acute lymphoblastic leukemia (n=91, 51%), followed by acute myeloid leukemia (n=47, 26%), Burkitt’s lymphoma (n=7, 4%) and neuroblastoma (n=7, 4%). Median absolute neutrophil count at FN diagnosis was 0 (0– 806) cells/mm3. IFD was diagnosed for 25 (14%) episodes. Mortality rates for FN and IFD were 4% and 20%, respectively. Respiratory compromise, oxygen requirement, hypotension, prolonged hospitalization, duration of fever and neutropenia, bacteremia, bacteriuria, funguria, abnormal liver-function results, and prolonged broad-spectrum antibiotic administration were factors associated with IFD (P< 0.05). Prolonged duration between initiation of fever and antifungal administration for nearly 10 days was an independent factor in prediction of IFD occurrence (P= 0.014).Conclusion: Respiratory compromise, oxygen requirement, hypotension, prolonged hospitalization, duration of fever and neutropenia, bacteremia, bacteriuria, funguria, abnormal liver-function results and prolonged broad-spectrum antibiotic administration were factors associated with IFD. Duration between initiation of fever and antifungal administration of nearly 10 days were considered a risk factors of IFD among patients with FN.IRB Reference Number: IRBRTA 825/2560.Keywords: febrile neutropenia, invasive fungal disease, pediatric oncology, risk factors, mortality

Chalinee Monsereenusorn,1 Thitiyaporn Sricharoen,2 Piya Rujkijyanont,1 Detchvijitr Suwanpakdee,3 Apichat Photia,1 Nawachai Lertvivatpong,1 Chanchai Traivaree1 1Division of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, Thailand; 2Buayai Hospital, Nakhon Ratchasima, Thailand; 3Division of Infectious Disease, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, ThailandCorrespondence: Chalinee MonsereenusornDivision of Hematology/Oncology, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, 315 Ratchawithi Road, Ratchathewi, Bangkok, 10400, ThailandEmail chalinee_monsereenusorn@pedpmk.orgBackground: The most common complication among pediatric oncology patients is febrile neutropenia (FN). Invasive fungal disease (IFD) is suspected when fever persists > 4– 7 days after empirical antibiotics. Its clinical characteristics and predictive factors associated with IFD among pediatric oncology patients with FN were thus explored.Methods: Pediatric oncology patients with FN between January 1, 2012 and December 31, 2016 were enrolled in this study. Clinical characteristics, including laboratory investigations, treatment modalities, and final outcomes of IFD were retrospectively reviewed and analyzed.Results: In all, 73 patients with 180 episodes of confirmed diagnosis of FN were studied. Median age at diagnosis was 6.2 years, with equal sex distribution. The most common diagnosis was acute lymphoblastic leukemia (n=91, 51%), followed by acute myeloid leukemia (n=47, 26%), Burkitt’s lymphoma (n=7, 4%) and neuroblastoma (n=7, 4%). Median absolute neutrophil count at FN diagnosis was 0 (0– 806) cells/mm3. IFD was diagnosed for 25 (14%) episodes. Mortality rates for FN and IFD were 4% and 20%, respectively. Respiratory compromise, oxygen requirement, hypotension, prolonged hospitalization, duration of fever and neutropenia, bacteremia, bacteriuria, funguria, abnormal liver-function results, and prolonged broad-spectrum antibiotic administration were factors associated with IFD (P< 0.05). Prolonged duration between initiation of fever and antifungal administration for nearly 10 days was an independent factor in prediction of IFD occurrence (P= 0.014).Conclusion: Respiratory compromise, oxygen requirement, hypotension, prolonged hospitalization, duration of fever and neutropenia, bacteremia, bacteriuria, funguria, abnormal liver-function results and prolonged broad-spectrum antibiotic administration were factors associated with IFD. Duration between initiation of fever and antifungal administration of nearly 10 days were considered a risk factors of IFD among patients with FN.IRB Reference Number: IRBRTA 825/2560.Keywords: febrile neutropenia, invasive fungal disease, pediatric oncology, risk factors, mortality

Fungal infections have increased in recent years due to host factors, such as oncohaematological and transplant-related disorders, immunosuppressive therapy, and AIDS. Additionally, molecular and proteomic facilities have become available to identify previously unrecognizable opportunists. For these reasons, reports on less-known and recalcitrant mycoses, such as those caused by black fungi, hyaline filamentous fungi, coelomycetes, Mucorales, and non-Candida yeasts have emerged. In this review, novel taxonomy in these groups, which often are multi-resistant to one or several classes of antifungals, is discussed. Clinical presentations, diagnosis and current treatment of some major groups are summarised.

Various uncommon fungal pathogens have been increasingly identified as causes of disseminated and invasive fungal disease (IFD) worldwide. Growing recognition and clinical knowledge of these emerging fungal pathogens has occurred through improved molecular diagnostics, nucleic sequence databases, and taxonomic reclassification of medically significant fungi. However, emerging fungal diseases carry significant morbidity and mortality and, due to a paucity of published literature, the collective clinical experience with these fungi is often limited. In this review, we focus on unusual emerging fungal pathogens not extensively covered elsewhere in this issue of Infectious Diseases Clinics of North America.

Malassezia spp.is a commensal yeast that represents normal microflora in humans and some animals. However,Malassezia spp.can cause life-threatening invasive mycosis. Evidence on Malassezia spp. infections is limited mostly to a case reports describing disease in newborns and premature infants, because lipid infusions (total parenteral nutrition) given through central venous catheter is a major risk factor. Here, we report two cases of CNS infection caused by Malassezia species in non-neonates with acute leukemia.

Objectives: Patients receiving remission induction therapy for acute myeloid leukaemia (AML) are at high risk of developing invasive fungal disease (IFD). Newer therapies with targeted antileukemic agents and the emergence of azole resistance pose a challenge to the strategy of primary antifungal prophylaxis. We report the experience of a diagnostic-driven care pathway (DCP) for the management of IFD in these patients, using only culture-directed mould inactive prophylaxis. Methods: Retrospectively, we used a single-centre study of consecutive patients receiving intensive chemotherapy for myeloid malignancies between 2014 and 2021. DCP consisted of serial cultures and serum galactomannan (sGM) screening, CT imaging, and bronchoscopy to direct targeted antifungal treatment. IFD was classified according to the 2020 EORTC/MSGERC criteria. Results: A total of 192 patients with myeloid malignancies received 300 courses of intensive chemotherapy. There were 14 cases of invasive yeast infections and 18 of probable/proven invasive mould disease (IMD). The incidence of probable/proven IMD during the first cycle of remission-induction chemotherapy was 4.6% (n = 9). sGM remained negative in all cases of invasive aspergillosis (IA), with positive mycology findings in bronchoalveolar lavage. All-cause mortality was 9.4% (n = 18) 100 days after starting chemotherapy and was comparable between patients with or without IFD. The fungal-related mortality was 1% (n = 2). Conclusion: Diagnostic-driven based management without universal mould active prophylaxis is a feasible strategy in the management of IFD and limits unnecessary antimould treatment during intensive chemotherapy. The poor performance of serial serum galactomannan screening in detecting IA warrants further investigation.

Invasive fungal diseases (IFD) still cause substantial morbidity and mortality, and new therapeutic approaches are urgently needed. Recent data suggest a benefit of checkpoint inhibitors (ICI). We report the case of a diabetic patient with refractory IFD following a SARSCoV-2 infection treated by ICI and interferon-gamma associated with antifungal treatment.

International audience; Invasive fungal diseases (IFD) still cause substantial morbidity and mortality, and new therapeutic approaches are urgently needed. Recent data suggest a benefit of checkpoint inhibitors (ICI). We report the case of a diabetic patient with refractory IFD following a SARSCoV-2 infection treated by ICI and interferon-gamma associated with antifungal treatment.

The potential drug-drug interactions of midostaurin may impact the choice of antifungal (AF) prophylaxis in FLT3-positive acute myeloid leukemia (AML) patients. To evaluate the incidence of invasive fungal diseases (IFD) during the treatment of FLT3-mutated AML patients and to correlate it to the different AF prophylaxis strategies, we planned a multicenter observational study involving 15 SEIFEM centers. One hundred fourteen patients treated with chemotherapy + midostaurin as induction/reinduction, consolidation or both were enrolled. During induction, the incidence of probable/proven and possible IFD was 10.5% and 9.7%, respectively; no statistically significant difference was observed according to the different AF strategy adopted. The median duration of neutropenia was similar in patients with or without IFD. Proven/probable and possible IFD incidence was 2.4% and 1.8%, respectively, during consolidation. Age was the only risk factor for IFD (OR, 95% CI, 1.10 [1.03–1.19]) and complete remission achievement after first induction the only one for survival (OR, 95% CI, 5.12 [1.93–13.60]). The rate of midostaurin discontinuation was similar across different AF strategies. The IFD attributable mortality during induction was 8.3%. In conclusion, the 20.2% overall incidence of IFD occurring in FLT3-mutated AML during induction with chemotherapy + midostaurin, regardless of AF strategy type, was noteworthy, and merits further study, particularly in elderly patients.

Introduction: Disease modifying treatments are commonly used in the treatment of multiple sclerosis. As different opportunistic infections have been reported, concerns are also raised regarding the risk of invasive fungal infections. Areas covered: Both clinical trials and observational studies on safety and efficacy of diseases modifying treatment for multiple sclerosis were reviewed and data regarding the occurrence of invasive fungal infections were reported. Papers evaluating the following drugs were reviewed: rituximab, ocrelizumab, alemtuzumab, fingolimod, natalizumab, dimethyl fumarate, interferon, glatiramer acetate, cladribine, teriflunomide. Expert opinion: Overall, the occurrence of invasive fungal infections was low, with most infective events reported among patients treated with monoclonal antibodies and fingolimod. Aspergillosis and cryptococcal meningitidis were the most representative fungal infections. Although not common, these infections may be difficult to diagnose and their fatality rate is often high. For this reason, screening protocols for fungal infections must be implemented in the clinical practice when managing patients with MS.

We describe 6 cases of invasive fungal diseases in the post kidney transplant setting. These include 2 cases each of mucormycosis and Aspergillosis and 1 case each of pheohyphomycosis and histoplasmosis. Our case series includes the first described case of aspergillus sacroilitis post kidney transplant and also reviews the literature on various modalities of treatment of fungal infections, follow up, diagnostic modalities and appropriate drug choices.

Background Allergic fungal rhinosinusitis (AFRS) is a common condition in which sinusitis develops as an IgE-mediated response to common sinonasal fungal organisms. If that response leads to blockage of sinus ostia, bone expansion and erosion by expansive cysts containing dense inspissated debris may occur with the potential for critical neurovascular compression including damage to the anterior visual pathway. Methods Review of clinical and imaging features of 2 patients who sustained catastrophic clinical outcomes. Results The first patient had pansinusitis with massive mucocele-like cysts expanding the sphenoid sinus and cranial base and causing compression of the anterior visual pathway that led to persistent severe vision loss despite extensive sinus surgery. The second patient developed sphenoethmoidal expansion with a marked inflammatory response and presumed conversion to invasive fungal sinusitis that caused anterior visual pathway vision loss, bilateral ocular motor palsies from extension into the cavernous sinuses, and death from a large middle cerebral artery stroke. Conclusions Although AFRS is most often benign and treatable, it may rarely produce catastrophic outcomes, especially if the sphenoid sinus is involved. Irreversible vision loss may occur from compression, and ocular motor palsies and death from conversion to invasive fungal disease. Close ophthalmologic and imaging monitoring is necessary in patients with expanded sinuses, and prophylactic sinus surgery may be indicated in certain cases.

The aim of this study is to compare the curative effect of empirical with diagnostic-driven (pre-emptive) therapy of voriconazole in severe aplastic anaemia patients (SAAs) with invasive fungal disease (IFD) after intensive immunosuppressive therapy (IST). Patients undergoing voriconazole antifungal therapy were randomized to empirical therapy group and diagnostic-driven therapy group. Empirical therapy group accounted for 48.5% of all cases, and diagnostic-driven therapy group accounted for 51.5%. The morbidity of IFD (probable and proven cases) was slightly increased in diagnostic-driven therapy group compared with empirical therapy group (P > 0.05). The total effective rate was 62.1%. The effective rate in empirical therapy group was 78.1%, which was significantly increased compared with diagnostic-driven therapy group (47.1%) (P

This review summarizes the literature around antifungal stewardship (AFS) with a focus on the cancer setting. We include a review of identified challenges to the implementation of AFS, summarize studies evaluating quality of prescribing and interventions to optimize invasive fungal disease management. We also provide a review of metrics for AFS programs and advances in fungal diagnostics which can be harnessed by the AFS team. In recent times, there has been an increase in targeted research assessing the quality of antifungal prescribing and the impact of AFS interventions, largely within single centers and observational in nature. Several challenges exist to the implementation of AFS programs. Studies have found high rates of suboptimal antifungal prescribing, and multifaceted interventions have been successful in optimizing the quality and reducing the volume of prescribing. Standardized metrics may assist hospitals to interpret data effectively and structure suitable quality improvement programs.

Background The introduction of mold-active antifungal drugs has led clinicians to reconsider the use of fluconazole for preventing invasive fungal disease (IFD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study of recipients of allo-HSCT, we evaluated the effects of different antifungal prophylaxes on the incidence of IFD at different times after transplantation. Methods Among the 1,401 patients registered in the prospective China Assessment of Antifungal Therapy in Haematological Disease (CAESAR) study database, there were 661 eligible patients who received primary antifungal prophylaxis. The incidence of IFD at different times after transplantation (early, late, and very late) and overall survival were compared for patients who received different drugs. Results The overall incidence of probable IFD was 7.0% in the fluconazole group, 12.6% in the itraconazole group, 1.4% in the voriconazole group, and 5.2% in the micafungin group (P=0.0379). However, the four groups had no significant differences in early, late, or very late IFD. The risk factors associated with IFD were neutropenia for more than 14 days, age greater than 18 years, and receipt of transplantation from an alternative (unrelated and haploidentical) donor (P

Background Invasive fungal disease (IFD) is a severe complication after haploidentical stem cell transplantation (haplo-HSCT) and has a poor prognosis. It has been shown that genetic polymorphism may be one possible reason for the increased risk of IFD. This study aimed to assess the role of genetic polymorphism in the level of susceptibility to IFD after haplo-HSCT. Methods In this study, we prospectively enrolled 251 patients who received haplo-HSCT at the Peking University Institute of Hematology from 2016 to 2018. Forty-three single nucleotide polymorphisms (SNPs) of the genomic DNA were genotyped in blood samples from both recipient and donor. Results Twenty-two patients (8.8%) were diagnosed with proven or probable IFD. The independent risk factors for IFD were grades 3–4 acute graft-versus-host disease, cytomegalovirus reactivation, and recipient and donor rs2305619 (PTX3) (P Conclusions PTX3 rs2305619 polymorphism increase the susceptibility of IFD after haplo-HSCT in the Chinese Han population, and the IFD scoring system could be useful in risk stratification for IFD after HSCT.

Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients with hematological malignancies. As chronic lymphocytic leukemia (CLL) is a rare hematological malignancy in Japan, IFD incidence in Japanese patients with CLL is unclear. This study aimed to investigate IFD incidence in Japanese patients with CLL. This retrospective cohort study used data of patients with CLL registered between April 2008 and December 2019 in the Medical Data Vision database (n = 3484). IFD incidence after CLL diagnosis in the watch-and-wait (WW) and drug therapy (DT) groups was 1.5% and 9.2%, respectively. The most common type of IFD was invasive aspergillosis (28.1%). Cox proportional hazards multivariate analysis revealed that DT (hazard ratio [HR]: 2.13) and steroid use (HR: 4.19) were significantly associated with IFD occurrence. IFD incidence was significantly higher in the DT group than in the WW group (log-rank p < 0.001); however, there was no significant between-group difference in the time to IFD onset or the type of IFD (p = 0.09). This study determined the incidence of IFD in patients with CLL during WW. Physicians should monitor for IFD, even among patients with CLL undergoing the WW protocol.

Background: Invasive fungal diseases (IFDs) increase the mortality rate of patients with neutropenia who receive chemotherapy or have previously undergone hematopoietic stem cell transplantation (HSCT). Micafungin is a broad-spectrum echinocandin with minimal toxicity and low drug interactions. We therefore investigated the efficacy and safety of prophylactic micafungin in pediatric and adolescent patients who underwent autologous HSCT. Methods: This was a phase II, prospective, single-center, open-label, and single-arm study. From November 2011 to February 2017, 125 patients were screened from Seoul National University Children’s Hospital, Korea, and 112 were enrolled. Micafungin was administered intravenously at a dose of 1 mg/kg/day (maximum 50 mg/day) from day 8 of autologous HSCT until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, or possible IFD up to 4 weeks after therapy. Results: The study protocol was achieved without premature interruption in 110 patients (98.2%). The reasons interrupting micafungin treatment included early death (n = 1) and patient refusal (n = 1). Treatment success was achieved in 109 patients (99.1%). Only one patient was diagnosed with probable IFD. No patients were diagnosed with possible or proven IFD. In the full analysis set, 21 patients (18.8%) experienced 22 adverse events (AEs); however, all AEs were classified as “unlikely” related to micafungin. No patient experienced grade IV AEs nor discontinued treatment, and none of the deaths were related to micafungin. Conclusions: Our study demonstrated that micafungin is a safe and effective option for antifungal prophylaxis in pediatric patients who underwent autologous HSCT, with promising efficacy without significant AEs.

Sinonasal teratoid carcinosarcoma or teratocarcinoma is an extremely rare aggressive tumour. It usually arises in the nasal cavity and paranasal sinuses. In this study, the authors described magnetic resonance imaging and computed tomography findings from a patient with sinonasal teratocarcinoma. Computed tomography of the sinonasal teratoid carcinosarcoma can mimic paranasal fungal infections. Magnetic resonance imaging is a very useful tool for making a differential diagnosis between the sinonasal teratoid carcinosarcoma and paranasal sinusitis.

The diagnostic utility and costs of panfungal PCR assays for invasive fungal disease (IFD) from bronchoalveolar lavage fluid (BALF) specimens are incompletely defined. In a retrospective audit, panfungal PCR results from 2014-2018 were matched with information on request forms and the registrar/microbiologist diary of clinical liaison. Identification of a single fungus other than a commensal was considered potentially clinically significant, and assessed for clinical relevance. Of 1002 specimens tested, an estimated 90% were requested in patients without clinical suspicion of IFD. There were 530 (52.9%) PCR-positive results of which 485/530 (91.5%) identified multiple fungal species or commensal fungi; 45 (8.5%) were clinically significant but only in 12 (1.2%) was panfungal PCR the sole diagnostic test leading to IFD diagnosis, all in immunocompromised patients with clinical suspicion of IFD. Costs of panfungal PCR tests averaged AUD 133 per test, or AUD 26,767/annum. However, the average cost-per-diagnosis achieved was AUD 15,978/annum. Limiting testing to patients at risk and with clinical suspicion of IFD, may save over AUD 13,383/annum (assuming 50-90% reduction in testing). The value-added utility of panfungal PCR on BALF is 1.2% (12/1002). We have since introduced pre-analytical stewardship limiting routine panfungal PCR testing of BALF to high-risk patients in our hospital.

Phaeohyphomycosis, or invasive disease caused by melanized fungi is an uncommon infection in humans, usually in immunocompromised patients. Large case reviews reveal infections in patients without typical risk factors. We examine the data regarding these infections in immunocompetent patients. Caspase-associated recruitment domain-9 (CARD-9) mutations have been proposed as a risk factor that would predispose previously healthy individuals to develop invasive fungal disease. Several specific CARD-9 mutations have been identified with the highest burden of infection in individuals with the homozygous state. The exact mechanism by which these mutations play a role in phaeohyphomycosis is still not fully understood and will likely be an area of further investigation. CARD-9 mutations and/or deficiency in humans is associated with invasive and disseminated infections due to melanized fungi. Further studies to examine the implications for prevention and management of these infections are needed.

This review summarizes epidemiological risk factors, clinical manifestations, diagnosis, and treatment of common emerging fungal infections that are associated with cutaneous manifestations, in immunocompromised patients including solid organ transplant and hematopoietic cell transplant recipients. Immunocompromised patients including transplant recipients are at an increased risk of invasive fungal disease due to emerging fungi, such as mucormycetes and Scedosporium spp. Although cutaneous involvement is common, there is a great degree of variation in clinical manifestations, diagnostic techniques, and more importantly, treatment with antifungals. The cutaneous manifestations of emerging fungal pathogens in immunocompromised patients can be localized or part of a disseminated disease. These fungal infections are remarkable for their varying resistance to antifungals. It is essential for clinicians to be knowledgeable about these infections as early treatment might improve outcomes including survival.

Background: The specificity and sensitivity of the (13)-β-d-glucan (BDG) assay in surgical patients needs further investigation. We hypothesized that the BDG assay would have lower sensitivity/spec...

Aims/Introduction A retrospective study was carried out to investigate the clinical characteristics and associated factors for invasive fungal disease in patients with type 2 diabetes mellitus. Materials and Methods Demographic and clinical data were recorded. Associated factors were analyzed by logistic regression analysis. Results Invasive fungal disease was diagnosed in 120 patients with type 2 diabetes mellitus (prevalence, 0.4%). Yeast infection (56/120, 46.7%), including candidiasis (31/56, 55.4%) and cryptococcosis (25/56, 44.6%), was the most common. The urinary tract was mainly involved in candidiasis (12/31, 38.7%). More than half of the cryptococcosis (16/25, 64.0%) presented as pneumonia. Mold infection accounted for 40.8% of the cases, and predominantly involved the lung (34/49, 69.4%). A total of 15 (12.5%) patients had mixed fungal infection. Candida albicans (24/111, 21.6%), Cryptococcus neoformans (19/111, 17.1%) and Aspergillus fumigatus (14/111, 12.6%) were the leading agents. Co‐infection occurred in 58 (48.3%) patients, mainly presenting as pneumonia caused by Gram‐negative bacteria. The inpatient mortality rate of invasive fungal disease was 23.3% (28/120). Glycated hemoglobin levels were higher in non‐survivors than survivors (8.8 ± 2.5 vs 7.7 ± 2.1%, P = 0.02). Anemia (adjusted odds ratio, 3.50, 95% confidence interval 1.95–6.27, P, We investigated the characteristics and associated factors of invasive fungal disease in patients with type 2 diabetes mellitus from Southern China for the first time. We found that Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus were the leading agents. Prolonged hyperglycemia results in unfavorable outcomes. Correction of anemia and hypoalbuminemia might improve prognosis.

Yingying Gong,1,* Chen Li,1,* Cuicui Wang,2,* Jin Li,1 Meilin Ding,1 Dongying Chen,2 Minxi Lao1,2 1Department of Geriatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Minxi LaoDepartment of Geriatrics, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, People’s Republic of ChinaEmail laomx3@mail.sysu.edu.cnDongying ChenDepartment of Rheumatology, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, People’s Republic of ChinaEmail cdongying@163.comIntroduction: Invasive fungal disease (IFD) is a life-threatening infection. The epidemiology and clinical features of IFD in the elderly population are less discussed. The aim of this study was to explore the epidemiology and mortality-associated factors for IFD in the elderly inpatients.Methods: A retrospective study enrolling 512 elderly inpatients from The First Affiliated Hospital of Sun Yat-sen University during the last two decades was performed.Results: The annual prevalence of IFD was 0.1– 0.5%. Candidiasis was the most common (236/521, 45.3%). An increasing trend was observed in aspergillosis from 11.1% in year 1998 to 28.8% in year 2018. The common infective sites of candidiasis were abdominal cavity (83/236, 35.2%) and bloodstream (55/236, 23.3%). Invasive aspergillosis mainly developed in the sinus (74/149, 49.7%) and lung (65/149, 43.6%). Patients with diabetes mellitus (DM) (59/126, 46.8%), solid organ malignancy (84/114, 73.7%), chronic kidney disease (CKD) (40/62, 64.5%) or receiving operation (109/147, 74.1%) were prone to develop candidiasis, while aspergillosis was usually complicated in patients with chronic obstructive pulmonary disease (COPD) (25/51, 49.0%). The all-cause mortality rate was 25.9% (135/521), and patients aged ≥ 80 years were the riskiest (20/51, 39.2%). Lymphopenia (59.5% vs 17.3%, P< 0.001) was significant in deceased patients with mold infection. Higher proportion of non-survivors with invasive candidiasis received central venous catheterization (CVC) (68.4% vs 40.6%, P< 0.001) or indwelling urinary catheter (68.4% vs 46.3%, P=0.001).Conclusion: IFD is a life-threatening complication especially in the oldest-old. Surveillance on lymphopenia, prompt treatment and reduce invasive procedures could benefit the prognosis.Keywords: invasive fungal disease, elderly, mortality, hypoalbuminemia

Purpose In patients with hematologic malignancies (HM), bloodstream infections (BSI) and invasive fungal disease (IFD) remain important complications causing considerable mortality and morbidity. At present, the morbidity of IFD and the strategies to initiate antifungal treatment in HM patients with BSI remain unclear. Patients and methods Patient characteristics, infection-related variables, and therapy-related features of 1374 HM patients with proven BSI from three hospitals were reviewed to investigate the epidemiology, risk factors and prognosis of IFD. Results The morbidity of proven and probable IFD in HM patients with BSI was 11.2%, and the mortality of those patients was 40.5%. Existing IFD risk scores were not accurate enough in distinguishing these patients benefiting from antifungal prophylaxis. Multivariate logistic regression identified age >45 years, profound neutropenia, hypoproteinemia, and use of vasopressors as independent variables associated with IFD morbidity in HM patients with BSI. In patients with proven and probable IFD patients, age >45 years, Pitt bacteremia score >3, use of vasopressors, abnormal blood coagulation, and initiation of antifungal therapy within 72 hrs after the onset of fever were independent prognostic factors. The mortality was significantly reduced in patients with high-risk factors of IFD if they initiate antifungal treatment within 72 hrs after the onset of fever compared to the patients not. Conclusion The morbidity and mortality of IFD increase significantly in HM patients with BSI. Early antifungal therapy may improve prognosis in HM patients with BSI complicated with IFD risk factors.

Diagnosis of invasive fungal disease remains an ongoing challenge for clinicians, while continuously evolving treatment regimens increase patient risk for invasive infection. This case highlights how molecular testing led to the diagnosis of co-infection with two fungal pathogens producing invasive disease in a hematopoietic stem cell transplant recipient with graft-versus-host disease (GVHD). Keywords: Invasive fungal infection, Molecular diagnostics, Ibrutinib, Aspergillus, Cunninghamella

Purpose Due to an increasing incidence of invasive fungal infections, the availability of reliable diagnostic tools for the fast detection of a wide spectrum of fungal pathogens is of vital importance. In this study, we aimed to conduct an extensive clinical evaluation of a recently published in-house panfungal PCR assay on samples from suspected invasive fungal infections. Methods Overall 265 clinical samples from 232 patients with suspected invasive fungal disease (96 deep airway samples, 60 sterile fluids, 50 tissue biopsies, and 59 blood samples) were included. All samples underwent standard culture-based diagnostics and were additionally analyzed with our panfungal PCR assay. Results Overall, 55.1% of agreement between culture and the panfungal PCR was observed; in 17% of all samples partial concordance was noted, while results between culture and our PCR assay were not in agreement in 27.9%. Our panfungal assay performed better in samples from normally sterile sites, while samples from the deep airways yielded the highest rate of discordant (39.6%) results. In two tissue and three blood samples an invasive pathogen was only detected by PCR while cultures remained negative. Conclusion In combination with routine methods, our panfungal PCR assay is a valuable diagnostic tool. Patients at risk for invasive fungal infections might profit from the reduced time to pathogen identification.

This review has incorporated the knowledge and experience of the leads of each of the laboratory working parties of the fungal PCR initiative in order to provide up-to-date information on the performance and developments of PCR methods for the detection of fungi that commonly cause invasive fungal disease (IFD). Molecular diagnosis of IFD enhances the current repertoire of mycological investigations. Providing superior sensitivity and turn-around-time over classical approaches, yet maintaining the benefits of classical tests (e.g. species level identification and identifying resistance). Standardization for Aspergillus PCR is almost complete; the recent release of commercial PCR assays for a wide range fungi (Aspergillus, Candida, Pneumocystis, Mucorales and Pan-fungal) and availability of external quality control schemes (e.g. Quality Control of Molecular Diagnostics for Aspergillus, Candida, Pneumocystis) means that fungal PCR testing is robust and ready for use, globally. Further work is needed to ascertain the utility of PCR in routine practice and to determine whether combining it with other biomarkers is an optimal strategy. PCR for detecting Mucorales sp. and on tissue, together with direct antifungal resistance detection in body fluids, may increase its diagnostic value across the board. This and the ability to diagnose Pneumocystis pneumonia and invasive candidiasis would go a long way towards attaining the long-held ambition of medical mycology to provide a comprehensive range of tests that can be relied upon to diagnose, at least, the common IFD. In short, PCR has a clear future and is close to achieving its full potential in our laboratories.

To provide an overview of the diagnostic tests available to identify invasive fungal disease (IFD) in children with a primary immunodeficiency and to evaluate the relative strengths and weaknesses of those tests. Novel tools to aid the diagnosis of IFD, such as fungal PCRs and lateral flow devices (for Aspergillus spp.), are emerging. However, the paucity of high-quality, multicentre clinical trials evaluating the performance of these diagnostic tools, particularly in the paediatric cohort of interest, remains a challenge. Children with primary immunodeficiencies are seldom referenced in existing studies. It is difficult to provide recommendations for the majority of fungal diagnostic tests, with the exception of histopathology, microscopy, culture, and imaging modalities, due to their poorly studied and largely unvalidated nature. Moving forward, multicentre trials considering the role of these tools in the investigation of children with probable IFD and a primary immunodeficiency are strongly encouraged.

This review examines how next-generation nucleic acid sequencing (NGS) is being used in the diagnosis of invasive fungal disease (IFD) and how well its implementation compares to PCR-based diagnosis. The comparison allows for the assessment of the advantages and potential limitations of NGS in the diagnosis of IFD. NGS is established as a method for sequencing of microbial genomes. It is increasingly being tested as a direct diagnostic method from various sample types including samples such as plasma, formalin fixed and paraffin embedded specimens, and bronchoalveolar lavage. In these cases, the methodology was generally able to identify the causative agents of IFD. NGS-based methods will play an increasingly important role in diagnosis of IFD. The major limitation is currently cost, the need to standardise methods of nucleic acid isolation, and sequence analysis to enable broad uptake and application of the method.

La histoplasmosis es una enfermedad endémica en las Américas, pero no es un evento de notificación obligatoria en muchos países incluido el nuestro, lo que genera el desconocimiento de las características clínicas y epidemiológicas de la enfermedad, produciendo demoras en el diagnóstico y su tratamiento, impactando negativamente en el pronóstico de los pacientes, en especial la población militar. Esta fue una serie de 29 acasos en donde se realizó descripción clínica y microbiológica de los pacientes usuarios del subsistema de sanidad de las fuerzas militares, que fueron atendidos en el Hospital Militar Central, esto a través de la revisión de las historias clínicas electrónicas registradas en dinámica gerencial entre 2012 y 2020, se encontró que el 89,65% fueron hombres, con promedio de edad de 35 años, el síntoma más frecuente fue la fiebre en el 65,52%, la presentación clínica más frecuente de la histoplasmosis fue la histoplasmosis diseminada en el 86,21% (25 pacientes), seguido de la presentación con nódulos pulmonares en el 13,79% (4 pacientes), de acuerdo a la clasificación de enfermedad fúngica invasiva el 44,83% presentó enfermedad posible y el 55,17% enfermedad probada. En nuestro estudio se describieron varias de las características clínicas y paraclínicas al ingreso a la institución de manera muy detallada lo que permite seguir aumentando el conocimiento nacional sobre la epidemiología, características clínicas, paraclínicas y de tratamiento en los pacientes con histoplasmosis, generando la necesidad de la búsqueda activa y la notificación obligatoria de una enfermedad endémica como esta. Ninguno Contenido 1. RESUMEN 7 2. MARCO TEORICO 8 INTRODUCCIÓN 8 MICROORGANISMO: 8 FACTORES DE RIESGO 14 MANIFESTACIONES CLÍNICAS 15 AYUDAS DIAGNÓSTICAS 20 DIAGNÓSTICO MICROBIOLÓGICO 20 DIAGNÓSTICO DIFERENCIAL 23 TRATAMIENTO 23 3. IDENTIFICACIÓN Y FORMULACIÓN DEL PROBLEMA 26 4. JUSTIFICACIÓN 28 5. OBJETIVOS 29 GENERAL 29 ESPECIFICOS 29 HIPÓTESIS 29 6. METODOLOGÍA 31 TIPO Y DISEÑO GENERAL DEL ESTUDIO 31 POBLACIÓN 31 CRITERIOS DE INCLUSIÓN Y EXCLUSIÓN 32 SELECCIÓN Y TAMAÑO DE LA MUESTRA 32 DEFINICIÓN DE LAS VARIABLES 32 ESTRATEGIAS PARA SUPRIMIR AMENAZAS A LA VALIDEZ DE RESULTADOS 140 MEDICIONES E INSTRUMENTOS A UTILIZAR 140 ESTUDIOS DE INTERVENCIÓN (PARA EPERIMENTALES, CUASI EXPERIMENTALES) 141 7. PLAN DE ANALISIS 142 PLAN DE RECOLECCIÓN DE LA INFORMACIÓN Y FUENTES 142 PROCESAMIENTO 142 8. RESULTADOS/PRODUCTOS ESPERADOS Y POTENCIALES BENEFICIARIOS: 143 RELACIONADOS CON LA GENERACIÓN DE CONOCIMIENTO Y/O NUEVOS DESARROLLOS 143 CONDUCENTES AL FORTALECIMIENTO DE LA CAPACIDAD CIENTÍFICA DEL HOSPITAL MILITAR CENTRAL 143 DIRIGIDOS A LA APROPIACIÓN SOCIAL DEL CONOCIMIENTO 143 9. CRONOGRAMA 145 10. PRESUPUESTO 147 11. ASPECTOS ÉTICOS 148 12. RESULTADO 149 13. DISCUSIÓN 160 14. CONCLUSIONES 165 15. REFERENCIAS BIBLIOGRAFICAS 167 Histoplasmosis is an endemic disease in the Americas, but it is not a mandatory notification event in many countries, including ours, which generates ignorance of the clinical and epidemiological characteristics of the disease, producing delays in diagnosis and treatment, impacting negatively in the prognosis of patients, especially the military population. This was a series of 29 cases in which a clinical and microbiological description was made of the patients who were users of the health subsystem of the military forces, who were treated at the Central Military Hospital, through the review of the electronic medical records registered in managerial dynamics between 2012 and 2020, it was found that 89.65% were men, with an average age of 35 years, the most frequent symptom was fever in 65.52%, the most frequent clinical presentation of histoplasmosis was disseminated histoplasmosis in 86.21% (25 patients), followed by presentation with pulmonary nodules in 13.79% (4 patients), according to the classification of invasive fungal disease, 44.83% presented possible disease and the 55.17% proven disease. In our study, several of the clinical and paraclinical characteristics on admission to the institution were described in a very detailed manner, which allows us to continue increasing national knowledge about the epidemiology, clinical, paraclinical and treatment characteristics of patients with histoplasmosis, generating the need for active search and mandatory notification of an endemic disease like this. Especialización

(1→3)-β-glucan (BDG) testing as an adjunct in the diagnosis of invasive fungal disease (IFD) has been in use for nearly three decades. While BDG has a very high negative predictive value in this setting, diagnostic false positives may occur, limiting specificity and positive predictive value. Although results may be diagnostically false positive, they are analytically correct, due to the presence of BDG in the circulation. This review surveys the non-IFD causes of elevated circulating BDG. These are in the main, iatrogenic patient contamination through the use of BDG-containing medical devices and parenterally-delivered materials as well as translocation of intestinal luminal BDG due to mucosal barrier injury. Additionally, infection with Nocardia sp. may also contribute to elevated circulating BDG. Knowledge of the factors which may contribute to such non-IFD-related test results can improve the planning and interpretation of BDG assays and permit investigational strategies, such as serial sampling and BDG clearance evaluation, to assess the likelihood of contamination and improve patient care.

Broad-range fungal PCR is a powerful tool for identifying pathogens directly from patient specimens; however, reported estimates of clinical utility vary and costs discourage universal testing. We investigated the diagnostic and clinical utility of broad-range fungal PCR by examining 9 years of results from sinonasal specimens, hypothesizing that this anatomic location would identify immunocompromised patients at high risk for invasive fungal disease. We retrospectively identified 644 PCRs and 1,446 fungal cultures from sinus sites. To determine the relative performance of each testing modality, we performed chart review on 52 patients having specimens submitted for culture and PCR on the same day. Positivity rates were significantly higher for PCR (37.1%) than culture (13.7%) but similar for formalin-fixed and fresh tissues (42.3% versus 34.6%). Relative to culture, PCR had significantly faster turnaround time to both preliminary (94.5 versus 108.8 h) and final positive (137.9 versus 278.5 h) results. Among chart-reviewed patients, 88% were immunocompromised, 65% had proven or probable fungal disease, and testing sensitivities for culture and PCR (67.5% and 85.0%) were not statistically different. Nevertheless, PCR identified pathogens not recovered by culture in 14.9% of cases and informed clinical decision-making in 16.7% of all reviewed cases, and sensitivity of PCR combined with culture (90.0%) was higher than that of culture alone. We conclude that broad-range fungal PCR is frequently informative for patients at risk of serious fungal disease and is complementary to and has faster turnaround time than culture. Formalin-fixed tissue does not adversely affect diagnostic yield, but anatomic site may impact assay positivity rates.

Invasive fungal disease (IFD) is a common cause of morbidity and mortality in patients with hematologic malignancies, especially among those undergoing allogeneic hematopoietic stem cell transplantation (HSCT). The epidemiology of IFD in HSCT patients has been evolving over the last decades, mainly in relation to changes in HSCT therapies such as antifungal prophylaxis. A progressive decrease in Candida albicans infection has been documented, alongside a progressive increase in infections caused by non-albicans Candida species, filamentous fungi, and/or multidrug-resistant fungi. Currently, the most frequent IFD is invasive aspergillosis. In some parts of the world, especially in north Central Europe, a high percentage of Aspergillus fumigatus isolates are azole-resistant. New diagnostic techniques have documented the existence of cryptic Aspergillus species with specific characteristics. An increase in mucormycosis and fusariosis diagnoses, as well as diagnoses of other rare fungi, have also been described. IFD epidemiology is likely to continue changing further due to both an increased use of mold-active antifungals and a lengthened survival of patients with HSCT that may result in hosts with weaker immune systems. Improvements in microbiology laboratories and the widespread use of molecular diagnostic tools will facilitate more precise descriptions of current IFD epidemiology. Additionally, rising resistance to antifungal drugs poses a major threat. In this scenario, knowledge of current epidemiology and accurate IFD diagnoses are mandatory in order to establish correct prophylaxis guidelines and appropriate early treatments.

Invasive fungal disease (IFD) is a growing health burden. High mortality rates, increasing numbers of at-risk hosts, and a limited availability of rapid diagnostics and therapeutic options mean that patients are increasingly exposed to unnecessary antifungals. High rates of prescriptions promote patient exposure to undue toxicity and drive the emergence of resistance. Antifungal stewardship (AFS) aims to guide antifungal usage and reduce unnecessary exposure and antifungal consumption whilst maintaining or improving outcomes. Here, we examine several AFS approaches from hospitals across the UK and Ireland to demonstrate the benefits of AFS practices and support the broader implementation of AFS as both a necessary and achievable strategy. Since the accuracy and turnaround times (TATs) of diagnostic tools can impact treatment decisions, several AFS strategies have included the development and implementation of diagnostic-driven care pathways. AFS informed treatment strategies can help stratify patients on a risk basis ensuring the right patients receive antifungals at the optimal time. Using a multidisciplinary approach is also key due to the complexity of managing and treating patients at risk of IFD. Through knowledge sharing, such as The Gilead Antifungal Information Network (GAIN), we hope to drive practices that improve patient management and support the preservation of antifungals for future use.

Summary Objectives By using data from the CEDMIC trial (n = 413), we conducted a post-hoc analysis of the diagnostic value of biomarker monitoring and chest computed tomography (CT) scans for the early detection of invasive fungal disease (IFD) in neutropenic hematological patients. Methods IFDs were defined in accordance with the EORTC/MSG definition with some modifications. Biomarkers such as Aspergillus galactomannan (GM) and (1→3)-β-D-glucan (βDG) were measured weekly. Results The positive predictive value (PPV) of GM and βDG in cases of high-risk treatment were 0.70 and 0.69, while those in low-risk treatment were 0.08 and 0, respectively. All of the positive biomarkers that were measured before the development of fever in low-risk treatment were false positives. The proportion of patients who had abnormal chest CT findings was 19% in persistent fever at 4–6 days, 57% at 7 days or later and 36% in recurrent fever. Sixty-nine percent of the patients who had abnormal findings at 7 days or later did not have abnormalities at 4–6 days. Conclusions Afebrile screening of biomarkers in low-risk treatment is not useful. Chest CT should be reevaluated in persistent fever lasting for 7 days or longer even in patients who did not have abnormalities within 6 days.