Interplay of Cytokines and Chemokines in Aspergillosis.

Aspergillosis is a fungal infection caused by various species of Aspergillus, most notably A. fumigatus. This fungus causes a spectrum of diseases, including allergic bronchopulmonary aspergillosis, aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis. The clinical manifestations and severity of aspergillosis can vary depending on individual immune status and the specific species of Aspergillus involved. The recognition of Aspergillus involves pathogen-associated molecular patterns (PAMPs) such as glucan, galactomannan, mannose, and conidial surface proteins. These are recognized by the pathogen recognition receptors present on immune cells such as Toll-like receptors (TLR-1,2,3,4, etc.) and C-type lectins (Dectin-1 and Dectin-2). We discuss the roles of cytokines and pathogen recognition in aspergillosis from both the perspective of human and experimental infection. Several cytokines and chemokines have been implicated in the immune response to Aspergillus infection, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), CCR4, CCR17, and other interleukins. For example, allergic bronchopulmonary aspergillosis (ABPA) is characterized by Th2 and Th9 cell-type immunity and involves interleukin (IL)-4, IL-5, IL-13, and IL-10. In contrast, it has been observed that invasive aspergillosis involves Th1 and Th17 cell-type immunity via IFN-γ, IL-1, IL-6, and IL-17. These cytokines activate various immune cells and stimulate the production of other immune molecules, such as antimicrobial peptides and reactive oxygen species, which aid in the clearance of the fungal pathogen. Moreover, they help to initiate and coordinate the immune response, recruit immune cells to the site of infection, and promote clearance of the fungus. Insight into the host response from both human and animal studies may aid in understanding the immune response in aspergillosis, possibly leading to harnessing the power of cytokines or cytokine (receptor) antagonists and transforming them into precise immunotherapeutic strategies. This could advance personalized medicine.

Isolation of triazole-resistant Aspergillus fumigatus harbouring cyp51A mutations from five patients with invasive pulmonary aspergillosis in Yunnan, China.

Invasive aspergillosis (IA) is the most severe type of Aspergillus infection. Yunnan has developed agriculture, and the proportion of triazole-resistant A. fumigatus induced by triazole fungicides is much higher than that in other regions of China. Inhalation of triazole-resistant A. fumigatus is one of the main factors inducing IA. We gathered five strains of A. fumigatus from the sputum or bronchoalveolar lavage fluid (BALF) of patients with IA in Yunnan. Subsequent testing showed that all of these strains were resistant to triazoles and harboured mutations in the tandem repeat sequence of the cyp51A promoter region, suggesting that they may be triazole-resistant A. fumigatus present in the environment.

Clinicomycological Study of the Spectrum of Pulmonary Aspergillosis at a Tertiary Care Hospital in Central India.

Knowing the spectrum, prevalence, and modes of diagnosis of pulmonary aspergillosis (PA) will be beneficial to clinicians for its early diagnosis and management. This study aims to estimate the prevalence, spectrum, and role of serological tests and radiological findings in the diagnosis of PA. A total of 150 patients were suspected of having PA after obtaining relevant clinical history and radiological imaging. The patients were grouped into each spectrum of PA as invasive PA (IPA), chronic necrotizing PA (CNPA), aspergilloma, allergic bronchopulmonary aspergillosis (ABPA) based on predisposing factors, clinical and radiological findings, and the guidelines of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG). Samples (bronchoalveolar lavage (BAL), sputum, blood) were collected from these patients and processed in a microbiology lab. BAL and sputum were subjected to microscopy by potassium hydroxide mount, calcofluor white mount, and culture. The serum was separated from blood by centrifugation and subjected to specific serological tests based on the spectrum of PA that the patient was suspected to have. For IPA, serum and BAL galactomannan antigen enzyme-linked immunosorbent assay (ELISA) was performed. For CNPA and aspergilloma, the anti-Aspergillus IgG antibody ELISA was performed. For ABPA, the tests performed were total immunoglobulin E (IgE) ELISA, Aspergillus fumigatus-specific IgE ELISA, and anti-Aspergillus immunoglobulin G (IgG) antibody ELISA. After compiling the clinical, radiological, culture, and serological findings, patients were diagnosed to have a particular spectrum of PA. The prevalence of IPA was 1.4%, CNPA was 4%, ABPA was 3.2%, and aspergilloma was 2.9%. CNPA was the predominant spectrum of PA in our study. Culture positivity for Aspergillus species was seen the highest in aspergilloma patients, followed by IPA, ABPA, and CNPA patients. A. fumigatus was the most common causative agent of PA, except for IPA for which Aspergillus flavus was the most common causative. Aspergillus niger and Aspergillus terreus were less the frequent causes of PA. A combination of radiological, microbiological, and serological tests along with clinical correlation is needed to confirm the diagnosis of PA.

Evaluation of the JF5-based Aspergillus galactomannoprotein lateral flow device for diagnosing invasive aspergillosis in cancer patients.

PURPOSE: Cancer patients are at heightened risk for invasive aspergillosis (IA), a condition associated with elevated mortality risk. The JF5-based Aspergillus Galactomannoprotein Lateral Flow Device (AspLFD) offers rapid point-of-care testing (POCT) for IA. This study evaluated the diagnostic performance of AspLFD in cancer populations. METHODS: This retrospective study examined cancer patient bronchoalveolar lavage fluid (BALF) and serum samples collected between September 2021 and January 2023. Both AspLFD and galactomannan (GM) assays were conducted, and the results were analysed by two independent researchers. RESULTS: This study included 242 samples from 218 cancer patients, with 58 BALF and 184 serum samples. The overall agreement between AspLFD and GM assay results was 92.1%, with a kappa value of 0.552. AspLFD diagnosed proven/probable IA with a sensitivity and specificity of 91.7% and 95.3%, respectively, whereas GM exhibited sensitivity and specificity values of 83.3% and 93.7%, respectively. There were no statistical differences in the sensitivity and specificity between the two methods (P > 0.05). For serum analyses, AspLFD and GM exhibited similar sensitivity (66.7% vs. 66.7%, P > 0.05) and specificity (98.6% vs. 96.6%, P > 0.05) values. However, the sensitivity of the AspLFD was superior to the GM assay (100% vs. 88.9%) in BALF analyses but the difference was not statistically significant (P > 0.05), with no difference in specificity (83.7% vs. 83.7%, P > 0.05). In the solid-tumour cohort, both the AspLFD and GM assay exhibited high sensitivity (100% for both) and specificity (94.2% vs. 92.8%, P > 0.05). CONCLUSION: The AspLFD demonstrated good performance in diagnosing IA in cancer patients, especially those with solid tumours. The AspLFD is thus an alternative POCT, particularly when GM evaluations are not readily available.

A Case of Pulmonary MALToma Camouflaged Within Invasive Pulmonary Aspergillosis.

A 59-year-old non-smoking male, with a known case of COPD (chronic obstructive pulmonary disease), treated pulmonary tuberculosis with Category 1 antitubercular drugs (six-month regimen) and was admitted with repeated bouts of moderate haemoptysis (~60 mL/day) for three days. The patient had a history of self-limiting occasional mild haemoptysis (~20 mL) over three years. An HRCT chest revealed a left upper lobe fibro-cavitary lesion with an intracavitary mass (air crescent sign), adjacent pleural thickening and fibrosis. Bronchoalveolar lavage (BAL) was positive for galactomannan and negative for Mycobacterium tuberculosis GeneXpert®. With the above clinical factors, host factors, and microbiological factors, the case was diagnosed as 'probable' invasive pulmonary aspergillosis and was treated with voriconazole. However, given relapsing haemoptysis despite adequate antifungal treatment, a left upper lobectomy was done. The resected left upper lobe specimen culture demonstrated Aspergillus fumigatus with histopathology confirming hyphae invading lung tissues confirming 'proven' invasive aspergillosis. Resected tissue also showed florid lymphoid tissue hyperplasia with Immunohistochemistry confirming the presence of a peculiar malignancy; MALT lymphoma/MALToma in the resected lobe. The association of a rare malignancy such as MALToma with invasive pulmonary aspergilloma (IPA) has been identified and reported for the first time. This could be because of a chronic inflammatory reaction elicited by the Aspergillus antigen. Long-standing fibro-cavitary disease and aspergillosis are partners in crime, augmenting the damages inflicted by one another. In such a scenario, early surgical intervention may be warranted if haemoptysis is moderate to severe or relapsing, following conservative medical management. Surgical resection may lead to the identification of unexpected diseases as in our case.

[Ruptured mycotic cerebral aneurysm in an adult T-cell leukemia/lymphoma patient undergoing allogeneic stem cell transplantation].

A 63-year-old man with adult T-cell leukemia-lymphoma underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. On day 17 after transplantation, chest computed tomography (CT) showed nodules in the lower lobes of both lungs, and invasive pulmonary aspergillosis (IPA) was suspected. Treatment with liposomal amphotericin B was started, and improvement of infectious lesions was confirmed with CT on day 28. The antifungal agent was changed to voriconazole on day 52 because of progressive renal dysfunction. Disorders of consciousness and paralysis of the left upper and lower extremities developed on day 61. Brain CT showed subcortical hemorrhage in the right parietal and occipital lobes, and the patient died on day 62. An autopsy revealed filamentous fungi, suspected to be Aspergillus, in the pulmonary nodules and a ruptured cerebral aneurysm. Although IPA occurs in 10% of transplant recipients, vigilant monitoring for mycotic cerebral aneurysms is required to prevent hematogenous dissemination of Aspergillus, which is associated with a high mortality rate.

Identification of closely related species in Aspergillus through Analysis of Whole-Genome.

The challenge of discriminating closely related species persists, notably within clinical diagnostic laboratories for invasive aspergillosis (IA)-related species and food contamination microorganisms with toxin-producing potential. We employed Analysis of the whole-GEnome (AGE) to address the challenges of closely related species within the genus Aspergillus and developed a rapid detection method. First, reliable whole genome data for 77 Aspergillus species were downloaded from the database, and through bioinformatic analysis, specific targets for each species were identified. Subsequently, sequencing was employed to validate these specific targets. Additionally, we developed an on-site detection method targeting a specific target using a genome editing system. Our results indicate that AGE has successfully achieved reliable identification of all IA-related species (Aspergillus fumigatus, Aspergillus niger, Aspergillus nidulans, Aspergillus flavus, and Aspergillus terreus) and three well-known species (A. flavus, Aspergillus parasiticus, and Aspergillus oryzae) within the Aspergillus section. Flavi and AGE have provided species-level-specific targets for 77 species within the genus Aspergillus. Based on these reference targets, the sequencing results targeting specific targets substantiate the efficacy of distinguishing the focal species from its closely related species. Notably, the amalgamation of room-temperature amplification and genome editing techniques demonstrates the capacity for rapid and accurate identification of genomic DNA samples at a concentration as low as 0.1 ng/µl within a concise 30-min timeframe. Importantly, this methodology circumvents the reliance on large specialized instrumentation by presenting a singular tube operational modality and allowing for visualized result assessment. These advancements aptly meet the exigencies of on-site detection requirements for the specified species, facilitating prompt diagnosis and food quality monitoring. Moreover, as an identification method based on species-specific genomic sequences, AGE shows promising potential as an effective tool for epidemiological research and species classification.

Human Vγ9Vδ2 T cells exhibit antifungal activity against Aspergillus fumigatus and other filamentous fungi.

Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus (Af293) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae, and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus, indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus. The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus. Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis. IMPORTANCE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.

Modeling Invasive Aspergillosis Risk for the Application of Prophylaxis Strategies.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flow's origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of America's aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

Diagnosis and management of invasive fungal diseases in non-neutropenic ICU patients, with focus on candidiasis and aspergillosis: a comprehensive review.

Invasive fungal diseases pose a significant threat to non-neutropenic ICU patients, with Candida and Aspergillus infections being the most common. However, diagnosing these infections in the ICU population remains challenging due to overlapping clinical features, poor sensitivity of blood cultures, and invasive sampling requirements. The classical host criteria for defining invasive fungal disease do not fully apply to ICU patients, leading to missed or delayed diagnoses. Recent advancements have improved our understanding of invasive fungal diseases, leading to revised definitions and diagnostic criteria. However, the diagnostic difficulties in ICU patients remain unresolved, highlighting the need for further research and evidence generation. Invasive candidiasis is the most prevalent form of invasive fungal disease in non-neutropenic ICU patients, presenting as candidemia and deep-seated candidiasis. Diagnosis relies on positive blood cultures or histopathology, while non-culture-based techniques such as beta-D-glucan assay and PCR-based tests show promise. Invasive aspergillosis predominantly manifests as invasive pulmonary aspergillosis in ICU patients, often associated with comorbidities and respiratory deterioration in viral pneumonia. Diagnosis remains challenging due to poor sensitivity of blood cultures and difficulties in performing lung biopsies. Various diagnostic criteria have been proposed, including mycological evidence, clinical/radiological factors and expanded list of host factors. Non-culture-based techniques such as galactomannan assay and PCR-based tests can aid in diagnosis. Antifungal management involves tailored therapy based on guidelines and individual patient factors. The complexity of diagnosing and managing invasive fungal diseases in ICU patients underscore the importance of ongoing research and the need for updated diagnostic criteria and treatment approaches. Invasive fungal disease, Invasive fungal infection, Invasive candidiasis, Invasive aspergillosis, Antifungal drugs.

Six-year experience with GM test in hematological patients in a public Brazilian tertiary hospital.

Invasive fungal infection (IFI) is frequent in patients with hematologic malignancies or submitted hematopoietic stem cell transplantation (HSCT). OBJECTIVES: To evaluate the role of the GM (galactomannan) test in prescribing therapeutic antifungals; to determine invasive aspergillosis (IA) frequency, the factors associated with positive GM test, and the in-hospital mortality. METHODS: We conducted a retrospective observational study including patients aged 18 or over with hematological malignancy or submitted to HSCT. GM test was measured twice weekly. The hypothesis of IFI was considered in patients with neutropenia and persistent fever despite broad-spectrum antibiotics. RESULTS: A total of 496 patients were evaluated; the mean of GM tests performed per patient was 4.2 (+3.1), and 86 (17.3 %) had positive results. IFI was diagnosed in 166 (33.5 %) and IA in 22 (24.6 %) patients. Positive GM test was more frequent in patients with IFI (72.2 % and 25.1 %; OR 8.1; 95 % CI 4.8 - 13.8), and was associated with therapeutic antifungals prescription (52, 9 % and 20.5 %; OR 4.3, 95CI% 2.0 - 9.4), as well as lung abnormalities on HRCT (45.3% vs. 21.5 %; OR 3.0, 95 %CI 1.4 - 6.5). Mortality was 31.6 %. In the multivariate analysis, the variables associated with mortality were the hypothesis of IFI (OR 6.35; 95 % CI 3.63-11.12.0), lung abnormalities on HRCT (57.9 % and 26.9 %; OR 2 0.6; 95 % CI 1.5 - 4.4), and positive GM test (57.9 % and 26.9 %; OR 2.7 95 % CI 1.6 - 4.5). CONCLUSIONS: Positive GM test was associated with lung abnormalities on HRCT and with the introduction of therapeutic antifungals. If adequate anti-mold prophylaxis is available, the GM test should not be used as screening, but to investigate IFI in high-risk patients. The diagnosis of IFI, positive GM test and lung abnormalities on HRCT were predictors of hospital mortality in patients with hematological malignancies or undergoing HSCT.

Increased Risk of Invasive Aspergillosis in Immunocompromised Patients With Persistent SARS-CoV-2 Viral Shedding >8 Weeks, Retrospective Case-control Study.

Background: Immunocompromised patients now represent the population most at risk for severe coronavirus disease 2019. Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral shedding was reported in these patients ranging from several weeks up to 9 months. We conducted a bicentric retrospective case-control study to identify risk and prognostic factors associated with persistent viral shedding in immunocompromised patients. Material and Methods: Symptomatic immunocompromised adults with persistent SARS-CoV-2 viral shedding >8 weeks were retrospectively included between 1 March 2020 and 24 April 2022 at 2 university hospitals in Paris, France, and matched with a control group consisting of symptomatic immunocompromised patients without persistent viral shedding. Results: Twenty-nine immunocompromised patients with persistent viral shedding were compared with 40 controls. In multivariate analysis, fever and lymphocytopenia (<0.5 G/L) were associated with an increased risk of persistent viral shedding (odds ratio [OR]: 3.3; 95% confidence interval [CI], 1.01-11.09) P = .048 and OR: 4.3; 95% CI, 1.2-14.7; P = .019, respectively). Unvaccinated patients had a 6-fold increased risk of persistent viral shedding (OR, 6.6; 95% CI, 1.7-25.1; P = .006). Patients with persistent viral shedding were at risk of hospitalization (OR: 4.8; 95 CI, 1.5-15.6; P = .008), invasive aspergillosis (OR: 10.17; 95 CI, 1.15-89.8; P = .037) and death (log-rank test <0.01). Conclusions: Vaccine coverage was protective against SARS-CoV-2 persistent viral shedding in immunocompromised patients. This new group of immunocompromised patients with SARS-CoV-2 persistent viral shedding is at risk of developing invasive aspergillosis and death and should therefore be systematically screened for this fungal infection for as long as the viral shedding persists.

Multi-Locus Microsatellite Typing of Colonising and Invasive Aspergillus fumigatus Isolates from Patients Post Lung Transplantation and with Chronic Lung Disease.

Aspergillus fumigatus can cause different clinical manifestations/phenotypes in lung transplant (LTx) recipients and patients with chronic respiratory diseases. It can also precipitate chronic lung allograft dysfunction (CLAD) in LTx recipients. Many host factors have been linked with the severity of A. fumigatus infection, but little is known about the contribution of different A. fumigatus strains to the development of different phenotypes and CLAD. We used multi-locus microsatellite typing (MLMT) to determine if there is a relationship between strain (i.e., genotype) and phenotype in 60 patients post LTx or with chronic respiratory disease across two time periods (1 November 2006-31 March 2009 and 1 November 2015-30 June 2017). The MLMT (STRAf) assay was highly discriminatory (Simpson's diversity index of 0.9819-0.9942) with no dominant strain detected. No specific genotype-phenotype link was detected, but several clusters and related strains were associated with invasive aspergillosis (IA) and colonisation in the absence of CLAD. Host factors were linked to clinical phenotypes, with prior lymphopenia significantly more common in IA cases as compared with A. fumigatus-colonised patients (12/16 [75%] vs. 13/36 [36.1%]; p = 0.01), and prior Staphylococcus aureus infection was a significant risk factor for the development of IA (odds ratio 13.8; 95% confidence interval [2.01-279.23]). A trend toward a greater incidence of CMV reactivation post-A. fumigatus isolation was observed (0 vs. 5; p = 0.06) in LTx recipients. Further research is required to determine the pathogenicity and immunogenicity of specific A. fumigatus strains.

Aspergillus granulosus femoral osteomyelitis in a cardiac transplant patient: first reported case and literature review.

Aspergillus osteomyelitis is a rare complication of extrapulmonary invasive aspergillosis, which usually presents as spondylodiscitis. The clinical picture is usually paucisymptomatic and of long evolution, which leads to diagnostic difficulties, especially in immunosuppressed patients presenting a delayed systemic host response. We report a case of femoral osteomyelitis caused by Aspergillus granulosus in a heart transplant recipient successfully treated with a combined surgical and antifungal approach. A 65-year-old heart transplant male presented with left knee pain lasting 3 months. X-ray and magnetic resonance imaging identified a lesion with aggressive characteristics at the distal third of the left femur, due to which the patient underwent excisional surgery. Aspergillus granulosus was cultured from the removed material and antifungal treatment with oral isavuconazole was started. Chest imaging excluded pulmonary aspergillosis, while the positron emission tomography/computed tomography (PET/CT) identified a remnant of a prosthetic vascular graft sewn to the proximal third of the right axillary artery, through which a catheter-based micro-axial left ventricular assist device was implanted previously as bridge to transplant therapy. The patient presented a rapid clinical improvement with complete functional recovery following the surgical treatment and the antifungal therapy and finally underwent surgical removal of the residual vascular graft. This is the first reported episode of long bone osteomyelitis due to A. granulosus that occurred in a heart transplant recipient without pulmonary infection and was successfully treated with isavuconazole. The PET/CT was useful in supporting the diagnostic process and follow-up. Cryptic fungal species can cause invasive infections, particularly in immunocompromised patients. Molecular methods are crucial in fungal identification.

Different forms of pulmonary aspergillosis: A pictorial essay.

Pulmonary aspergillosis is a group of mycotic diseases affecting the lungs. The form of the disease mainly depends on the immune status of the patient and underlying conditions. Invasive pulmonary aspergillosis usually affects immunocompromised patients - angio-invasive and airway-invasive forms are possible. Chronic aspergillosis usually appears in mildly immunosuppressed or immunocompetent patients with underlying structural lung changes and may have diverse forms: simple aspergilloma, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, subacute invasive pulmonary aspergillosis, aspergillus nodules and endobronchial aspergilloma. Allergic bronchopulmonary aspergillosis is a hyper-reactivity reaction to Aspergillus species, and usually develops in asthma and cystic fibrosis patients. The aim of this article is to comprehensively overview different forms of aspergillosis, their symptoms and underlying conditions and to present imaging findings.

Influenza-associated invasive aspergillosis in patients admitted to the intensive care unit in Sweden: a prospective multicentre cohort study.

BACKGROUND: The purpose of this study was to prospectively investigate the incidence of influenza-associated pulmonary aspergillosis (IAPA) in influenza patients admitted to intensive care units in Sweden. METHODS: The study included consecutive adult patients with PCR-verified influenza A or B in 12 Swedish intensive care units (ICUs) over four influenza seasons (2019-2023). Patients were screened using serum galactomannan and ß-d-glucan tests and fungal culture of a respiratory sample at inclusion and weekly during the ICU stay. Bronchoalveolar lavage was performed if clinically feasible. IAPA was classified according to recently proposed case definitions. RESULTS: The cohort included 55 patients; 42% were female, and the median age was 59 (IQR 48-71) years. All patients had at least one galactomannan test, ß-d-glucan test and respiratory culture performed. Bronchoalveolar lavage was performed in 24 (44%) of the patients. Five (9%, 95% CI 3.8% - 20.4%) patients were classified as probable IAPA, of which four lacked classical risk factors. The overall ICU mortality was significantly higher among IAPA patients than non-IAPA patients (60% vs 8%, p = 0.01). CONCLUSIONS: The study represents the first prospective investigation of IAPA incidence. The 9% incidence of IAPA confirms the increased risk of invasive pulmonary aspergillosis among influenza patients admitted to the ICU. Therefore, it appears reasonable to implement a screening protocol for the early diagnosis and treatment of IAPA in influenza patients receiving intensive care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04172610, registered November 21, 2019.

Invasive pulmonary aspergillosis following human metapneumovirus infection in solid-organ transplant recipients: Another virus to add to the list.

There is increasing recognition that respiratory viral infections such as influenza, respiratory syncytial virus, parainfluenza virus, adenovirus, and SARS-CoV-2 can promote the development of invasive fungal pulmonary coinfections, particularly invasive aspergillosis, both in immunocompetent and immunocompromised patients. To date, there are no case reports exploring the role of human metapneumovirus as a risk factor for fungal coinfection. Below, we describe the case of a 63-year-old woman who received a kidney transplant and developed invasive pulmonary aspergillosis after a human metapneumovirus infection and discuss the possible phenomena that could favor this association.

Performance of the Aspergillus galactomannan lateral flow assay with a digital reader for the diagnosis of invasive aspergillosis: a multicenter study.

PURPOSE: The objective of this multicenter study was to compare the diagnostic performance of lateral flow assay (LFA) and enzyme-linked immunosorbent assay (ELISA) to detect the Dynamiker Aspergillus Galactomannan levels in serum and bronchoalveolar lavage fluid (BALF) samples for I. METHODS: We registered 310 clinically suspected Aspergillus infection patients from December 2021 to February 2023 and classified them into subgroups as the "IA group" and "non-IA group" based on the latest EORTC/MSG guidelines. The immunoassays were analyzed by LFA and ELISA respectively. RESULTS: Galactomannan was examined using LFA, and serum and BALF samples demonstrated sensitivities of 82.57% and 89.47%, specificities of 90.76% and 92.00%, PPVs of 89.11% and 96.23%, and NPVs of 85.04% and 79.31%, respectively. Galactomannan was observed using two assays in serum and BALF samples and showed PPAs of 95.11% and 93.33%, NPAs of 89.19% and 96.30%, and TPAs of 92.47% and 94.25%, respectively. The ROC curve demonstrated that LFA had optimum diagnostic value when the index value (I value) = 0.5, the sensitivity was 84.94%, and the specificity was 90.97%. CONCLUSION: Compared to the ELISA method, the LFA has shown excellent performance for the diagnosis of IA in serum and BALF sample and can be used as an assay for the early diagnosis of patients with IA. The dynamic change in galactomannan levels may be useful for assessing treatment response.

Six-year experience with GM test in hematological patients in a public Brazilian tertiary hospital

Abstract Invasive fungal infection (IFI) is frequent in patients with hematologic malignancies or submitted hematopoietic stem cell transplantation (HSCT). Objectives To evaluate the role of the GM (galactomannan) test in prescribing therapeutic antifungals; to determine invasive aspergillosis (IA) frequency, the factors associated with positive GM test, and the in-hospital mortality. Methods We conducted a retrospective observational study including patients aged 18 or over with hematological malignancy or submitted to HSCT. GM test was measured twice weekly. The hypothesis of IFI was considered in patients with neutropenia and persistent fever despite broad-spectrum antibiotics. Results A total of 496 patients were evaluated; the mean of GM tests performed per patient was 4.2 (+3.1), and 86 (17.3 %) had positive results. IFI was diagnosed in 166 (33.5 %) and IA in 22 (24.6 %) patients. Positive GM test was more frequent in patients with IFI (72.2 % and 25.1 %; OR 8.1; 95 % CI 4.8 - 13.8), and was associated with therapeutic antifungals prescription (52, 9 % and 20.5 %; OR 4.3, 95CI% 2.0 - 9.4), as well as lung abnormalities on HRCT (45.3% vs. 21.5 %; OR 3.0, 95 %CI 1.4 - 6.5). Mortality was 31.6 %. In the multivariate analysis, the variables associated with mortality were the hypothesis of IFI (OR 6.35; 95 % CI 3.63-11.12.0), lung abnormalities on HRCT (57.9 % and 26.9 %; OR 2 0.6; 95 % CI 1.5 - 4.4), and positive GM test (57.9 % and 26.9 %; OR 2.7 95 % CI 1.6 - 4.5). Conclusions Positive GM test was associated with lung abnormalities on HRCT and with the introduction of therapeutic antifungals. If adequate anti-mold prophylaxis is available, the GM test should not be used as screening, but to investigate IFI in high-risk patients. The diagnosis of IFI, positive GM test and lung abnormalities on HRCT were predictors of hospital mortality in patients with hematological malignancies or undergoing HSCT.

Using staged tree models for health data: Investigating invasive fungal infections by aspergillus and other filamentous fungi.

Machine learning models are increasingly used in the medical domain to study the association between risk factors and diseases to support practitioners in understanding health outcomes. In this paper, we showcase the use of machine-learned staged tree models for investigating complex asymmetric dependence structures in health data. Staged trees are a specific class of generative, probabilistic graphical models that formally model asymmetric conditional independence and non-regular sample spaces. An investigation of the risk factors in invasive fungal infections demonstrates the insights staged trees provide to support medical decision-making.