Prevalence Of Invasive Fungal Infections Research Articles

Exploring European Consensus About the Remaining Treatment Challenges and Subsequent Opportunities to Improve the Management of Invasive Fungal Infection (IFI) in the Intensive Care Unit

BackgroundThe global prevalence of invasive fungal infections (IFI) is increasing, particularly within Intensive Care Units (ICU), where Candida spp. and Aspergillus spp. represent the most important pathogens. Diagnosis and management of IFIs becomes progressively challenging, with increasing antifungal resistance and the emergence of rare fungal species.Through a consensus survey focused on assessing current views on how IFI should be managed, the aim of this project was to identify challenges around diagnosing and managing IFIs in the ICU. The current status in different countries and perceived challenges to date amongst a multidisciplinary cohort of healthcare professionals involved in the care of IFI in the ICU was assessed.MethodsUsing a modified Delphi approach, an expert panel developed 44 Likert-scale statements across 6 key domains concerning patient screening and minimal standards for diagnosis of IFIs in ICU; initiation and termination of antifungal treatments and how to minimise their side effects and insights for future research on this topic. These were used to develop an online survey which was distributed on a convenience sampling basis utilising the subscriber list held by an independent provider (M3 Global). This survey was distributed to intensivists, infectious disease specialists, microbiologists and antimicrobial/ICU pharmacists within the UK, Germany, Spain, France and Italy. The threshold for consensus was set at 75%.ResultsA total of 335 responses were received during the five-month collection period. From these, 29/44 (66%) statements attained very high agreement (≥ 90%), 11/44 (25%) high agreement (< 90% and ≥ 75%), and 4/44 (9%) did not meet threshold for consensus (< 75%). ConclusionThe results outline the need for physicians to be aware of the local incidence of IFI and the associated rate of azole resistance in their ICUs. Where high clinical suspicion exists, treatment should start immediately and prior to receiving the results from any diagnostic test. Beta-D-glucan testing should be available to all ICU centres, with results available within 48 h to inform the cessation of empirical antifungal therapy. These consensus statements and proposed measures may guide future areas for further research to optimise the management of IFIs in the ICU.

Risk of Invasive Fungal Infections in Patients With Chronic Lymphocytic Leukemia Treated With Bruton Tyrosine Kinase Inhibitors: A Case-Control Propensity Score-Matched Analysis.

Prior reports have suggested a possible increase in the frequency of invasive fungal infections (IFIs) with use of a Bruton tyrosine kinase inhibitor (BTKi) for treatment of chronic lymphoid malignancies such as chronic lymphocytic leukemia (CLL), but precise estimates are lacking. We aim to characterize the prevalence of IFIs among patients with CLL, for whom a BTKi is now the first-line recommended therapy. We queried TriNetX, a global research network database, to identify adult patients with CLL using the International Classification of Diseases, Tenth Revision code (C91.1) and laboratory results. We performed a case-control propensity score-matched analysis to determine IFIs events by BTKi use. We adjusted for age, sex, ethnicity, and clinical risk factors associated with an increased risk of IFIs. Among 5358 matched patients with CLL, we found an incidence of 4.6% of IFIs in patients on a BTKi versus 3.5% among patients not on a BTKi at 5 years. Approximately 1% of patients with CLL developed an IFI while on a BTKi within this period. Our adjusted IFI event analysis found an elevated rate of Pneumocystis jirovecii pneumonia (PJP) (0.5% vs 0.3%, P = .02) and invasive candidiasis (3.5% vs 2.7%, P = .012) with the use of a BTKi. The number needed to harm for patients taking a BTKi was 120 and 358 for invasive candidiasis and PJP, respectively. We found an adjusted elevated rate of PJP and invasive candidiasis with BTKi use. The rates are, however, low with a high number needed to harm. Additional studies stratifying other IFIs with specific BTKis are required to identify at-risk patients and preventive, cost-effective interventions.

Observation of a Bone Invasion Model of Aspergillus fumigatus In Vitro and Analysis of the Antifungal Susceptibility.

Recently, the prevalence of invasive fungal infections has been on the rise, and one of the prevalent symptoms frequently observed is bone deterioration and bone loss. Using an in vitro model we studied how Aspergillus fumigatus invades the bone. Pathological analysis was then employed to observe the structure and distinctive features of the invading fungal elements within the bone invasion model. Meanwhile, the antifungal effects of itraconazole, voriconazole, posaconazole, and amphotericin B were evaluated. The pathological findings showed that in the experimental group, fungal spores and hyphae invaded the bone tissue or were observed growing in the vicinity of the bone edge tissues, as indicated by both HE and PAS staining. In contrast, no fungal elements were observed in the control group, indicating that the in vitro bone invasion model of A. fumigatus was successfully constructed. Furthermore, the findings from the antifungal sensitivity test demonstrated that the lowest effective concentrations of antifungal drugs against the bone invasion model were as follows: 4μg/ml for itraconazole, 0.5μg/ml for voriconazole, 2μg/ml for posaconazole, and 2μg/ml for amphotericin B. The successful construction of the bone invasion model of A. fumigatus has provided a solid basis for future investigations into the mechanisms underlying A. fumigatus bone invasion and the study of its virulence factors. Utilizing bone models is of utmost importance in advancing the development of novel antifungal treatment approaches, as well as in effectively preventing and treating fungal bone invasion and osteolytic diseases.

Invasive fungal infection in ANCA-associated vasculitis: Between the Devil and Deep blue sea. Case series and review of the literature.

Patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are susceptible to opportunistic infections, including invasive fungal infections (IFI). This is due to many factors, including prolonged immunosuppressive therapy. The treatment of AAV with such IFIs is challenging. A descriptive analysis of 5 patients with AAV complicated by concomitant invasive fungal infections was performed. We also have done a comprehensive literature review of IFIs in AAV using PubMed and Google Scholar databases. All 5 patients initially received immunosuppressive medication but subsequently acquired IFI. One patient had sphenoid sinus involvement, and four had lung parenchymal involvement. Aspergillus infection was diagnosed in three patients, Cryptococcus infection in one patient and mixed infection with Aspergillus and Mucor infection in one patient. All our patients were on low doses of corticosteroids for several months to years or had received high-dose pulse steroids with cyclophosphamide in the last few weeks before being diagnosed with IFI. It was difficult to distinguish disease activity from IFI in all the cases. Two of the five patients died despite antifungal therapy. The literature review revealed a prevalence of IFIs ranging from 1 to 9.6% (excluding pneumocystis pneumonia). Aspergillosis was the predominant type of IFI, affecting 46 of 86 patients. Most of these patients (40/46) had pulmonary involvement. The prognosis for patients with IFI was consistently poor, as evidenced by 19 deaths out of 29 reported outcomes. Overall, IFIs have a poor prognosis in patients with AAV. Differentiating disease activity from IFI is difficult because of similar organ distribution, imaging lesions, and histopathological characteristics. A high suspicion index and good-quality microbiology are needed for early treatment and prevention of mortality.

Racial disparities in the outcomes of allogeneic bone marrow transplant: A 5-year nationwide inpatient study.

e19060 Background: Allogeneic bone marrow transplantation (ABMT) is a life-saving procedure in hematological malignancies and bone marrow failure disorders. Despite advances in the field, literature proposes racial disparities in the outcomes of ABMT. This study aims to investigate this difference among distinct racial cohorts. Methods: We identified patients who underwent ABMT for malignant and nonmalignant hematologic diseases from 2016-2020 using the nationwide inpatient sample (NIS) database. We compared the racial differences in outcomes during the hospitalization, including immunologic and hematologic complications, associated infections, length of stay, and mortality rate. Baseline characteristics were compared using a T-test and Chi-Square. Multivariate regression analysis was applied to estimate differences in outcomes. We used STATA Version 17.0 Software for data analysis. The p-value was set at p &lt; 0.05 for statistical significance. Results: A retrospective study was conducted on a cohort of 14,599 adults who underwent ABMT. Out of which 30% (4,379) developed complications. The mean age for ABMT was 54, and the average length of stay was 29 days. In this cohort, 79.5% (11,325) were whites, 4.2% (610) were blacks, 8.3% (1,185) were Hispanics, and 7.8% (1,125) were others. When comparing the outcomes among racial groups, invasive fungal infections 15.5% (95), mucositis 36% (220), septic shock 9% (55), and respiratory failure 14.7% (90) were more common in blacks (p &lt; 0.05). Neutropenia 41.3% (490) and cytomegalovirus (CMV) infection 12.2% (145) were more common in Hispanics (p &lt; 0.05). However, no significant difference was noted in immunologic complications (graft versus host disease (GVHD), bone marrow rejection (BMR), bone marrow failure (BMF)), pancytopenia, clostridium difficile infection (CDI), and mortality (p &lt; 0.05). Conclusions: Our study shows that blacks had a higher prevalence of invasive fungal infections, mucositis, septic shock, and respiratory failure, while Hispanics reported a higher prevalence of neutropenia and CMV infection. However, no significant differences were noted in GVHD, BMR, BMF, pancytopenia, CDI, and mortality rates. Therefore, it can be concluded that while there are some differences in post-ABMT complications among racial groups, overall, the rates of major complications and mortality do not significantly differ.

Fungal Infections in the ICU during the COVID-19 Pandemic in Mexico

Background: Invasive Fungal Infections (IFI) are emergent complications of COVID-19. In this study, we aim to describe the prevalence, related factors, and outcomes of IFI in critical COVID-19 patients. Methods: We conducted a nested case-control study of all COVID-19 patients in the intensive care unit (ICU) who developed any IFI and matched age and sex controls for comparison (1:1) to evaluate IFI-related factors. Descriptive and comparative analyses were made, and the risk factors for IFI were compared versus controls. Results: We found an overall IFI prevalence of 9.3% in COVID-19 patients in the ICU, 5.6% in COVID-19-associated pulmonary aspergillosis (CAPA), and 2.5% in invasive candidiasis (IC). IFI patients had higher SOFA scores, increased frequency of vasopressor use, myocardial injury, and more empirical antibiotic use. CAPA was classified as possible in 68% and 32% as probable by ECMM/ISHAM consensus criteria, and 57.5% of mortality was found. Candidemia was more frequent for C. parapsilosis Fluconazole resistant outbreak early in the pandemic, with a mortality of 28%. Factors related to IFI in multivariable analysis were SOFA score > 2 (aOR 5.1, 95% CI 1.5-16.8, p = 0.007) and empiric antibiotics for COVID-19 (aOR 30, 95% CI 10.2-87.6, p = <0.01). Conclusions: We found a 9.3% prevalence of IFIs in critically ill patients with COVID-19 in a single center in Mexico; factors related to IFI were associated with higher SOFA scores and empiric antibiotic use for COVID-19. CAPA is the most frequent type of IFI. We did not find a mortality difference.

Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms.

The increasing prevalence of invasive fungal infections in immuno-compromised patients is a considerable cause of morbidity and mortality. With the rapid emergence of antifungal resistance and an inadequate pipeline of new therapies, novel treatment strategies are now urgently required. The antifungal activity of the alginate oligosaccharide OligoG in conjunction with nystatin was tested against a range of Candida spp. (C. albicans, C. glabrata, C. parapsilosis, C. auris, C. tropicalis and C. dubliniensis), in both planktonic and biofilm assays, to determine its potential clinical utility to enhance the treatment of candidal infections. The effect of OligoG (0-6%) ± nystatin on Candida spp. was examined in minimum inhibitory concentration (MIC) and growth curve assays. Antifungal effects of OligoG and nystatin treatment on biofilm formation and disruption were characterized using confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM) and ATP cellular viability assays. Effects on the cell membrane were determined using permeability assays and transmission electron microscopy (TEM). MIC and growth curve assays demonstrated the synergistic effects of OligoG (0-6%) with nystatin, resulting in an up to 32-fold reduction in MIC, and a significant reduction in the growth of C. parapsilosis and C. auris (minimum significant difference = 0.2 and 0.12 respectively). CLSM and SEM imaging demonstrated that the combination treatment of OligoG (4%) with nystatin (1 µg/ml) resulted in significant inhibition of candidal biofilm formation on glass and clinical grade silicone surfaces (p < 0.001), with increased cell death (p < 0.0001). The ATP biofilm disruption assay demonstrated a significant reduction in cell viability with OligoG (4%) alone and the combined OligoG/nystatin (MIC value) treatment (p < 0.04) for all Candida strains tested. TEM studies revealed the combined OligoG/nystatin treatment induced structural reorganization of the Candida cell membrane, with increased permeability when compared to the untreated control (p < 0.001). Antimicrobial synergy between OligoG and nystatin against Candida spp. highlights the potential utility of this combination therapy in the prevention and topical treatment of candidal biofilm infections, to overcome the inherent tolerance of biofilm structures to antifungal agents.

Can amphotericin B and itraconazole be co-delivered orally? Tailoring oral fixed-dose combination coated granules for systemic mycoses

The incidence and prevalence of invasive fungal infections have increased significantly over the last few years, leading to a global health problem due to the lack of effective treatments. Amphotericin B (AmB) and itraconazole (ITR) are two antifungal drugs with different mechanisms of action. In this work, AmB and ITR have been formulated within granules to elicit an enhanced pharmacological effect, while enhancing the oral bioavailability of AmB. A Quality by Design (QbD) approach was utilised to prepare fixed-dose combination (FDC) granules consisting of a core containing AmB with functional excipients, such as inulin, microcrystalline cellulose (MCC), chitosan, sodium deoxycholate (NaDC) and Soluplus® and polyvinyl pyrrolidone (PVP), coated with a polymeric layer containing ITR with Soluplus® or a combination of Poloxamer 188 and hydroxypropyl methyl cellulose-acetyl succinate (HPMCAS). A Taguchi design of experiments (DoE) with 7 factors and 2 levels was carried out to understand the key factors impacting on the physicochemical properties of the formulation followed by a Box-Behnken design with 3 factors in 3 levels chosen to optimise the formulation parameters. The core of the FDC granules was obtained by wet granulation and later coated using a fluidized bed. In vitro antifungal efficacy was demonstrated by measuring the inhibition halo against different species of Candida spp., including C. albicans (24.19–30.48 mm), C. parapsilosis (26.38–27.84 mm) and C. krusei (11.48–17.92 mm). AmB release was prolonged from 3 to 24 h when the AmB granules were coated. In vivo in CD-1 male mice studies showed that these granules were more selective towards liver, spleen and lung compared to kidney (up to 5-fold more selective in liver, with an accumulation of 8.07 µg AmB/g liver after twice-daily 5 days administration of granules coated with soluplus-ITR), resulting in an excellent oral administration option in the treatment of invasive mycosis. Nevertheless, some biochemical alterations were found, including a decrease in blood urea nitrogen (∼17 g/dl) and alanine aminotransferase (<30 U/l) and an increase in the levels of bilirubin (∼0.2 mg/dl) and alkaline phosphatase (<80 U/l), which could be indicative of a liver failure. Once-daily regimen for 10 days can be a promising therapy.

Invasive Fungal Infections in Acute Haematological Malignancies: A Cross-sectional Study

Introduction: Fungal infections are common complications of acute haematological malignancies i.e. acute myeloid and acute lymphoblastic leukaemia. The cells in these two groups are different morphologically and immunologically. Hence the interaction with the different types of fungi may vary. Aim: To identify the acute leukaemia cases and fungal infection among myeloid and lymphoid groups and to find out association of types of invasive fungal infection according to cell line affected. Materials and Methods: A cross-sectional observational hospital-based prospective study was conducted in a risk group of acute haematological malignancy over a period of six months from July 2021 to December 2021 in a tertiary care Hospital, Medical College Kolkata, West Bengal, India. Study tools were questionnaire based on European Organisation for Research and Treatment of Cancer /Mycoses Study Group (EORTC/MSG) criteria, clinical reports and standard laboratory procedures were practiced in Microbiology laboratory. The data was entered in excel spreadsheet and analysed using Statistical Package for the Social Sciences (SPSS) 28th version. Results: A total of 24 cases of Invasive Fungal Infections (IFI) were observed out of the 78 patients included in the study. This corresponds to an IFI prevalence of 30.77%. Patients with proven IFI constituted 8 (33.33%), probable IFI accounted for 15 (62.5%) where as those with possible IFI accounted for 1 (4.2%) of total IFI cases. There were age and sex wise variation in IFI. The prevalence of IFI was found to be higher in Acute Myeloid Leukaemia (AML) (48.5%) patients as compared to Acute Lymphoblastic Leukaemia (ALL) (19.14%). Of all AML patients invasive candidiasis was the most common type followed by aspergillosis. In ALL patients invasive candidiasis also constituted 44.44% followed by dematiaceous mycosis, followed by aspergillosis. Conclusion: AML patients suffer more from IFI than ALL ones. Invasive non albicans candidiasis affected both types but more incidence was seen in AML affected group. Aspergillus spp. affected lungs of both groups but dematiaceous fungi were isolated only from ALL affected paediatric patients and in samples other than pulmonary or blood sample.

Exposure-Response Relationship of Posaconazole Suspension in Theprophylaxis of Invasive Fungal Infections in Patients with Acute Myeloid Leukemia.

Antifungal prophylaxis with posaconazole has demonstrated a reduction in the risk of death due to Invasive fungal infections (IFI)in patients with acute myeloid leukemia (AML) during induction therapy. However, various factors affect the plasma levels of posaconazole and can potentially limit its efficacy. Therapeutic drug monitoring (TDM) can help optimize the dose, but literature is scant from centers with a high IFI burden. This study aimed to evaluate the proportion of de-novo AML patients on induction who could achieve the target level of 700ng/mL with posaconazole prophylaxis,factors that can influence the plasma levels, and the impact of plasma posaconazole levels on incidence of IFI. Patients with AML on induction therapy with no baseline IFI were enrolled at our tertiary cancer center which has high prevalence of IFI. These patients received posaconazole suspension as prophylaxis. Daily plasma levels were measured from Day 4 till Day 12 of posaconazole prophylaxis. All patients were monitored for the development of IFI. The data on adverse events, concomitant drugs, mucositis, vomiting, and diarrhea were recorded. A total of 411 samples from fifty patients were collected. Only 177 out of 411 samples had levels > 700 ng/mL. The median trough level was 610 ng/mL (range30-3000 ng/mL). The median time to achieve target trough concentration was four days (range 4-12 days) from the start of induction.Thirty-eight (76%) patients achieved target plasma levels by day 12 of induction.The median plasma level on day 12 was 690 ng/mL (range,30-1270) in patients who achieved target levels as compared to 340 (50-560) ng/mL in those who did not. Twenty-six (52%) patients had IFI in our study, and the median time to develop breakthrough IFI was 14 days (range 4-24 days). Median and range of plasma levels were 690 ng/ml (30-2410; n = 22) in those who developed IFI, while 590 ng/mL (50-2300 n = 24) in those who did not. The odds of developing IFI in patients who did not achieve the threshold trough concentration of 700 ng/mL was 7.14 (95% CI; 1.35-37.75, p = 0.0206). Occurrence of vomiting (p = 0.02), diarrhea (p = 0.0008), mucositis (p = 0.003) had adverse impact on achievement of target plasma posaconazole levels. A significant proportion of patients receiving posaconazole prophylaxis fail to achieve target plasma levels which can result in high risk of development of IFI. Occurrence of diarrhea, vomiting and mucositis can adversely affect the achievement target plasma levels.

Key thermally dimorphic fungal pathogens: shaping host immunity.

Exposure to fungal pathogens from the environment is inevitable and with the number of at-risk populations increasing, the prevalence of invasive fungal infection is on the rise. An interesting group of fungal organisms known as thermally dimorphic fungi predominantly infects immunocompromised individuals. These potential pathogens are intriguing in that they survive in the environment in one form, mycelial phase, but when entering the host, they are triggered by the change in temperature to switch to a new pathogenic form. Considering the growing prevalence of infection and the need for improved diagnostic and treatment approaches, studies identifying key components of fungal recognition and the innate immune response to these pathogens will significantly contribute to our understanding of disease progression. This review focuses on key endemic dimorphic fungal pathogens that significantly contribute to disease, including Histoplasma, Coccidioides and Talaromyces species. We briefly describe their prevalence, route of infection and clinical presentation. Importantly, we have reviewed the major fungal cell wall components of these dimorphic fungi, the host pattern recognition receptors responsible for recognition and important innate immune responses supporting adaptive immunity and fungal clearance or the failure thereof.

The prevalence of pulmonary aspergillosis in coronavirus disease 19 (COVID-19) patients in Shebin El-Kom teaching hospital in Egypt

BackgroundA high rate of invasive fungal infection has been demonstrated among critically COVID-19 ill patients admitted to the ICU, with high odds of mortality. Simple and rapid risk stratification methods are mandatory to recognize severe patients.ObjectivesThe aims was to study the prevalence of invasive fungal infection in Corona virus disease 19 (COVID-19) patients, the effect of some inflammatory markers that lead to the development and progression of invasive fungal infection and to assess the value of PCR in early and rapid detection of invasive fungal infection in immune compromised patients with COVID-19.MethodsThis study was conducted at the period from October 2020 to October 2021 on two groups classified as following: Group I: included 120 immuno-compromised inpatients (2-80 years), (68 males and 52 females) from ICUs. Group II: included 40 outpatient's COVID-19 (4 – 56 years). All basic laboratory biomarkers at time of admission were recorded.ResultsOf this study showeda highly significant increase in neutrophil/ lymph, IL6,CRP, D-dimer and malondialdhyde (MDA) in COVID-19 patients in ICU compared with outpatient one with P value < 0.001). No significant difference between them in LDH, ferritin and procalcitonine. The most common isolated organisms (167 isolates) from group I (230 samples from 120 patients) were bacterial spp. (111/167, 66.5%)followed by Candida spp. (30, 17.9%), Aspergillus spp. (11, 6.6%) while mucormycosis was 5 isolates (3%) and associated bacterial infection represented 5.9%of all. Out of 120 patients suspected of complaining of BSI 17 (14.1%) of them proved to be fungemia. The most common isolated yeast was Candida spp. (11/120, 9.1%) followed by Aspergillus spp. (6/120, 5%). While out of 20 patients (group I) suspected of complaining of eye infections, mucormycosis was represented by 5/20 (25%). Fungaemia was detected by PCR and blood culture in 50 high risk ICU patients was 22/50 (44%) and 17/50 (34%) respectively. PCR is more sensitive than blood culture, as blood culture failed to detect 5 cases of fungemia with a significant difference (P-value <0.05).ConclusionIncrease in neutrophil/lymph, IL6,CRP, D-dimer and MDA in COVID-19 ICU patients compared with outpatients may be significant biomarkers used to detect severity of disease in ICU patients and monitor treatment. Also decrease in immunity as results of corticostorides admission, lead to presence of fungaemia in some patients in ICU.

Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study

BackgroundPatients with severe COVID-19 have emerged as a population at high risk of invasive fungal infections (IFIs). However, to our knowledge, the prevalence of IFIs has not yet been assessed in large populations of mechanically ventilated patients. We aimed to identify the prevalence, risk factors, and mortality associated with IFIs in mechanically ventilated patients with COVID-19 under intensive care.MethodsWe performed a national, multicentre, observational cohort study in 18 French intensive care units (ICUs). We retrospectively and prospectively enrolled adult patients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and requiring mechanical ventilation for acute respiratory distress syndrome, with all demographic and clinical and biological follow-up data anonymised and collected from electronic case report forms. Patients were systematically screened for respiratory fungal microorganisms once or twice a week during the period of mechanical ventilation up to ICU discharge. The primary outcome was the prevalence of IFIs in all eligible participants with a minimum of three microbiological samples screened during ICU admission, with proven or probable (pr/pb) COVID-19-associated pulmonary aspergillosis (CAPA) classified according to the recent ECMM/ISHAM definitions. Secondary outcomes were risk factors of pr/pb CAPA, ICU mortality between the pr/pb CAPA and non-pr/pb CAPA groups, and associations of pr/pb CAPA and related variables with ICU mortality, identified by regression models. The MYCOVID study is registered with ClinicalTrials.gov, NCT04368221.FindingsBetween Feb 29 and July 9, 2020, we enrolled 565 mechanically ventilated patients with COVID-19. 509 patients with at least three screening samples were analysed (mean age 59·4 years [SD 12·5], 400 [79%] men). 128 (25%) patients had 138 episodes of pr/pb or possible IFIs. 76 (15%) patients fulfilled the criteria for pr/pb CAPA. According to multivariate analysis, age older than 62 years (odds ratio [OR] 2·34 [95% CI 1·39–3·92], p=0·0013), treatment with dexamethasone and anti-IL-6 (OR 2·71 [1·12–6·56], p=0·027), and long duration of mechanical ventilation (>14 days; OR 2·16 [1·14–4·09], p=0·019) were independently associated with pr/pb CAPA. 38 (7%) patients had one or more other pr/pb IFIs: 32 (6%) had candidaemia, six (1%) had invasive mucormycosis, and one (<1%) had invasive fusariosis. Multivariate analysis of associations with death, adjusted for candidaemia, for the 509 patients identified three significant factors: age older than 62 years (hazard ratio [HR] 1·71 [95% CI 1·26–2·32], p=0·0005), solid organ transplantation (HR 2·46 [1·53–3·95], p=0·0002), and pr/pb CAPA (HR 1·45 [95% CI 1·03–2·03], p=0·033). At time of ICU discharge, survival curves showed that overall ICU mortality was significantly higher in patients with pr/pb CAPA than in those without, at 61·8% (95% CI 50·0–72·8) versus 32·1% (27·7–36·7; p<0·0001).InterpretationThis study shows the high prevalence of invasive pulmonary aspergillosis and candidaemia and high mortality associated with pr/pb CAPA in mechanically ventilated patients with COVID-19. These findings highlight the need for active surveillance of fungal pathogens in patients with severe COVID-19.FundingPfizer.

Invasive fungal rhinosinusitis associated with COVID-19: An observational study

Respiratory Viral infections predispose patients to various coinfections and this may lead to enhanced disease severity and mortality. Despite the proven importance of co-infections, these are understudied during the large outbreaks of respiratory infections. Occurrence of invasive fungal respiratory superinfections in patients with COVID-19 has gained increasing attention recently. This study aims to assess Clinical &amp; Microbiological profile of patients with invasive sinusitis in setting of COVID-19 disease at our institute Study Design: A retrospective observational study. Study included patients diagnosed with acute invasive fungal rhinosinusitis (AIFR) suffering from or having a history of coronavirus disease infection over the period of three months.(April 21 – June 21). The patients’ presentation details, imaging findings, co-morbidities, management details, and follow-up information were obtained, recorded and analysed. A total of 32 patients with AIFR with a mean age of 54.46±13.13 years old were included. Most common associated disease was diabetes mellitus (62.5%). Mycological analysis revealed most common fungi isolated from these patients were Mucor species.(56.25%) followed by Aspergillus species(15.62%) while coinfection with both of these species was seen in 5 patients.(15.62%) Candida species was isolated from samples of 4 patients (12.5%). Radiological studies of nose and paranasal sinuses showed that ethmoid (62.5%) and maxillary (46.87%) sinuses being the most commonly affected sinuses followed by Frontal (31.25%) and sphenoid (21.87%) sinuses. Peri-orbital invasion was seen in 5 (15.62%) cases whereas intracranial involvement was seen in 1 patient.(3.12%) In 8 (25%) patients only medical line of treatment was sufficient whereas 20 (62.5%) patients required surgical debridement during the treatment. 4 patients were lost to follow up. Overall survival was 90.62% (29/32) at the conclusion of the study. We are still learning the new and long-term complications of COVID- 19.The puzzle still remains unsolved about the cause and increased prevalence of invasive fungal infections in post-covid-19 population. High clinical suspicion and early and accurate diagnosis of AIFR in COVID-19 patients are essential for better prognosis.

Poor outcome and high prevalence of invasive fungal infections in patients with adult T-cell leukemia/lymphoma exposed to zidovudine and interferon alfa.

Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we retrospectively analyzed 47 consecutive ATL (acute, n = 23; lymphoma, n = 14; chronic, n = 8; smoldering, n = 2) patients between 2006 and 2016 (median age 51years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response [CR] 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (n = 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (n = 14/19) and 89% (n = 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI, n = 11) included 2 Pneumocystis jirovecii pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (n = 10/11) and experiencing prolonged (> 10days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4months versus 18.4months, p = 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.

Invasive Fungal Diseases in Children with Acute Leukemia and Severe Aplastic Anemia.

Although the outcomes of childhood leukemia and severe aplastic anemia (SAA) have improved, infectious complications are still the major concern. Particularly worrisome are invasive fungal diseases (IFDs), one of the most common causes of infectious-related deaths in patients with prolonged neutropenia. A retrospective study was conducted of IFDs in pediatric patients with newly diagnosed or relapsed acute leukemia, or with SAA, at Siriraj Hospital, Mahidol University, Thailand. There were 241 patients: 150 with acute lymphoblastic leukemia (ALL), 35 with acute myeloid leukemia (AML), 31 with relapsed leukemia, and 25 with SAA. Their median age was 5.4 years (range, 0.3–16.0 years). The overall IFD prevalence was 10.7%, with a breakdown in the ALL, AML, relapsed leukemia, and SAA patients of 8%, 11.4%, 19.3%, and 16%, respectively. Pulmonary IFD caused by invasive aspergillosis was the most common, accounting for 38.5% of all infection sites. Candidemia was present in 34.6% of the IFD patients; Candida tropicalis was the most common organism. The overall case-fatality rate was 38.5%, with the highest rate found in relapsed leukemia (75%). The incidences of IFDs in patients with relapsed leukemia and SAA who received fungal prophylaxis were significantly lower than in those who did not (P = N/A and 0.04, respectively). IFDs in Thai children with hematological diseases appeared to be prevalent, with a high fatality rate. The usage of antifungal prophylaxes should be considered for patients with SAA to prevent IFDs.

Utility of Panfungal PCR in the diagnosis of invasive fungal infections in febrile neutropenia.

Background:The prevalence of invasive fungal infections (IFIs) is increasing due to the increasing population of immunocompromised patients. Fungal culture is the gold standard for diagnosis but not sensitive and the turnaround time is long. Samples for histopathology are difficult to obtain because of profound cytopenias. We conducted this study with the aim to evaluate panfungal PCR for the diagnosis of IFIs in patients of febrile neutropenia.Methods:This was a single-centre, cross-sectional observational study. Patients of febrile neutropenia suspected of having IFI were included in the study. Panfungal PCR was performed on the blood of included patients along with other investigations for diagnosis of IFI. The sensitivity, specificity, positive predictive value, and negative predictive value of panfungal PCR were calculated using EORTC/MSG 2008 criteria as the gold standard.Results:Fifty patients of febrile neutropenia were included in the study, of which 52% were diagnosed positive by panfungal PCR assay. The sensitivity, specificity, positive predictive value, and negative predictive value of panfungal PCR assay was found to be 82.76%, 90.48%, 92.31% and 79.17% respectively.Conclusion:Panfungal PCR is a promising and highly sensitive diagnostic test for screening at-risk patients suspected to have IFIs. The use of panfungal PCR assay in combination with other diagnostic modalities and clinical judgment can be very helpful in the early diagnosis of IFI.

Prevalence of opportunistic invasive aspergillosis in COVID-19 patients with severe pneumonia.

BackgroundAs the global coronavirus pandemic (COVID‐19) spreads across the world, new clinical challenges emerge in the hospital landscape. Among these challenges, the increased risk of coinfections is a major threat to the patients. Although still in a low number, due to the short time of the pandemic, studies that identified a significant number of hospitalised patients with COVID‐19 who developed secondary fungal infections that led to serious complications and even death have been published.ObjectivesIn this scenario, we aim to determine the prevalence of invasive fungal infections (IFIs) and describe possible associated risk factors in patients admitted due to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection.Patients/MethodsWe designed an open prospective observational study at the Rey Juan Carlos University Hospital (Mostoles, Spain), during the period from February 1 to April 30, 2020.ResultsIn this article, we reported seven patients with COVID‐19‐associated pulmonary aspergillosis (CAPA) who had a poor prognosis. Severely ill patients represent a high‐risk group; therefore, we must actively investigate the possibility of aspergillosis in all of these patients. Larger cohort studies are needed to unravel the role of COVID‐19 immunosuppressive therapy as a risk factor for aspergillosis.ConclusionsAs the pandemic continues to spread across the world, further reports are needed to assess the frequency of emergent and highly resistant reemergent fungal infections during severe COVID‐19. These coinfections are leading a significant number of patients with COVID‐19 to death due to complications following the primary viral disease.

Distribution of invasive fungal infections: Molecular epidemiology, etiology, clinical conditions, diagnosis and risk factors: A 3-year experience with 490 patients under intensive care

Recently, the prevalence of invasive fungal infections (IFIs) is rising. The global mortality rate of IFIs is 10–49%. This study aimed to determine the prevalence, the causative agents, and the risk factors associated with the invasive fungal infections in a tertiary health center to provide valid decision-grounds for healthcare professionals to effectively prevent, control, and treat fungal infections. The current study was conducted on 1477 patients suspected to have systemic fungal infections from different units of the hospital. After screening using routine mycological examination, the patients were confirmed with complementary mycological and molecular methods. Patients were included based on the confirmed diagnosis of IFI and excluded based on lack of a microbiologically and histologically proven diagnosis of IFI. Of the 1477 patients recruited in this study, confirmed cases of fungal infection were 490 (169 proven; 321 cases probable). Among the fungi recovered, Candida species had the highest frequency 337 (68.8%) followed by Aspergillus species 108 (22.1%), Zygomycetes species 21 (4.3%), non-Candida yeast 9 (1.8%). Others were black fungi 5 (1%), mycetoma agents 5 (1%), Fusarium 4 (0.8%), and Trichoderma (0.2%). Hematologic malignancies and diabetes mellitus were the most common underlying diseases among IFI-confirmed patients. This study observed an increased frequency of invasive candidiasis with non-albicans Candida and other invasive saprophytic fungal infections. The increased rate of invasive candidiasis with non-albicans agents highlights a new perspective in the epidemiology and treatment of invasive fungal infections.

Immune Response to Fungal Pathogens

Fungi rarely cause disease in individuals with normal immunity. However, fungi present in the normal biota of the skin, mucous membranes, intestinal tract, and fungi in the environment that are normally non-pathogenic, can cause life-threatening infections in individuals with suppressed immunity. In the past decades, the prevalence of opportunistic fungal infections has increased, and these are associated with lowered immunity due to chemotherapy, HIV infection, and aging. The development of traditional antifungal agents has not kept pace with the increasing prevalence of invasive fungal infections, and the resistance to antifungal agents has become a major problem. Fortunately, study of the molecular and cellular mechanisms of the host immune response to fungi is increasing day-by-day. These studies indicate that fungal-specific mechanisms exist in the human body, including maintenance of immunological homeostasis in tissues, destruction of homeostasis by fungal infections, elimination of fungi by the host immune response, and recovery of homeostasis. Research into the mechanisms of fungal infection in humans suggests a new treatment paradigm that goes beyond traditional antifungal agents. Vaccines against fungi and immunotherapy using the host immune mechanism against fungi have recently been developed and are nearing use in the clinic.