OBJECTIVE: Mycobacterium avium complex pulmonary disease (MAC-PD) is occasionally complicated by interstitial lung disease (ILD) in clinical practice, but clinical studies are limited. This study aims to elucidate the clinical and imaging characteristics of MAC-PD in patients with ILD.
METHODS: We retrospectively analyzed imaging and clinical data from medical records of 54 consecutive ILD patients diagnosed with MAC-PD from 2011 to 2021 at our institution. We compared the imaging and clinical data of these patients with 2218 ILD patients diagnosed at our institution.
RESULTS: The mean age of the patients was 74 years, with 25 males and 29 females, and a mean body mass index (BMI) of 20.0 kg/m2. Compared to all ILD patients, ILD-associated MAC-PD had older ages, lower BMI. The most common underlying ILD diagnosis was unclassifiable interstitial pneumonia. MAC-PD imaging classification was nodular-bronchiectatic (NB) type in 17 patients, fibro-cavitary (FC) type in 15 patients, and unclassifiable (UC) type in 22 patients. Many UC types were difficult to diagnose due to the absence of clear findings indicative of MAC infection. Chronic pulmonary aspergillosis complication was 24.1 %. The mean survival of ILD-associated MAC-PD was 55.6 months, shorter than that of regular MAC-PD. The UC type had a shorter survival than the NB type, similar to the FC type.
CONCLUSIONS: MAC-PD associated with ILD frequently complicates chronic pulmonary aspergillosis and has a poor prognosis. The most common imaging type, UC type, particularly has a shorter survival. Careful management is essential for MAC-PD associated with ILD.

BACKGROUND: Reports of pulmonary aspergillosis and mucormycosis co-infections are rare; thus, limited guidance is available on early diagnosis and treatment. We present a case of mixed pulmonary Aspergillus and Mucor infection and review the literature regarding this co-infection. The diagnosis and treatment methods are summarized to improve clinicians\' understanding of the disease and to facilitate early diagnosis and treatment.
METHODS: A 60-year-old male farmer with poorly controlled diabetes mellitus was admitted to hospital with a fever of unknown origin that had been present for 15 days and pulmonary aspergillosis complicated by Mucor spp.
BACKGROUND: Because multiple lobes were involved, the infection worsened despite surgical resection and antifungal therapy. Finally, we treated this patient with a bronchoscopic infusion of amphotericin B. After four courses of bronchoscopic amphotericin B infusion, we observed rapid clinical improvement and subsequent resolution of pulmonary infiltrates.
CONCLUSIONS: Our case highlights the use of bronchoscopy in the successful clinical treatment of invasive fungal diseases of the lung.

Fungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains of Aspergillus fischeri, a non-pathogenic close relative of the major pathogen Aspergillus fumigatus. In vitro immune response assays and in vivo virulence assays using a mouse model of pulmonary aspergillosis showed that A. fischeri strains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest that A. fischeri genomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.

Chronic pulmonary aspergillosis (CPA) represents a spectrum of lung disorders caused by local proliferation of Aspergillus hyphae in individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. While long-term systemic antifungal treatment is still the mainstay for management, surgery is considered mainly in rarer invasive disease manifestations such as sinusitis and osteomyelitis. Optimal application of existing antifungal agents with suitable pharmacokinetic properties is important for the treatment of diseases such as CPA, which requires long-term use. Appropriate management of side effects by therapeutic drug monitoring, maintenance of adherence, and assessment of drug resistance to Aspergillus can provide safe and effective treatment in the future. Most available antifungal agents for the management of mycoses in humans have disadvantages that can limit their use in clinical practice. By contrast, second generation antifungals such as triazoles have advantages of extended antifungal spectrum and availability in both oral and intravenous formulations. Isavuconazole, a new extended spectrum triazole, has been shown to be effective against Aspergillus. The safety profile and excellent pharmacokinetic characteristics of isavuconazole make it an attractive option for treatment of invasive fungal infections including CPA. With this drug now available in Japan, new evidence is expected to expand treatment options. This review focuses on the selection of antifungal agents based on national and international guidelines and the characteristics of each agent for their appropriate use in CPA.

Aspergillus-specific antibodies are diagnostic indicators of allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). Tests for detecting Aspergillus-specific antibodies were not used clinically in Japan, and the production of the Aspergillus precipitin test was discontinued. Thus, alternative tests for diagnosing aspergillosis are urgently needed. We retrospectively evaluated 64 patients with suspected ABPA and CPA who underwent precipitin antibody testing. Serum Aspergillus IgG levels were measured and compared using the Bordier Aspergillus fumigatus ELISA and the Platelia Aspergillus IgG (Bio-Rad) kits. Of the participants, 18 were diagnosed with CPA, and 8 were diagnosed with ABPA. Both the Bordier and Bio-Rad kits showed high sensitivity and specificity for CPA and ABPA. The area under the receiver operating characteristic curves for the Bordier and Bio-Rad kits were 0.97 and 0.95, respectively, for CPA, and 0.89 and 0.91, respectively, for ABPA. In contrast to the Bordier kit, the Bio-Rad kit showed relatively low anti-Aspergillus IgG levels and lower sensitivity to non-fumigatus Aspergillus infections. The Aspergillus-specific IgG ELISA tests showed sufficient diagnostic accuracy. Therefore, these assays are recommended as alternatives to the precipitin kit for diagnosing aspergillosis in clinical settings in Japan.

During the COVID-19 pandemic, many patients in intensive care units (ICUs) were affected by invasive fungal infections, including aspergillosis, contributing to a high mortality rate. Diagnosing proven COVID-19-associated pulmonary aspergillosis (CAPA) requires clinical and radiological evaluations, along with laboratory testing of bronchoalveolar lavage samples or lung biopsies. However, these procedures and equipment are often inaccessible in developing countries or regions with limited resources, including Brazil. Consequently, alternative diagnostic methods, such as measuring Aspergillus galactomannan (GM) in tracheal aspirate (TA), have been explored for CAPA diagnosis. Nonetheless, research on the efficacy of TA-based diagnostic tests is limited. This study aimed to assess the performance of the IMMY® Sona Aspergillus lateral flow assay (LFA) for GM detection in TA samples from 60 ICU patients with suspected CAPA at two tertiary hospitals in Campo Grande, Brazil. The ELISA method (Platelia Aspergillus AG, Bio-Rad®) was used to detect Aspergillus GM in TA samples, serving as the microbiological criterion and reference test. Fifteen patients (12.4%) were identified as having possible CAPA. The overall accuracy of LFA was 94%, and the tests demonstrated an agreement of 93.1% (Cohen\'s kappa of 0.83). Based on our findings, the LFA for Aspergillus GM detection in TA samples exhibited excellent performance, proving to be a valuable diagnostic tool for potential CAPA. In a systematic review, two studies were included, and the meta-analysis revealed pooled estimates provided a sensitivity of 86% (95% CI, 80%-91%) and specificity of 93% (95% CI, 86%-97%). The diagnostic odds ratio (DOR) for identification of Aspergillus using LFA was 103.38 (95% CI, 38.03-281.03). Despite its lower sensitivity compared to our study, the LFA appears to be a promising diagnostic option for CAPA, particularly in suspected cases that have not received antifungal therapy. This enables timely antifungal treatment and could reduce mortality rates in regions where bronchoscopy is unavailable or limited.

OBJECTIVE: To evaluate the clinical characteristics and treatment outcomes of patients with chronic pulmonary aspergillosis (CPA) and to determine risk factors for disease recurrence.
METHODS: A total of 43 patients with CPA (mean ± SD age: 61.4 ± 10.5 years, 83.7% were males) were included in this retrospective study. Data on demographic, clinical and disease-related characteristics, galactomannan (GM) test positivity in bronchoalveolar lavage (BAL) samples, histopathological diagnosis, imaging (CT) findings and CPA forms, antifungal therapy, recurrence rate and time to recurrence were recorded.
RESULTS: Chronic obstructive pulmonary disease (COPD;76.7%) was the leading predisposing factor, and the aspergillus nodule (37.2%) was the most prevalent CPA form.GM test positivity was noted in 89.7% (35/39) of BAL samples. Median duration of voriconazole treatment was 180 days. CPA recurrence was noted in 14.0% of patients, while the comorbid tuberculosis sequela (66.7% vs. 16.2%, p = 0.02) and mild immunosuppressive disorder (100.0% vs. 51.4%, p = 0.032) were significantly more common in patients with recurrence vs. those without recurrence. Recurrence rate was 50.0% (3 of 6 patients) in patients with simple aspergilloma, and ranged from 0.0% to 25.0% in those with other CPA forms. Treatment duration and time to recurrence ranged 70-270 days and 1.1-37 months, respectively in simple aspergilloma, while they were ranged 150-180 days and 30-43.3 months, respectively in other CPA forms.
CONCLUSIONS: Our findings indicate the importance of considering CPA in differential diagnosis in patients with predisposing conditions, and emphasize the tuberculosis sequela, immunosuppressive disorder and the certain CPA forms managed with shorter duration of antifungal therapy (i.e., simple aspergilloma) as the potential risk factors of CPA recurrence.

UNASSIGNED: Metagenomic next-generation sequencing(mNGS) is a novel molecular diagnostic technique. For nucleic acid extraction methods, both whole-cell DNA (wcDNA) and cell-free DNA (cfDNA) are widely applied with the sample of bronchoalveolar lavage fluid (BALF). We aim to evaluate the clinical value of mNGS with cfDNA and mNGS with wcDNA for the detection of BALF pathogens in non-neutropenic pulmonary aspergillosis.
UNASSIGNED: mNGS with BALF-cfDNA, BALF-wcDNA and conventional microbiological tests (CMTs) were performed in suspected non-neutropenic pulmonary aspergillosis. The diagnostic value of different assays for pulmonary aspergillosis was compared.
UNASSIGNED: BALF-mNGS (cfDNA, wcDNA) outperformed CMTs in terms of microorganisms detection. Receiver operating characteristic (ROC) analysis indicated BALF-mNGS (cfDNA, wcDNA) was superior to culture and BALF-GM. Combination diagnosis of either positive for BALF-mNGS (cfDNA, wcDNA) or CMTs is more sensitive than CMTs alone in the diagnosis of pulmonary aspergillosis (BALF-cfDNA+CMTs/BALF-wcDNA+CMTs vs. CMTs: ROC analysis: 0.813 vs.0.66, P=0.0142/0.796 vs.0.66, P=0.0244; Sensitivity: 89.47% vs. 47.37%, P=0.008/84.21% vs. 47.37%, P=0.016). BALF-cfDNA showed a significantly greater reads per million (RPM) than BALF-wcDNA. The area under the ROC curve (AUC) for RPM of Aspergillus detected by BALF-cfDNA, used to predict \"True positive\" pulmonary aspergillosis patients, was 0.779, with a cut-off value greater than 4.5.
UNASSIGNED: We propose that the incorporation of BALF-mNGS (cfDNA, wcDNA) with CMTs improves diagnostic precision in the identification of non-neutropenic pulmonary aspergillosis when compared to CMTs alone. BALF-cfDNA outperforms BALF-wcDNA in clinical value.

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BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is one of the noticeable complications of COVID-19 and its incidence varies widely. In Japan, research on the incidence, risk factors and mortality associated with CAPA is limited.
OBJECTIVE: This study aimed to explore the incidence and potential risk factors for CAPA in patients with severe or critical COVID-19 and evaluate the relationship between CAPA and mortality of patients with severe or critical COVID-19.
METHODS: We investigated the incidence of CAPA in patients with severe and critical COVID-19 using administrative claims data from acute care hospitals in Japan. We employed multivariable regression models to explore potential risk factors for CAPA and their contribution to mortality in patients with severe and critical COVID-19.
RESULTS: The incidence of CAPA was 0.4%-2.7% in 33,136 patients with severe to critical COVID-19. Age, male sex, chronic lung disease, steroids, immunosuppressants, intensive care unit admission, blood transfusion and dialysis were potential risk factors for CAPA in patients with severe to critical COVID-19. CAPA was an independent factor associated with mortality.
CONCLUSIONS: CAPA is a serious complication in patients with severe and critical COVID-19 and may increase mortality.