Chronic disseminated candidiasis (CDC) is an invasive fungal infection typically affecting patients with hematological diseases and severe neutropenia, associated with increased mortality. However, there is a global shortage of clinical evidence on CDC. We retrospectively analyzed clinical data from 49 CDC patients over the past decade. Clinical characteristics of primary hematological diseases, CDC diagnosis, treatment and response evaluations were included. Clinical factors associated with CDC remission and patients' survival were analyzed. The majority of patients had hematological malignancies (n = 43, 87.8%), and 27 patients (55.1%) had persistent severe neutropenia for more than 10 days prior to CDC. CT scans revealed liver lesions in 44 patients, spleen lesions in 34 patients, and kidney lesions in 9 patients. Proven, probable and possible CDC was diagnosed in 5 (10.2%), 3 (6.1%) and 41 patients (83.7%), respectively, and treatment outcomes at 3 months included 5 complete response (CR, 10.2%), 34 partial response (PR, 69.4%) and 10 treatment failure (20.4%). Caspofungin treatment showed a trend towards improving CR/PR rate, while severe neutropenia > 20 days and proven diagnosis were significantly associated with 3-month treatment failure. Kaplan-Meier curve showed achieving CR/PR within 3 months did not significantly prolong OS compared to treatment failure patients (1197.6 days vs. 564.8 days, P = 0.074). Additionally, no patient deaths were directly attributed to CDC infection. Age > 45 years old and malignancy non-remission were prognostic factors of overall survival (OS). Furthermore, a prediction model identified severe neutropenia > 20 days, proven/probable diagnosis and concomitant bacteremia as risk factors to effectively predict treatment failure. Also, patients with a risk score < 0.203 in the model exhibited more rapid treatment response. After CDC symptoms onset, lymphocyte levels remained consistently higher in treatment failure patients, while the neutrophil-to-lymphocyte ratio was persistently higher in CR/PR patients. Our findings recommend CT scans for diagnosis and caspofungin as first-line therapy while continuing scheduled chemotherapy or bone marrow transplantation. Notably, risk factors identified by the prediction model could be used to predict treatment response.

We present the largest prospective real-world experience in 159 patients who received the triple combination of tacrolimus/sirolimus/mycophenolate mofetil after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-alloHSCT) from matched-related (MRD), matched-unrelated (MUD) or mismatched-unrelated donors (MMURD). Despite the high-risk and elderly population, non-relapse mortality (NRM) at day +100 and 1 year was 5.1% and 8.6%. Grades 2-4 and 3-4 acute Graft-versus-host disease (GvHD) at day +180 was 30.3% and 13%, respectively. Chronic GvHD at 1 and 3 years was 23.2% and 41% and for moderate/severe was 13.2% and 26.6%, respectively. With a median follow-up of 20 months, the 1- and 3-year progression-free survival was 60% and 49%, the GvHD-free relapse-free survival was 44% and 32%, and the overall survival was 70.3% and 61%, respectively, for the entire cohort. Patients receiving allo-HSCT from MMURD showed a higher incidence of aGvHD with impact on survival endpoints. GvHD prophylaxis with the triple-drug combination tacrolimus/sirolimus/mycophenolate mofetil showed excellent results in terms of NRM, GvHD and survival in a high-risk, frail and elderly population in the context of RIC-HSCT from MRD and MUD. The subgroup of patients receiving RIC-HSCT from MMURD might probably benefit from other prophylaxis strategies.

Fungal infections of the central nervous system (FI-CNS) pose substantial diagnostic challenges, owing to their diverse clinical presentations and the limited sensitivity of conventional diagnostic tests. Although serum (1→3)-β-d-glucan (BDG) and galactomannan (GM) assays are FDA-approved for the diagnosis of invasive fungal infections (IFIs), their effectiveness in cerebrospinal fluid (CSF) remains underexplored, and optimal cutoff values in CSF are not well established. This study aimed to assess the utility of BDG and GM assays in CSF for diagnosing non-cryptococcal FI-CNS. We conducted a prospective observational study at the National Institute of Mental Health and Neuro Sciences in India from January 2022 to December 2023, including CSF samples from patients suspected of fungal meningitis. The cases were categorized as proven, probable, or possible FI-CNS based on the revised EORTC/MSGERC criteria. Among 61 suspected cases, 2 were proven, 48 were probable, and 11 were possible FI-CNS. The control group included 23 patients without FI-CNS suspicion. BDG and GM testing in CSF followed manufacturers' guidelines for serum. At the manufacturer's recommended cutoff of 80 pg/ml, sensitivity of BDG was 94% and specificity was 78.3%. For GM, using the manufacturer's recommended cutoff of 0.5 optical density index (ODI), sensitivity was 42% and specificity was 100%. Receiver operating characteristic curve analysis indicated optimal cutoffs of 72 pg/ml for BDG (sensitivity 96%, specificity 78.3%) and 0.47 ODI for GM (sensitivity 44%, specificity 100%). Combining both biomarkers increased sensitivity to 97.8%, suggesting that combined BDG and GM testing in CSF could significantly enhance the diagnostic accuracy and management of FI-CNS.

Chronic disseminated candidiasis (CDC) is a rare complication of immunosuppression. This review describes the presentation, management, and outcomes of CDC in pediatric patients with cancer or following hematopoietic cell transplant (HCT). PubMed, Embase, and Medline were searched identifying 32 studies, describing 95 cases of CDC. CDC occurred almost exclusively in patients with leukemia (91%), with only 5% occurring in lymphoma, 1% post HCT, and 3% in solid tumor. The most frequent presenting symptoms were fever (97%) and abdominal pain (45%), with lesions in liver in 63% and spleen in 54% (less common in kidney, lungs and skin/soft tissue). Of the 67 (71%) episodes with microbiological confirmation, Candida tropicalis (28%) was the most common causative species. Antifungal treatment durations varied from 14 days to 28 months. Additionally, 31 (33%) patients received an adjuvant therapy, the most common being corticosteroids. Mortality, directly attributable to CDC, occurred in nine (9%). There remains insufficient data to guide a unified approach to management.

Our aim was to compare epidemiological, clinical and treatment characteristics, and outcomes between patients with diagnoses of coronavirus disease 2019-associated pulmonary aspergillosis (CAPA) or putative invasive pulmonary aspergillosis (PIPA), without hematological cancers.

Retrospective, monocentric comparative observational cohort study, including nonhematological patients treated for invasive pulmonary aspergillosis between 2018 and 2022. Primary study end points were risk factors for 30-day mortality and clinical failure. To account for the imbalance in antifungal treatment allocation, a propensity score weighting approach was adopted.

A total of 209 patients were included, 93 (44.5%) with CAPA and 116 (55.5%) with PIPA; 144 (68.9%) we admitted to the intensive care unit. Patients with PIPA had higher Charlson Comorbidity Index values (mean [SD], 5.8 [2.6]; range, 0-14) and higher prevalences of chronic obstructive pulmonary disease (30.7%), solid cancer (36.8%), liver cirrhosis (12.3%), and concomitant immunosuppressive therapies (26.1%). Patients with CAPA received more invasive mechanical ventilation (70.5%) and corticosteroids (90.1%), more frequently had positive galactomannan (GM) results with bronchoalveolar lavage (80.5%), and had longer mean hospital stays (62.7 [SD, 52.1; range, 8-276] days) and intensive care unit stays (36 [30.7; 2-168] days). No differences in clinical cure or mortality rates were observed between groups. In multivariable analysis, isavuconazole was the only independent factor for clinical cure, reported also in the propensity score matching analysis (odds ratio, 0.41 [95% confidence interval, .16-1.03]; P = .06). A positive serum GM result was independently associated with 30-day mortality (hazard ratio, 1.78 [95% confidence interval, 1.02-3.10]; P = .04).

Patients with CAPA have fewer comorbid conditions and higher fungal burden than those with PIPA, but clinical outcomes are similar between groups. Isavuconazole was an independent predictor for clinical cure, and serum GM positivity an independent predictor for 30-day mortality.

Isavuconazole (ISA) is a newer triazole that has activity against most mold species and has been utilized for prophylaxis as well as treatment in patients with hematologic malignancies (HM) and hematopoietic stem cell transplant (HSCT). However, several studies have documented breakthrough invasive fungal infections (bIFIs). Thus, we conducted a systematic review and meta-analysis to investigate the incidence of bIFIs among patients receiving ISA prophylaxis.

We conducted a systematic review and meta-analysis of the published literature using the concept of ISA, HSCT, and HM from 5 search engines. In patients with HSCT and HM, the pooled incidence of bIFI while undergoing ISA prophylaxis was calculated via the DerSimonian-Laird random effect model.

The systematic review and meta-analysis included 35 and 19 studies, respectively. In total, 991 patients were identified as using ISA prophylaxis, and the majority had either acute myeloid leukemia or myelodysplastic syndrome (69.9%). The pooled incidence of proven/probable bIFI was 7% (95% CI, 4%-12%, I2 = 55%). The most common pathogen was Aspergillus species (43.1%), followed by Candida (22.4%) and Mucorales (12.1%). In 19 studies, mortality rates were documented and ranged between 0% and 100%; the majority of which were >50%.

In patients with HM or HSCT, we found a high incidence of bIFI while undergoing ISA prophylaxis, with high mortality. Given the lack of randomized clinical trials evaluating ISA in this indication, its role in prophylaxis remains unclear.

Immune suppression heightens the risk for fungal infections, but the mechanisms that result in clinical disease are poorly understood. Here we demonstrate that macrophage ferroptosis, an iron-dependent form of regulated cell death, inhibits Aspergillus fumigatus ( Af ) killing. In a mouse tracheal transplant model of Af infection, we observed an increase in macrophage lipid peroxidation, a decreased expression of negative ferroptosis regulators Gpx4 and Slc7a11 , and an increase in positive regulators Ptgs2 and Nox2 , relative to syntransplants. Depletion of macrophages in transplant recipients decreased Af invasion. In vitro , iron overload reduced macrophage viability and decreased their capability to kill Af spores, through a decrease in lysosomal acidification and lysosomal loss. Treatment with ferrostatin-1, a ferroptosis inhibitor, and deferasirox (an iron chelator) restored Af killing. Ferroptotic alveolar macrophages isolated from lung transplant patients also showed a decreased ability to kill Af spores and the patients' bronchoalveolar lavage was characterized by higher iron levels and markers of ferroptotic stress compared to non-lung transplants. These characteristics were strongly correlated with a clinical history of fungal infections, independent of immune suppressive medications. Our findings indicate that macrophage ferroptosis augments the risk of invasive aspergillosis, representing a novel mechanism for host immune dysfunction.

This study explored the effectiveness of secondary metabolites of referred traditional Ayurvedic plants in treating fungal infections, particularly targeting Candida auris. Recognized as a global health threat, this fungus is notorious for its resistance to several antifungal treatments. The inhibition of lanosterol 14α-demethylase causes the depletion of ergosterol, ultimately resulting in the inhibition of fungal cell growth. A total of 469 metabolites, including alkaloids, flavonoids, and tannins from Ayurvedic plants, were screened against CYP51 (PDB ID: 4UYL) using molecular docking. Key active site residues, namely HIS461, CYS463, and TYR122, were targeted to inhibit the ergosterol synthesis, with VNI employed to benchmark the findings. Shortlisted metabolites underwent physicochemical analysis, ADMET analyses, and the principles of medicinal chemistry, which were confirmed through pharmacokinetic simulations. Further, this study investigated the molecular dynamics (MD) of co-crystalized VNI, trans-p-coumaric acid, and MCPHB [(r)-n-(1'-methoxycarbonyl-2'-phenylethyl)-4-hydroxybenzamide] to evaluate RMSD, RMSF, Rg, SASA, cross-correlation of residue motions, PCA, and free energy decomposition. The top compounds demonstrated favorable drug-like criteria. They exhibited good absorption potential with high gastrointestinal uptake. Distribution and metabolism were manageable with low risks of drug-drug interactions. Excretion profiles indicated proper clearance, and toxicity assessments showed low potential for cardiovascular issues. The results showed stable interactions for trans-p-coumaric acid and MCPHB, suggesting that all the ligands maintain stable binding interactions with the protein, which preserves structural integrity across all systems. This comprehensive approach suggests that these natural metabolites from Ayurvedic medicine could potentially serve as primary agents against fungal diseases, pending further validation through controlled in vitro and in vivo clinical trials.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome, and the incidence of invasive fungal infection (IFI) among hospitalized patients with ACLF is steadily increasing. The aim of this study is to develop a diagnostic nomogram to assist in the identification of IFI in these patients.

A retrospective study included 705 patients from January 1, 2019, to October 31, 2023, randomly divided into training (n = 493) and validation (n = 212) cohorts. The diagnosis of IFI includes proven diagnosis and probable diagnosis. Kaplan analysis was performed to analyze the survival prognosis of ACLF patients with and without IFI. A nomogram was developed based on a logistic regression model derived through least absolute shrinkage and selection operator (LASSO) regression. The discrimination, accuracy, and clinical utility of the model were assessed using receiver operating characteristic curves, Hosmer-Lemeshow tests, calibration plots, and decision curve analysis.

Kaplan-Meier survival analysis confirmed that the median survival time of ACLF patients with IFI was significantly lower (by 68 days) than that of ACLF patients without IFI, and there were significant differences in the 90-day, 180-day, and 360-day survival rates between the two groups (P < 0.05). Based on LASSO regression, the following factors were identified as significant risk factors for predicting IFI: aminotransferase levels, prothrombin activity, hemoglobin, neutrophil-to-lymphocyte ratio, and serum total bilirubin. A nomogram was constructed incorporating these variables. The nomogram demonstrated good discriminative ability, with an area under the receiver operating characteristic curve (AUC) of 0.78 (95% confidence interval [CI]: 0.72-0.84) in the training cohort and 0.79 (95% CI: 0.70-0.87) in the validation cohort. Decision curve analysis further validated the clinical applicability of the nomogram.

ACLF patients with IFI have lower survival time than those without IFI. A nomogram was developed and validated to assist clinicians in the early prediction of IFI in hospitalized patients with ACLF.

Not applicable.

Invasive pulmonary aspergillosis (IPA) is typically associated with immunocompromised patients, but rare occurrences have been documented in immunocompetent individuals. This presents diagnostic and therapeutic challenges due to atypical presentations and less apparent risk factors.

A 67-year-old Cambodian American female with a history of stable pulmonary nodules and a left neck schwannoma presented with a two-week history of cough and hemoptysis. Imaging revealed a left lower lobe lung mass suspicious for malignancy. Biopsy and bronchoalveolar lavage confirmed the diagnosis of invasive pulmonary aspergillosis, despite the patient's lack of traditional immunosuppressive risk factors. Her environmental exposures, including a recent trip to Cambodia and a history of gardening, were likely contributing factors. The diagnosis of IPA in this immunocompetent patient was established through a combination of clinical presentation, radiographic findings, and microbiological evidence. Bronchoalveolar lavage and galactomannan testing were crucial in identifying the presence of Aspergillus. Histopathological examination of the biopsy specimen revealed the presence of Aspergillus fruiting bodies, an uncommon finding indicative of invasive disease. The patient was promptly started on voriconazole, the first-line antifungal agent for IPA, which led to an improvement in her symptoms. Moreover, her left neck mass schwannoma in the thyroid bed was also a rare entity.

This case highlights the importance of considering IPA as a differential diagnosis in immunocompetent individuals with relevant environmental exposures and preexisting lung conditions, even in the absence of classic immunosuppressive risk factors.

Invasive pulmonary aspergillosis (IPA) is the most frequent invasive fungal disease occurring in patients with hematological malignancies. Serum galactomannan (GM) antigen monitoring is thought to be helpful in the diagnosis of IPA. The aim of this study was to determine the role of a GM assay in serum samples for the diagnosis of IPA in patients with hematological disease. The data of 366 immunosuppressed patients that were hospitalized and followed up in the hematology clinic from January 2017 to December 2019 were retrospectively analyzed. The clinical and radiological findings of the patients and the GM results, requested twice a week, were evaluated. In this study, the incidence of probable and possible IPA was determined to be 15.3% (56/366). Of the cases detected, 28 (50.0%) were patients diagnosed with acute myeloid leukemia (AML), and 34 (60.7%) patients who had compatible clinical and examination findings were started on antifungal treatment. Additionally, area under the curve (AUC) values were calculated by receiver operating characteristic (ROC) analysis, and it was determined that the diagnostic efficiency was more predictive when the cut-off was 0.5 in the GM test for IPA disease. The detection of GM antigen in serum is a very useful and rapid method for diagnosing IPA disease in immunosuppressed hematology patients. However, GM results should be evaluated together with clinical and radiological findings for early diagnosis, and the treatment approach should be determined accordingly.

The negative impact of invasive pulmonary aspergillosis (IPA) in acute myeloid leukemia (AML) is well known whereas its clinical relevance in acute lymphoid leukemia (ALL) is still unclear. We have carried out a prospective multicentric observational study within the Rete Ematologica Lombarda to describe the incidence of IPA in acute leukemia (AL) patients, focusing on differences between AML and ALL. Between 2018 and 2020, 207 AL patients (AML: 165, ALL: 42) were evaluated. During induction, proven/probable and possible IPA were diagnosed in 32/207 patients (15.4%), equally divided into proven/probable and possible (16 each, 7.7%). IPA diagnosis was made in 23/165 (13.9%) AML and in 9/42 (21.4%) ALL patients (p = 0.2374). Proven/probable IPA were more frequent in ALL than in AML (ALL: 7/42, 16.6% vs. AML: 9/165, 5.4%; p = 0.0235). OS was similar in patients with or without proven/probable IPA (not reached vs. 63 months, p = 0.588), while OS was significantly reduced in possible IPA (22 months vs. not reached, p = 0.0167). More than 15 days of neutropenia duration and lack of antimold prophylaxis were associated with IPA. Achieving complete remission was protective, whereas age over 60 years and, with a borderline significance, possible IPA were associated with risk of death. In conclusion, Ph-negative ALL should be considered at the same high risk for IPA as AML. Antimold prophylaxis should be probably extended also to ALL.

Immune checkpoint inhibitors (ICIs) therapy has revolutionized anti-cancer therapy, with lung cancer exhibiting sustained clinical responses to it. However, there remains a lack of research into the risk factors of serious infections in patients with lung cancer following ICIs therapy. Therefore, we aimed to investigate the incidence and risk factors of serious infections in these patients.

Medical records were retrospectively collected and reviewed from 710 patients with lung cancer receiving ICIs therapy at Zhongshan Hospital between January 2021 and February 2023. Serious infections were defined as infections requiring hospitalization or parenteral antimicrobials occurring at any time from the initiation of the ICIs therapy to 3 months after its discontinuation.

Among the study population, 191 patients had suffered from serious infections, with an overall infection rate of 26.90% during an average follow-up period of (432.62 ± 377.09) days. The predominant site of infection was the lung (75.61%), and the most prevalent pathogens were bacteria (85.07%), followed by Mycobacterium tuberculosis (6.47%), viruses (4.98%), and fungi (3.48%). In addition to chronic obstructive pulmonary disease (COPD), asthma, and systemic glucocorticoids use, low lymphocyte count and CD4/CD8 ratio were identified as independent risk factors (all p < 0.05).

Laboratory parameters may serve as strong predictors for serious infections in patients with lung cancer following ICIs therapy. Chronic airway diseases including COPD and asthma should be managed effectively. Systemic glucocorticoids should be used prudently to prevent serious infections in these patients.

Anti-mold azoles have improved the outcomes of invasive aspergillosis (IA) when used therapeutically, but they are extensively used as prophylaxis. There are limited data regarding the outcomes of patients with hematologic malignancy who develop breakthrough IA on anti-mold azoles. We aimed to determine whether breakthrough IA on azole prophylaxis shows worse outcomes compared to no prophylaxis.

We compared outcomes including therapy response and mortality between antifungal regimens in hematologic malignancy patients with IA between July 1993 and July 2023.

Compared to an amphotericin B-containing regimen (AMB), an anti-mold azole as the primary therapy was independently associated with successful response at the end of therapy (OR = 4.38, p < 0.0001), protective against 42-day IA-associated mortality (OR = 0.51, p = 0.024) or all cause mortality (OR = 0.35, p < 0.0001), and protective against 84-day mortality, both IA-associated (OR = 0.50, p = 0.01) and all-cause mortality (OR = 0.27, p < 0.0001). Azole prophylaxis was independently associated with higher IA-associated mortality at 42 days (OR = 1.91, p = 0.012) and 84 days (OR = 2.03, p = 0.004), compared to fluconazole or no prophylaxis.

Patients with breakthrough IA on anti-mold azole prophylaxis show a worse prognosis than those on other or no prophylaxis, possibly related to the emergence of azole resistance due to their widespread use as prophylaxis agents. On the other hand, anti-mold azole primary therapy is superior to AMB therapy in the treatment of IA.

Itraconazole is the treatment of choice for many fungal infections, including histoplasmosis. While the tolerability of itraconazole has been described in short-term trial settings, there are few studies on side effects during long-term therapy. Fluconazole, which is usually thought to be less toxic, is associated with 52% toxicity in long-term treatment.

To determine the frequency, types, and timing of side effects from itraconazole therapy, the resulting changes to treatment plans, and associations between patient characteristics and itraconazole serum levels with side effect status.

We conducted a single-centre, retrospective study of adult patients with histoplasmosis receiving itraconazole therapy for at least 28 days from 2002 to 2021. Reported side effects were characterized, and propensity score matching was used to compare itraconazole serum levels between patients with and without side effects.

Sixty-three out of 227 (27.8%) patients experienced at least one side effect, the most common of which were hepatotoxicity (7.0%), nausea/vomiting (6.6%), and diarrhoea (6.2%). 12 (19.0%) patients with side effects underwent an itraconazole dose reduction and 29 (46.0%) had itraconazole discontinued. The median time to side effect was 45 days. Median itraconazole serum levels were significantly higher among patients with side effects than in a propensity score-matched population without side effects (2.9 versus 1.8 mcg/mL, P = 0.009).

Side effects were experienced by approximately one-quarter of patients with histoplasmosis receiving long-term itraconazole therapy. About two-thirds of these patients had a therapeutic intervention. Itraconazole resulted in a lower frequency of side effects than fluconazole, as measured in other studies.

Invasive fungal infections (IFI) represent a significant contributor to mortality among sepsis patients in the Intensive Care Unit (ICU). Early diagnosis of IFI is challenging, and currently, there are no predictive tools for identifying sepsis patients who may develop IFI. Our study aims to develop a predictive scoring system to assess the risk of IFI in patients with sepsis admitted to the ICU.

A retrospective collection of data from a total of 549 patients was conducted. Data-driven, clinically knowledge-driven, and decision tree models were used to identify predictive variables for risk of IFI in ICU patients with sepsis. Demographic data, vital signs, laboratory values, comorbidities, medication use, and clinical outcomes were all collected. The optimal model was selected based on model performance and clinical utility to establish a risk score.

Among adult patients with sepsis admitted to the ICU, 127 patients (23.1%) developed IFI. The final data-driven model included four predictive factors, the clinically knowledge-driven model included three predictive factors, and the decision tree model included two. Based on the good performance and clinical utility of the clinically knowledge-driven model, it was chosen as the optimal risk scoring model (C-statistics: 0.79 (95% confidence interval (CI): 0.75-0.83); Hosmer-Lemeshow (H-L) test P = 0.884). The ICU sepsis patient invasive fungal infection risk (AMI) score, created based on the clinically knowledge-driven model, includes mechanical ventilation, application of immunosuppressants, and the types of antibiotics used. The C-statistics for this risk score was 0.79 (95% CI:0.75-0.84) with good calibration (H-L test P = 0.992 and see calibration curve: Fig. 2). Moreover, in terms of clinical utility, the decision curve analysis for AMI showed a favorable net benefit.

The application of the AMI score can effectively distinguish whether ICU sepsis patients will develop IFI, which is beneficial for clinicians to formulate targeted and timely preventive and treatment measures based on the risk of IFI.

The flagellated protozoan Lophomonas spp. is a commensal microorganism found in the intestinal tracts of cockroaches, termites, mites, and certain birds. It is the causative agent of a rare infection in humans called lophomoniasis, primarily affecting the lungs and mainly immunocompromised individuals. This parasitosis is transmitted to humans by air or through ingestion of the cystic forms of the parasite. We describe the case of a 50-year-old patient treated at a tertiary hospital in southern Chile with a history of B-cell acute lymphocytic leukemia. Radiological findings, along with increased levels of inflammatory parameters and galactomannan antigen in serum and Bronchoaveolar Lavage (BAL) raised the suspicion of a pulmonary infection. Microscopic study of BAL revealed oval to pyriform cells with mobile flagella at the anterior end, which were identified as Lophomonas spp. trophozoites, which based on EORTC/MSG criteria were associated with diagnosis of a probable pulmonary aspergillosis. Lophomoniasis was treated with metronidazole (500 mg IV every 8 h) for 14 days and pulmonary aspergillosis required a combination of fluconazole, voriconazole, anidulafungin, liposomal amphotericin B and isavuconazole. The patient responded favorably and was discharged after 95 days of hospitalization. This case highlights the importance of recognizing lophomoniasis as a parasitic infection in respiratory samples from immunocompromised patients who present pulmonary symptoms, especially those who do not respond satisfactorily to conventional antimicrobial treatments. Further research is needed to understand the various sources of Lophomonas spp. infection and develop infection prevention strategies particularly for high-risk patients.

Understanding differences in clinical outcomes between PBSCT and BMT is important, and this study compared outcomes of HLA-matched related PBSCT and BMT using reduced-intensity conditioning (RIC) in adult acute myeloid leukemia (AML) patients.

Data from 402 patients who underwent either PBSCT (n = 294) or BMT (n = 108) between 2000 and 2022 were analyzed using the Japanese nationwide registry database. The primary endpoint was overall survival (OS), and secondary endpoints included disease-free survival (DFS), non-relapse mortality (NRM), and GVHD.

Results indicated no significant difference in 3-year OS (44.6% for PBSCT vs. 46.9% for BMT, HR 1.173, P = 0.299) and DFS (42.1% vs. 41.8%, HR 1.073, P = 0.639). PBSCT was more beneficial for avoiding relapse (20.3% vs. 12.4%, HR, 0.715, P = 0.059). However, PBSCT was associated with higher NRM (20.3% vs. 12.4%, HR 1.801, P = 0.025) due to more frequent, chronic GVHD (HR 1.889, P = 0.035). Subgroup analysis did not reveal specific patient groups that benefited more from PBSCT or BMT. Incidence of extensive chronic GVHD and NRM has improved in PBSCT recipients in recent years (2014-2022).

We conclude that related PBSCT with RIC regimens offers comparable prognosis to BMT for adult AML patients. Further optimization of prophylactic strategies for chronic GVHD is required to improve outcomes after PBSCT.

A 69-year-old immunocompetent male with uncontrolled type 2 diabetes mellitus (T2DM) presented with atypical left-sided headaches, diverging from his usual migraine pattern. Historically experiencing right-sided migraines, the patient's shift to left-sided headaches occurred after a month of using fluticasone for cold-like symptoms and potential mold exposure at home. Computed tomography (CT) and magnetic resonance imaging (MRI) suggested the diagnosis of skull base osteomyelitis. Endoscopic sphenoidotomy revealed Aspergillus species, leading to treatment with voriconazole. Despite the rarity of skull base Aspergillus osteomyelitis in patients who are not classically immunocompromised, this case underscores its possibility, especially in the context of diabetes and prolonged corticosteroid use. Similar literature is limited but highlights the high fatality rate of invasive fungal infections in diabetic patients and the complexity of diagnosing skull base osteomyelitis due to its varied presentations. Management involved surgical debridement and systemic antifungal therapy. This case aims to add to the limited literature on cranial Aspergillus osteomyelitis, advocating for heightened clinical vigilance, a multifaceted approach involving prompt evaluation, surgical intervention, and tailored antifungal therapy. The case highlights the need for considering fungal etiologies in atypical headache presentations and emphasizes multidisciplinary management for favorable outcomes in an otherwise morbid condition.

Chronic granulomatous disease (CGD) is a disorder of immunity characterized by phagocyte dysfunction. Mold infections in patients with CGD are often severe and disseminated. We present patient characteristics, microbiological data, and outcomes for 26 patients with CGD who received hematopoietic cell transplantation (HCT) or gene therapy-modified cells (GT) between 2008 and 2019, with proven fungal infection either before or during their transplant. All patients engrafted, and all but one GT recipient had neutrophil recovery and evidence of functional correction. Eighteen patients (69%) are currently alive and 19 patients (73% of total, 90% of patients with repeat imaging performed) had evidence of radiographic improvement. With 3 exceptions, deaths were not principally related to the fungal infection and duration of antecedent infection did not correlate with death. Aspergillus species accounted for the majority of disease (50%), followed by Phellinus species (18%). Osteomyelitis and disseminated disease were common, as only 11 patients (42%) had disease restricted to pneumonia. Triazole therapy was used in all 26 patients, with combination therapy used in 25 (96%). HCT or gene therapy, with appropriate antifungal therapy, are viable therapies for refractory fungal infections in patients with CGD.

Several antifungals are available for the treatment of patients with invasive aspergillosis (IA). This study aims to evaluate the relative efficacy and safety of the first-line monotherapies in primary therapy of IA through network meta-analysis (NMA).

We systematically searched PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, VIP database, Wanfang database, and China Biology Medicine for randomized controlled trials (RCTs) up to July 2023 that evaluated the efficacy and safety of monotherapies. We performed NMA with a frequentist random effects model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Primary outcomes were the all-cause mortality at week 12, and secondary outcomes included overall response rate, and incidence of adverse events (AEs) and severe adverse events (SAEs).

A total of three RCTs involving 1,368 participants (four antifungals) were included. The NMA showed that compared to amphotericin B deoxycholate (D-AmB), the triazoles (posaconazole (POS), isavuconazole (ISA) and voriconazole (VCZ)) can improve the overall response rate in primary therapy of IA, but only VCZ and ISA can reduce the all-cause mortality at week 12 for patients with proven and probable IA (VCZ vs D-AmB: RR = 0.66, 95%CI = 0.47-0.93, moderate certainty; ISA vs D-AmB: RR = 0.52, 95%CI = 0 .31-0.86, low certainty). ISA (SUCRA = 93.50%; mean rank, 1.20) seemed to be the most effective therapy in the above population. As to proven, probable, and possible IA patients, the triazoles were superior to D-AmB in terms of reducing all-cause mortality. Furthermore, the risk of AEs and SAEs was comparable for the three triazoles, but the risk of SAEs was significantly higher for D-AmB than others.

The efficacy and safety of triazoles are more favorable than D-AmB in the primary therapy of IA, with ISA being the optimal choice.

PROSPERO CRD42023407632.

Invasive infections with Aspergillus fumigatus in ICU patients are linked to high morbidity and mortality. Diagnosing invasive pulmonary aspergillosis (IPA) in non-immunosuppressed patients is difficult, as Aspergillus antigen (galactomannan [GM]) may have other causes. This retrospective study analyzed 160 ICU surgical patients with positive GM in broncho-alveolar lavage fluid (BALF), classifying them based on AspICU criteria for suspected IPA (pIPA) or aspiration. Patients with pIPA had higher disease severity than those with aspiration, including higher dialysis rates, organ transplantation, corticosteroid use, and Sequential Organ Failure Assessment (SOFA) score. Aspergillus culture was positive in 47.0% of pIPA cases but only 2.6% of aspiration cases (p < 0.001). SOFA score at first positive GM in BALF independently predicted 28-day mortality. In surgical patients with a positive GM in BALF, aspiration is more likely if there's no corticosteroid therapy, negative Aspergillus culture, and a history of aspiration events. Diagnosis of pIPA requires Aspergillus culture or prior corticosteroid therapy in this cohort of critically ill patients.

Invasive pulmonary aspergillosis (IPA) increases the risk of mortality of critically ill patients. Diagnostic criteria specifically targeting patients in intensive care units(ICUs) have been developed to improve diagnostic sensitivity. This study investigated health outcomes among patients in ICUs with Aspergillus isolates identified using bronchoscopy.

This retrospective cohort study obtained data from the Chang Gung Research Database of Chang Gung Memorial Hospital. Patients admitted to the ICU between January 2017 and December 2022 who received bronchoalveolar lavage were enrolled. Patients with a fungus culture yielding Aspergillus spp. isolates or who had an Aspergillus galactomannan antigen index value of >1.0 were categorized into the Aspergillus-positive group.

A total of 2372 patients were enrolled, and 146 patients (6.16%) tested positive for Aspergillus. Of the patients who tested positive for Aspergillus, 37.67% had a positive culture result, and 77.4% had a positive galactomannan antigen result. Patients with Aspergillus isolates were more likely to have a recent influenza infection, concurrent bacterial sepsis, and a cavitation and to die in hospital (in-hospital mortality rate 58.9% vs. 48.57%, P = 0.016).

Identifying Aspergillus through bronchoscopy in the ICU is associated with higher mortality rates than in patients who test negative for Aspergillus. Galactomannan antigen from bronchoalveolar lavage may provide higher diagnostic sensitivity.

The antifungal audit aimed to evaluate antifungal usage in a tertiary care center. It focused on patient profiles, the appropriateness of antifungal use, associated adverse drug reactions, reasons for suboptimal usage, and the economic burden caused by prolonged non-optimal antifungal use.

Conducted at All India Institute of Medical Sciences, New Delhi, India from January 2019 to December 2020, the study evaluated systemic antifungal use in 100 hospitalized adults with invasive fungal infections. Data collected included patient characteristics, evidence of disease, antifungal agents used, drug ADRs, appropriateness, and economic impact. Antifungal use was assessed using a predefined score (score <10 considered non-optimal), and ideal therapy duration was calculated based on treatment guidelines (IDSA & ECIL).

Optimal antifungal use was observed in 66.0 % of cases. Common reasons for non-optimal use included alternate drug selection (18 %), inappropriate dosage (12 %), lack of adjustment after microbiological results (14 %), and incorrect therapy duration (16 %). Targeted antifungal therapy was observed in 39 out of 100 patients, while pre-emptive antifungal therapy was used in 32 out of 100 patients. Voriconazole (35.1 %), caspofungin (23.1 %), and liposomal amphotericin B (20.1 %) were commonly prescribed. Liposomal amphotericin B had the highest adverse reaction rate (81.4 %). The total cost of antifungal therapy for 100 patients was ₹67,06,840 (approximately 80,350 $), with non-optimal prolonged therapy leading to an additional economic burden of ₹1,149,191 (approximately 13,841 $). Overall, 748 (39.7 %) day of therapy were non-optimal, contributing to 17.1 % of the total cost of antifungal therapy.

We observed non-optimal use of antifungal agents in 34 % of the study participants. The study results show that the antifungal audit enhances stewardship by pinpointing causes of non-optimal use, ensuring adherence to prescribing standards, optimizing clinical outcomes, and minimizing drug-related toxicities in tertiary care centres.

Lower respiratory tract illness or disease (LRTI/LRTD) represents a significant source of morbidity and mortality following viral respiratory illnesses, yet a consensus definition for this outcome is lacking. Recent studies of novel vaccines against respiratory syncytial virus (RSV) for older adults used LRTI/LRTD as the primary outcome to assess vaccine efficacy. However, the different vaccine trials have used highly variable criteria to define this outcome, leading to difficulty in comparison of vaccine efficacy results between trials. Here we review the key differences in criteria for case definitions, highlight strategies to best approximate compatibility between definitions, and review vaccine efficacy results among currently US Food and Drug Administration (FDA)-approved vaccines using these strategies. We hope this overview will support the need to develop a consensus definition for LRTI/LRTD to improve future research related to viral respiratory disease.

We aimed to investigate the approaches for antifungal prophylaxis (AFP) and antifungal treatment in breakthrough invasive fungal diseases (IFDs) under AFP in high-risk hematology patients. Patients ≥ 18-years who received chemotherapy for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or a conditioning regimen for allogeneic hematopoietic stem cell transplantation (AHSCT) with a duration of neutropenia (< 500 cells/mm3) ≥ 10 days were included in a prospective multicenter observational study. Patients were followed until one week after recovery from neutropenia, discharge from the hospital, or death, which comes first to define the success of AFP. A total of 230 patients were recruited from 18 centers in seven months. Posaconazole prophylaxis was used in 134 (44 of whom failed) and 96 patients received fluconazole (28 of whom failed). The survival rate at 12 weeks after the initiation of AFP was higher in patients with successful prophylaxis (96.2% vs 56.9%, p < 0.001). IFDs were diagnosed in 27 patients. Duration of neutropenia was the only risk factor (OR: 1.03; 95% CI: 1.004-1.053) for development of IFDs. The types of breakthrough IFDs were; possible IFD in 15 patients, probable invasive aspergillosis (IA) in 9 patients, proven IA in 2 patients; and proven mucormycosis in 1 patient. Voriconazole was the drug of choice in 16 patients (5 of whom failed). Liposomal amphotericin B was used in the treatment of 8 patients (4 of whom failed). Posaconazole was the most frequently prescribed AFP in AML patients with high compliance to international guidelines. Approximately, one-third of ALL patients and AHSCT recipients received off-label posaconazole prophylaxis.

This study aimed to develop and validate a nomogram based on lymphocyte subtyping and clinical factors for the early and rapid prediction of Intra-abdominal candidiasis (IAC) in septic patients. A prospective cohort study of 633 consecutive patients diagnosed with sepsis and intra-abdominal infection (IAI) was performed. We assessed the clinical characteristics and lymphocyte subsets at the onset of IAI. A machine-learning random forest model was used to select important variables, and multivariate logistic regression was used to analyze the factors influencing IAC. A nomogram model was constructed, and the discrimination, calibration, and clinical effectiveness of the model were verified. High-dose corticosteroids receipt, the CD4+T/CD8+ T ratio, total parenteral nutrition, gastrointestinal perforation, (1,3)-β-D-glucan (BDG) positivity and broad-spectrum antibiotics receipt were independent predictors of IAC. Using the above parameters to establish a nomogram, the area under the curve (AUC) values of the nomogram in the derivation and validation cohorts were 0.822 (95% CI 0.777-0.868) and 0.808 (95% CI 0.739-0.876), respectively. The AUC in the derivation cohort was greater than the Candida score [0.822 (95% CI 0.777-0.868) vs. 0.521 (95% CI 0.478-0.563), p < 0.001]. The calibration curve showed good predictive values and observed values of the nomogram; the Decision Curve Analysis (DCA) results showed that the nomogram had high clinical value. In conclusion, we established a nomogram based on the CD4+/CD8+ T-cell ratio and clinical risk factors that can help clinical physicians quickly rule out IAC or identify patients at greater risk for IAC at the onset of infection.

We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert.

In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms.

The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 μg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group.

The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Amphotericin B lipid complex (ABLC) is an effective antifungal agent for treating invasive fungal infections (IFIs) even though its formulation is associated with potential adverse events, including those related to its infusion. This study aimed to analyze the incidence of acute infusion-related side effects (IRSE) associated with ABLC and their relationship with the profile of patients with oncohematological disease admitted in Brazilian reference tertiary hospitals.

This is an observational retrospective study that included clinical records of patients hospitalized, in a period of 6 years, diagnosed with probable or proved IFI and treated with at least two doses of ABLC.

A total of 229 patients were included, with a male prevalence and an average age of 44 years for adults and 10 years for children. Seventy-nine (34.5%) developed some IRSE, 5.1% of which progressed in severe form to discontinuation of treatment. The most prevalent events in adults were fever (66.7%), tremor/chills (53.3%), and tachycardia (24.4%). In children, the most common were fever (64.7%), tremors/chills (50%), and skin rash/itching (17.6%). Statistical significance was found for premedication use from the first dose of ABLC in relation to the onset of infusion reactions (P = 0.006). Multivariate analysis revealed that ABLC, when compared to liposomal AMB (L-AMB), and neutropenia were associated with a higher risk of developing IRSE (odds ratio [OR] 3.04, P = 0.008; and OR 11.02, P = 0.025, respectively).

The use of premedication was a protective factor against the occurrence of IRSE. Therefore, services providing amphotericin B (AMB) must reinforce protocols or implement new measures that optimize tolerability and safety during the treatment of patients with oncohematological disease, with special attention to patients with neutropenia, prioritizing the liposomal formulation of AMB whenever possible.

Histoplasmosis is an important infection among transplant recipients. Few studies have described its epidemiology and outcomes in the modern era.

We conducted a retrospective analysis using medical records from a single center in the United States. We included patients 18 years or older with histoplasmosis. We divided the cohort into transplant recipients and immunocompetent groups to assess the outcomes in both groups. We utilized Cox hazard models to assess 90-day all-cause mortality.

The study included 137 patients; with 28 (20%) transplant recipients. After the first year post-transplant, patients with lung transplant (30%) had a diagnosis of histoplasmosis. Transplant recipients exhibited a significantly higher incidence of disseminated histoplasmosis than immunocompetent patients (64% vs. 34%, p = 0.001), higher admission to ICU (39% vs. 16%; p = 0.01) and higher but not significant 90-day crude all-cause mortality (14% vs. 11%, p = 0.71). Patients with transplants had a higher, but not significant hazard of all-cause mortality at 90 days (hazard ratio: 1.5; 95% confidence interval: 0.4-3.9) when compared to immunocompetent patients.

Transplant recipients were more commonly diagnosed with histoplasmosis after the first year post-transplantation, and although they exhibited a higher hazard for death at 90 days, this increase was not statistically significant.

Invasive fungal diseases (IFDs) are a serious threat to immunocompromised patients. Routine diagnostic methods have limited performance in identifying IFDs. Next-generation sequencing (NGS), including metagenomic NGS (mNGS) and whole-genome sequencing (WGS), recently emerged as diagnostic methods that could provide more accurate and timely diagnoses and management of IFDs.

This article describes the emergence of NGS as a diagnostic tool to address the limitations of current tests. The literature regarding its application and clinical utility in the diagnosis of IFDs is reviewed. Practical considerations, challenges, and opportunities as they relate to the development and implementation of mNGS and WGS for fungal pathogens are discussed.

NGS emerged over a decade ago with the potential to solve many of the challenges in diagnosing infectious diseases, including IFDs. However, published literature has yielded conflicting data about its clinical utility. The increased clinical adoption of NGS is improving our understanding of how to interpret and use its results to guide actionable decisions. Still, several gaps remain. As the cost, effort, and expertise involved in performing NGS decrease and the reporting of its results becomes standardized, NGS is poised to fill current gaps in the diagnosis of IFDs.

Intra-abdominal candidiasis (IAC) is difficult to predict in elderly septic patients with intra-abdominal infection (IAI). This study aimed to develop and validate a nomogram based on lymphocyte subtyping and clinical factors for the early and rapid prediction of IAC in elderly septic patients.

A prospective cohort study of 284 consecutive elderly patients diagnosed with sepsis and IAI was performed. We assessed the clinical characteristics and parameters of lymphocyte subtyping at the onset of IAI. A machine-learning random forest model was used to select important variables, and multivariate logistic regression was used to analyze the factors influencing IAC. A nomogram model was constructed, and the discrimination, calibration, and clinical effectiveness of the model were verified.

According to the results of the random forest and multivariate analyses, gastrointestinal perforation, renal replacement therapy (RRT), T-cell count, CD28+CD8+ T-cell count and CD38+CD8+ T-cell count were independent predictors of IAC. Using the above parameters to establish a nomogram, the area under the curve (AUC) values of the nomogram in the training and testing cohorts were 0.840 (95% CI 0.778-0.902) and 0.783 (95% CI 0.682-0.883), respectively. The AUC in the training cohort was greater than the Candida score [0.840 (95% CI 0.778-0.902) vs. 0.539 (95% CI 0.464-0.615), p< 0.001]. The calibration curve showed good predictive values and observed values of the nomogram; the DCA results showed that the nomogram had high clinical value.

We established a nomogram based on the T-cell count, CD28+CD8+ T-cell count, CD38+CD8+ T-cell count and clinical risk factors that can help clinical physicians quickly rule out IAC or identify elderly patients at greater risk for IAC at the onset of infection.

[chictr.org.cn], identifier [ChiCTR2300069020].