Prevalence, Risk Factors, and Mortality of Invasive Pulmonary Aspergillosis in Patients with Anti-MDA5+ Dermatomyositis: A Retrospective Study in China.

Objective: To investigate the prevalence, risk factors and prognosis of invasive pulmonary aspergillosis (IPA) in patients with anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+ DM). Methods: A retrospective analysis was conducted in anti-MDA5+ DM patients diagnosed between January 2016 and March 2023. Patients with lower respiratory tract specimens were categorized into IPA+ and IPA- groups based on the presence of IPA and their clinical characteristics and prognoses then compared. Results: Of the 415 patients diagnosed with anti-MDA5+ DM, 28 cases had IPA (prevalence rate of 6.7%) with Aspergillus fumigatus being the most common species. The patients were categorized into IPA+ (n=28) and IPA- (n=98) groups, with no significant age or gender-related differences (P>0.05). The IPA+ group had a lower lymphocyte count, particularly the CD4+ T-cell count, and reduced serum albumin and higher serum ferritin levels (P all<0.05). An elevated bronchoalveolar lavage fluid (BALF) galactomannan level was found to be the sole independent risk factor for the occurrence of IPA (adjusted OR=2.191, P=0.029) with a cut-off value of 0.585 and area under the curve of 0.779. The mortality rate in the IPA+ group was 25%. Compared to survivors, non-survivors in this group exhibited a higher incidence of rapidly progressive interstitial lung disease, lower lymphocyte counts, and increased co-infection with Pneumocystis jirovecii (P all<0.05). Conclusion: IPA was not rare in patients with anti-MDA5+ DM, with elevated BALF galactomannan levels being an independent risk factor for IPA occurrence. Clinicians must exercise vigilance to identify patients exhibiting the aforementioned risk factors.

Invasive Aspergillosis in Liver Transplant Recipients in The Current Era.

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multi-center 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in eight cases (13%). 12-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotics usage (adjusted odds ratio [aOR], 4.74; p=0.03) and history of pneumonia (aOR, 48.7; p=0.01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; p=0.01), systemic antibiotics usage (aOR, 5.03; p=0.04), and anti-mold prophylaxis (aOR, 11.9; p=0.02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ration [aHR], 86.9; p<0.001), ICU stay (aHR, 3.67; p=0.02), disseminated IA (aHR, 8.98; p<0.001), and dialysis (aHR, 2.93; p=0.001) were identified as independent risk factors associated with 12-week all-cause mortality; while recent receipt of tacrolimus (aHR, 0.11; p=0.001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted anti-mold prophylactic and appropriate treatment strategies against IA.

Prevalence and prognostic relevance of invasive fungal disease during veno-arterial ECMO: A retrospective single-center study.

PURPOSE: To assess the prevalence and relevance of invasive fungal disease (IFD) during veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO). METHODS: Retrospective analysis from January 2013 to November 2023 of adult V-A ECMO cases at a German University Hospital. Parameters relating to IFD, demographics, length of stay (LoS), days on ECMO and mechanical ventilation, prognostic scores and survival were assessed. Multivariable logistic regression analyses with IFD and death as dependent variables were performed. Outcome was assessed after propensity score matching IFD-patients to non-IFD-controls. RESULTS: 421 patients received V-A ECMO. 392 patients with full electronic datasets were included. The prevalence of IFD, invasive candidiasis and probable invasive pulmonary aspergillosis was 4.6%, 3.8% and 1.0%. Severity of acute disease, pre-existing moderate-to-severe renal disease and continuous kidney replacement therapy were predictive of IFD. In-hospital mortality (94% (17/18) compared to 67% (252/374) in non-IFD patients (p = 0.0156)) was predicted by female sex, SOFA score at admission, SAVE score and IFD (for IFD: OR: 8.31; CI: 1.60-153.18; p: 0.044). There was no difference in outcome after matching IFD-cases to non-IFD-controls. CONCLUSIONS: IFD are detected in about one in 20 patients on V-A ECMO, indicating mortality >90%. However, IFD do not contribute to prognosis in this population.

Report of three azole-resistant Aspergillus fumigatus cases with TR34/L98H mutation in hematological patients in Barcelona, Spain.

OBJECTIVES: We aimed to report the emergence of azole-resistant invasive aspergillosis in hematologic patients admitted to a tertiary hospital in Spain during the last 4 months. METHODS: Prospective, descriptive study was performed to describe and follow all consecutive proven and probable invasive aspergillosis resistant to azoles from hematological cohort during the last 4 months. All patients had fungal cultures and antifungal susceptibility or real-time PCR detection for Aspergillus species and real-time PCR detection for azole-resistant mutation. RESULTS: Four cases of invasive aspergillosis were diagnosed in 4 months. Three of them had azole-resistant aspergillosis. Microbiological diagnosis was achieved in three cases by means of fungal culture isolation and subsequent antifungal susceptibility whereas one case was diagnosed by PCR-based aspergillus and azole resistance detection. All the azole-resistant aspergillosis presented TR34/L98H mutation. Patients with azole-resistant aspergillosis had different hematologic diseases: multiple myeloma, lymphoblastic acute leukemia, and angioimmunoblastic T lymphoma. Regarding risk factors, one had prolonged neutropenia, two had corticosteroids, and two had viral co-infection. Two of the patients developed aspergillosis under treatment with azoles. CONCLUSION: We have observed a heightened risk of azole-resistant aspergillosis caused by A. fumigatus harboring the TR34/L98H mutation in patients with hematologic malignancies. The emergence of azole-resistant aspergillosis raises concerns for the community, highlighting the urgent need for increased surveillance and the importance of susceptibility testing and new drugs development.

Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population. Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.

Chronic cavitary pulmonary aspergillosis as a sequela of pulmonary tuberculosis: A case report from Pakistan.

Chronic pulmonary aspergillosis is a lung disorder characterized by the presence of single or multiple cavities with or without an aspergilloma or nodules on chest imaging, with mycological evidence of and/or demonstration of immunological response to Aspergillus spp. The affected patient should manifest relevant symptoms for at least 3 months. Chronic cavitary pulmonary aspergillosis is the most common subset of chronic pulmonary aspergillosis, which is often reported in patients previously treated for pulmonary tuberculosis, having residual cavities in their lungs. We present a case of a 55-year-old male patient treated for pulmonary tuberculosis 2 years back, now presenting with fever, shortness of breath, and hemoptysis with overt radiological changes from the baseline, positive direct microscopy, and serology for Aspergillus spp. and thus meeting the criteria for chronic cavitary pulmonary aspergillosis. Treatment with oral antifungal was initiated, but the follow-up data are unavailable due to patient noncompliance and lack of resources. We aim to emphasize the radiological and microbiological features of this condition to aid the early diagnosis and prompt treatment, as this may mimic similar pulmonary disorders and pose a significant challenge in the diagnosis and management outcomes.

Invasive aspergillosis: A comprehensive review.

Invasive aspergillosis (IA) is a severe fungal infection caused by Aspergillus species, particularly Aspergillus fumigatus, although new species, sometimes resistant to antifungals are becoming more common. IA predominantly affects immunocompromised patients, such as those with haematological malignancies, solid organ transplant recipients, and critically ill patients. However, new at-risk populations have emerged in recent years, such as IA associated with severe viral infections. Advanced diagnostic methods are crucial, especially considering the rising concern of antifungal resistance. Early detection is critical for successful treatment, typically involving antifungal medications like voriconazole or amphotericin B, but new antifungals are arriving to complete the therapeutic strategies. Despite advancements, mortality rates remain high, underscoring the importance of timely interventions and ongoing research. Healthcare providers should maintain a high index of suspicion, especially in immunocompromised patients and other new risk factors that are arising, to promptly diagnose and manage invasive aspergillosis.

Fungal infections in patients after recovering from COVID-19: a systematic review.

Background and aims: The presence of fungal infections has been described in patients after recovering from COVID-19. This study aims to conduct a systematic review of studies that reported fungal infections (Mucor spp., Pneumocystis jirovecii, or Aspergillus spp.) in adults after recovering from COVID-19. Methods: We performed a systematic review through PubMed, Web of Science, OVID-Medline, Embase, and Scopus. The study selection process was performed independently and by at least two authors. We performed a risk of bias assessment using the Newcastle-Ottawa Scale for cohort and case-control studies, and the Joanna Briggs Institute's Checklists for Case Series and Case Reports. Results: The systematic search found 33 studies meeting all inclusion criteria. There was a total population of 774 participants, ranging from 21 to 87 years. From them, 746 developed a fungal infection. In 19 studies, Mucor spp. was reported as the main mycosis. In 10 studies, P. jirovecii was reported as the main mycosis. In seven studies, Aspergillus spp. was reported as the main mycosis. Regarding the quality assessment, 12 studies were classified as low risk of bias and the remaining studies as high risk of bias. Conclusion: Patients' clinical presentation and prognosis after recovering from COVID-19 with fungal infection differ from those reported patients with acute COVID-19 infection and those without COVID-19 infection.

Comparison of different lateral flow assays on bronchoalveolar lavage fluid for invasive aspergillosis screening in non-hematological patients.

Several lateral flow assays (LFA) capable of detecting Aspergillus fumigatus in serum and broncho-alveolar lavage fluid (BALF) within the hour, thereby potentially accelerating the screening process, are now commercially available. We prospectively compared three LFA targeting A. fumigatus on BALF collected from non-surgical intensive care patients between June 2022 and February 2023. The three LFA tested were Sõna Aspergillus galactomannan LFA (Immy), Fungadia Aspergillus antigen (Gadia), and AspLFD (OLM Diagnostics). We compared the results of these LFA with those of the galactomannan (GM) Platelia Aspergillus enzyme immunoassay (Bio-Rad), culture on Sabouraud medium and Aspergillus qPCR. We tested 97 BALF samples from 92 patients. In total 84 BALF samples tested negative with all three LFA, and four BALF samples tested positive with the AspLFD assay only (OLM). Only one BALF sample tested positive with the three LFA. In addition, three BALF samples tested positive only with the GM Platelia immunoassay. Four diagnosis of probable invasive aspergillosis were retained for the 92 patients tested. This prospective series included very few positive samples. From a practical point of view, the LFA from OLM presented the simplest protocol for use.

MicroRNA expression profile of alveolar epithelial cells infected with Aspergillus fumigatus.

There are limited number of studies investigating the role of microRNAs (miRNAs) in Aspergillus infections. In this study, we designed an in vitro aspergillosis model to identify differentially expressed Aspergillus-related miRNAs. For this purpose, carcinoma cell lines "A549" and "Calu-3" were infected with Aspergillus fumigatus. Total miRNA was isolated at 0, 1, 6, and 24 h post-infection. Quantitative real-time PCR assay was conducted to screen 31 human miRNAs that were possibly related to aspergillosis. Up- and downregulated miRNAs were detected in the infected cells. Highest level of miRNA expression was detected at 6 h post-infection. miR-21, hsa-miR-186-5p, hsa-miR-490-5p, miR-26a-5p, miR-26b-5p, hsa-miR-424-5p, hsa-miR-548d-3p, hsa-miR-196a-5p, miR-150-5p, miR-17-5p, and hsa-miR-99b-5p were found to be significantly upregulated (p < 0.001) at 6 h after A. fumigatus infection compared with the controls. Among the screened miRNAs, hsa-miR-145-5p (p < 0.001); hsa-miR-583 and hsa-miR-3978 (p < 0.01); and miR-21-5p, hsa-miR-4488, and hsa-miR-4454 (p < 0.05) were found to be downregulated compared with the controls. In conclusion, screening the identified miRNAs may reveal the personal predisposition to aspergillosis, which might be valuable from the perspective of personalized medicine.

Severe mold fungal infections in critically ill patients with COVID-19.

The SARS-CoV-2 pandemic put an unprecedented strain on modern societies and healthcare systems. A significantly higher incidence of invasive fungal co-infections was noted compared with the pre-COVID-19 era, adding new diagnostic and therapeutic challenges in the critical care setting. In the current narrative review, we focus on invasive mold infections caused by Aspergillus and Mucor species in critically ill COVID-19 patients. We discuss up-to-date information on the incidence, pathogenesis, diagnosis and treatment of these mold-COVID-19 co-infections, as well as recommendations on preventive and prophylactic interventions. Traditional risk factors were often not recognized in COVID-19-associated aspergillosis and mucormycosis, highlighting the role of other determinant risk factors. The associated patient outcomes were worse compared with COVID-19 patients without mold co-infection.

Antifungal Treatment Duration in Hematology Patients With Invasive Mold Infections: A Real-life Update.

Background: Limited data exist on when and how to stop antifungal treatment (AFT) in patients with invasive mold infections (IMIs) who are immunocompromised. Methods: This retrospective multicenter study included adult patients with acute myelogenous leukemia and proven/probable IMI (1 January 2010-31 December 2022) in 3 university hospitals. The primary objective was to describe AFT duration and adaptation. Secondary objectives were to investigate the reasons for AFT adjustments and prolongation. Results: In total 71 patients with 73 IMIs were identified; 51 (71.8%) had an allogeneic hematopoietic cell transplant. Most infections were invasive aspergillosis (IA; 49/71, 69%), followed by mucormycosis (12, 16.9%) and other (12, 16.9%); there were 2 mixed infections. Median treatment duration was 227 days (IQR, 115.5-348.5). There was no difference in AFT duration between patients with IA and non-IA IMI (P = .85) or by center (P = .92). Treatment was longer in patients with an allogeneic hematopoietic cell transplant vs not (P = .004). Sixteen patients (22.5%) had no therapy modifications. In 55 patients (77.5%), a median 2 changes (IQR, 1-3; range, 1-8) were observed. There were 182 reasons leading to 165 changes, associated with clinical efficacy (82/182, 44.5%), toxicity (47, 25.8%), and logistical reasons (22, 12.1%); no reason was documented in 32 changes (18.8%). AFT was continued beyond days 90 and 180 in 59 (83%) and 39 (54.9%) patients, respectively, mostly due to persistence of immunosuppression. Conclusions: AFT in patients with acute myelogenous leukemia and IMI is longer than that recommended by guidelines and is frequently associated with treatment adjustments due to variable reasons. More data and better guidance are required to optimize AFT duration and secondary prophylaxis administration according to immunosuppression.

Isavuconazole for the Treatment of Fungal Infections: A Real-life Experience From the Fungal Infection Network of Switzerland (FUNGINOS).

This analysis of 116 isavuconazole therapy courses shows that hepatic test disturbances (HTDs) were relatively frequent (29% of cases) but rarely led to treatment interruption (5%). Importantly, patients with baseline HTDs, including those attributed to a first-line triazole, did not exhibit a higher risk of subsequent HTD under isavuconazole therapy.

Innate and adaptive immune responses in subjects with CPA secondary to post-pulmonary tuberculosis lung abnormalities.

BACKGROUND: Post-tuberculosis lung abnormality (PTLA) is the most common risk factor for chronic pulmonary aspergillosis (CPA), and 14%-25% of the subjects with PTLA develop CPA. The pathogenesis and the host immune response in subjects with PTLA who develop CPA need to be better understood. METHODS: We prospectively compared the innate and adaptive immune responses mounted by patients of PTLA with or without CPA (controls). We studied the neutrophil oxidative burst (by dihydrorhodamine 123 test), classic (serum C3 and C4 levels) and alternative (mannose-binding lectin [MBL] protein levels) complement pathway, serum immunoglobulins (IgG, IgM and IgA), B and T lymphocytes and their subsets in subjects with PTLA with or without CPA. RESULTS: We included 111 subjects (58 CPA and 53 controls) in the current study. The mean ± SD age of the study population was 42.6 ± 15.7 years. The cases and controls were matched for age, gender distribution and body weight. Subjects with CPA had impaired neutrophil oxidative burst, lower memory T lymphocytes and impaired Th-1 immune response (lower Th-1 lymphocytes) than controls. We found no significant difference between the two groups in the serum complement levels, MBL levels, B-cell subsets and other T lymphocyte subsets. CONCLUSION: Subjects with CPA secondary to PTLA have impaired neutrophil oxidative burst and a lower Th-1 response than controls.

Invasive Pulmonary Aspergillosis in Critically Ill Patients with Hantavirus Infection, Austria.

We investigated a cohort of 370 patients in Austria with hantavirus infections (7.8% ICU admission rate) and detected 2 cases (cumulative incidence 7%) of invasive pulmonary aspergillosis; 1 patient died. Hantavirus-associated pulmonary aspergillosis may complicate the course of critically ill patients who have hemorrhagic fever with renal syndrome.

Chronic pulmonary aspergillosis incidence in newly detected pulmonary tuberculosis cases during follow-up.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) is known to complicate patients with post-tubercular lung disease. However, some evidence suggests that CPA might co-exist in patients with newly-diagnosed pulmonary tuberculosis (P.TB) at diagnosis and also develop during therapy. The objective of this study was to confirm the presence of CPA in newly diagnosed P.TB at baseline and at the end-of-TB-therapy. MATERIALS AND METHODS: This prospective longitudinal study included newly diagnosed P.TB patients, followed up at third month and end-of-TB-therapy with symptom assessment, anti-Aspergillus IgG antibody and imaging of chest for diagnosing CPA. RESULTS: We recruited 255 patients at baseline out of which 158 (62%) completed their follow-up. Anti-Aspergillus IgG was positive in 11.1% at baseline and 27.8% at end-of-TB-therapy. Overall, proven CPA was diagnosed in 7% at baseline and 14.5% at the end-of-TB-therapy. Around 6% patients had evidence of aspergilloma in CT chest at the end-of-TB-therapy. CONCLUSIONS: CPA can be present in newly diagnosed P.TB patients at diagnosis and also develop during anti-tubercular treatment. Patients with persistent symptoms or developing new symptoms during treatment for P.TB should be evaluated for CPA. Whether patients with concomitant P.TB and CPA, while receiving antitubercular therapy, need additional antifungal therapy, needs to be evaluated in future studies.

Invasive pulmonary aspergillosis among patients with severe community-acquired pneumonia and influenza in ICUs: a retrospective cohort study.

RATIONALE: The prevalence, clinical characteristics, and outcomes of invasive pulmonary aspergillosis in patients with severe community-acquired pneumonia (CAP) in intensive care units remain underestimated because of the lack of a disease-recognition scheme and the inadequacy of diagnostic tests. OBJECTIVES: To identify the prevalence, risk factors, and outcomes of severe CAP complicated with invasive pulmonary aspergillosis (IPA) in intensive care units (ICUs). METHODS: We conducted a retrospective cohort study including recruited 311 ICU-hospitalized patients with severe CAP without influenza or with influenza. Bronchoalveolar lavage fluid (BALF) samples were from all patients and subjected to mycological testing. Patients were categorized as having proven or probable Aspergillus infection using a modified form of the AspICU algorithm comprising clinical, radiological, and mycological criteria. MEASUREMENTS AND MAIN RESULTS: Of the 252 patients with severe CAP and 59 influenza patients evaluated, 24 met the diagnostic criteria for proven or probable Aspergillus infection in the CAP group and 9 patients in the influenza group, giving estimated prevalence values of 9.5% and 15.3%, respectively. COPD and the use of inhaled corticosteroids were independent risk factors for IPA. IPA in patients with severe CAP was significantly associated with the duration of mechanical support, the length of ICU stay, and the 28-day mortality. CONCLUSIONS: An aggressive diagnostic approach for IPA patients with severe CAP and not only influenza or COVID-19 should be pursued. Further randomized controlled trials need to evaluate the timing, safety, and efficacy of antifungal therapy in reducing IPA incidence and improving clinical outcomes.

Mapping the Burden of Fungal Diseases in the United Arab Emirates.

The United Arab Emirates has very little data on the incidence or prevalence of fungal diseases. Using total and underlying disease risk populations and likely affected proportions, we have modelled the burden of fungal disease for the first time. The most prevalent serious fungal conditions are recurrent vulvovaginitis (~190,000 affected) and fungal asthma (~34,000 affected). Given the UAE's low prevalence of HIV, we estimate an at-risk population of 204 with respect to serious fungal infections with cryptococcal meningitis estimated at 2 cases annually, 15 cases of Pneumocystis pneumonia (PCP) annually, and 20 cases of esophageal candidiasis in the HIV population. PCP incidence in non-HIV patients is estimated at 150 cases annually. Likewise, with the same low prevalence of tuberculosis in the country, we estimate a total chronic pulmonary aspergillosis prevalence of 1002 cases. The estimated annual incidence of invasive aspergillosis is 505 patients, based on local data on rates of malignancy, solid organ transplantation, and chronic obstructive pulmonary disease (5.9 per 100,000). Based on the 2022 annual report of the UAE's national surveillance database, candidaemia annual incidence is 1090 (11.8/100,000), of which 49.2% occurs in intensive care. Fungal diseases affect ~228,695 (2.46%) of the population in the UAE.

Silicosis-Allergic Bronchopulmonary Aspergillosis Overlap-A Rare Duet!

Silicosis is a progressive pneumoconiosis caused by inhalation of crystalline silica dust commonly seen in workers of construction sites, flour mills, and mining. Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus antigens commonly encountered in patients with asthma and cystic fibrosis. We report a case of 60-year-old flour mill worker presented with clinico-radiological features of silicosis; further evaluation was found to have an overlap of ABPA in view of severe atopic symptoms. We describe a rare duet of silicosis with ABPA overlap.