Aspergillus nodules: Natural history and the effect of antifungals.

BACKGROUND: Aspergillus nodules are classified as a subset of chronic pulmonary aspergillosis. The optimal management approach is not known as their natural evolution following biopsy, the rate of progression to chronic cavitary pulmonary aspergillosis (CCPA) and the effect of antifungal treatment have not been described. OBJECTIVES: To describe the clinical course of patients diagnosed with Aspergillus nodules and the effect of antifungal treatment. PATIENTS/METHODS: We present a series of 23 patients with histologically confirmed Aspergillus nodules and describe serial imaging, antifungal treatment and progression to other diagnoses. RESULTS: Thirteen patients were diagnosed after a CT-guided biopsy and 10 after surgical resection. Among those who had CT-guided biopsy, 8 did not receive antifungal treatment; the nodule was stable or smaller in all cases on subsequent CT scan after a mean of 15.5 months. However, one patient developed squamous cell carcinoma after 16 months and another developed CCPA after 7 months. Among the 5 patients who received antifungals for at least 4 weeks, the nodule was smaller in 1 and stable in 4. One patient developed CCPA 3 years after the biopsy. No patient who had a surgical resection subsequently had a CCPA diagnosis. CONCLUSION: Most Aspergillus nodules remained stable or improved following biopsy, irrespective of the effect of antifungals. However, CCPA can develop occasionally in patients with Aspergillus nodules and ongoing radiological follow-up may be warranted when the nodule is not resected.

Chronic pulmonary aspergillosis - a guide for the general physician.

This collaborative article presents a review of chronic pulmonary aspergillosis (CPA) from the perspective of a multidisciplinary team comprising of respiratory physicians, radiologists, mycologists, dietitians, pharmacists, physiotherapists and palliative care specialists. The review synthesises current knowledge on CPA, emphasising the intricate interplay between clinical, radiological, and microbiological aspects. We highlight the importance of assessing each patient as multidisciplinary team to ensure personalised treatment strategies and a holistic approach to patient care.

Pulmonary cryptococcosis complicated with pulmonary aspergillosis: a series of studies and a literature review.

BACKGROUND/OBJECTIVE: With the development of society, pulmonary fungal diseases, represented by pulmonary aspergillosis and pulmonary cryptococcosis, have become increasingly common. However, there is a lack of clear understanding regarding coinfection by these two types of fungi in immunocompetent individuals. METHODS: A retrospective study from 2014 to 2022 and a systematic literature review of original articles published in English were performed. Patients with pulmonary cryptococcosis complicated with pulmonary aspergillosis including 5 in the retrospective study and 6 in the systematic literature review. RESULT: The diagnosis of concurrent pulmonary cryptococcosis and pulmonary aspergillosis in patients was confirmed through repeated biopsies or surgical resection. Pulmonary cryptococcosis is often diagnosed initially (6/11, 55%), while the diagnosis of pulmonary aspergillosis is established when the lesions become fixed or enlarged during treatment. Transbronchial lung biopsy (3/11, 27%), thoracoscopic lung biopsy (2/11, 18%), and percutaneous aspiration biopsy of the lung (1/11, 9%) were the main methods to confirm concurrent infection. Most patients were treated with voriconazole, resulting in a cure for the coinfection (6/11, 55%). CONCLUSION: Pulmonary cryptococcosis complicated with pulmonary Aspergillus is an easily neglected mixed fungal infection. During the treatment of lesion enlargement in clinical cryptococcus, we need to watch out for Aspergillus infection.

Pulmonary Aspergillosis in People with Cystic Fibrosis.

In the last decade, fungal respiratory diseases have been increasingly investigated for their impact on the clinical course of people with cystic fibrosis (CF), with a particular focus on infections caused by Aspergillus spp. The most common organisms from this genus detected from respiratory cultures are Aspergillus fumigatus and Aspergillus terreus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus nidulans. These species have been identified to be both chronic colonizers and sources of active infection and may negatively impact lung function in people with CF. This review article discusses definitions of aspergillosis, challenges in clinical practice, and current literature available for laboratory findings, clinical diagnosis, and treatment options for pulmonary diseases caused by Aspergillus spp. in people with CF.

Antifungal Resistance in Pulmonary Aspergillosis.

Aspergilli may cause various pulmonary diseases in humans, including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and acute invasive pulmonary aspergillosis (IPA). In addition, chronic colonization may occur in cystic fibrosis (CF). Aspergillus fumigatus represents the main pathogen, which may employ different morphotypes, for example, conidia, hyphal growth, and asexual sporulation, in the various Aspergillus diseases. These morphotypes determine the ease by which A. fumigatus can adapt to stress by antifungal drug exposure, usually resulting in one or more resistance mutations. Key factors that enable the emergence of resistance include genetic variation and selection. The ability to create genetic variation depends on the reproduction mode, including, sexual, parasexual, and asexual, and the population size. These reproduction cycles may take place in the host and/or in the environment, usually when specific conditions are present. Environmental resistance is commonly characterized by tandem repeat (TR)-mediated mutations, while in-host resistance selection results in single-resistance mutations. Reported cases from the literature indicate that environmental resistance mutations are almost exclusively present in patients with IA indicating that the risk for in-host resistance selection is very low. In aspergilloma, single-point mutations are the dominant resistance genotype, while in other chronic Aspergillus diseases, for example, ABPA, CPA, and CF, both TR-mediated and single-resistance mutations are reported. Insights into the pathogenesis of resistance selection in various Aspergillus diseases may help to improve diagnostic and therapeutic strategies.

Chronic Pulmonary Aspergillosis Caused by Aspergillus tubingensis Diagnosed by a Bronchoscopic Biopsy.

We herein report a case of chronic pulmonary aspergillosis (CPA) caused by Aspergillus tubingensis diagnosed by a bronchoscopic biopsy with negative serological and sputum culture findings. A 66-year-old man was referred for the assessment of a pulmonary cavity. Computed tomography showed a thick-walled cavity in the upper right pulmonary lobe. Serum ß-D glucan, Aspergillus galactomannan, and Aspergillus antibody tests were negative. Aspergillus species were not detected in the sputum. Culture and pathological specimens were obtained from the mass by bronchoscopy. Microscopic examination findings were consistent with Aspergillus niger complex morphologically and identified as Aspergillus tubingensis through DNA sequencing. The patient was diagnosed with chronic pulmonary aspergillosis.

Risk Factors of Chronic Pulmonary Aspergillosis in Patients with Etiology Positive Pulmonary Tuberculosis.

Objective: Pulmonary tuberculosis (PTB) and chronic pulmonary aspergillosis (CPA) have many similarities in clinical symptoms. In patients with etiology-positive pulmonary tuberculosis (EPTB), Aspergillus infection is easily overlooked, and missed diagnosis occurs. We attempted to analyze the clinical characteristics and risk factors of EPTB combined with CPA (EPTB-CPA), and to suggest to clinicians the possibility of CPA in EPTB patients. Methods: 58 patients with EPTB-CPA diagnosed and treated in Wuhan Pulmonary Hospital from April 2021 to March 2022 were retrospectively collected as the case group. According to the age group of the case group, 174 patients with EPTB were randomly selected as the control group at a ratio of 1:3. Multivariate logistic regression analysis was utilized to analyze the risk factors. Results: Multivariate Logistic regression analysis was performed on the pulmonary cavity, chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, lung damage, anemia, and hypoproteinemia. Among them, pulmonary cavity (P = .001), COPD (P = .006), and bronchiectasis (P = .020) were statistically significant. Conclusion: Our findings suggest that when EPTB patients present with pulmonary cavities and comorbidities such as COPD or bronchiectasis, clinicians should consider the possibility of CPA. Identifying these risk factors can help improve the accuracy of diagnosis and facilitate early detection and management of EPTB-CPA.

An immunocompetent case of chronic pulmonary aspergillosis caused by Aspergillusviridinutans.

We encountered an extremely rare immunocompetent case of chronic pulmonary aspergillosis (CPA) caused by Aspergillus viridinutans. A 74-year-old woman was admitted with fever and hemoptysis. Chest computed tomography revealed a nodule in the left upper lobe. Bronchoscopy was performed, and the transbronchial biopsy specimen revealed Aspergillus fungi. Treatment of the nodule was initially ineffective with voriconazole but effective with liposomal amphotericin B. The causative organism was later identified as A. viridinutans based on the gene sequence of ß-tubulin. This is the first immunocompetent case of CPA caused by A. viridinutans.

Chronic Pulmonary Aspergillosis: Clinical Presentation and Management.

Chronic pulmonary aspergillosis (CPA) refers to a number of clinical syndromes resulting from the presence and local proliferation of Aspergillus organisms in the lungs of patients with chronic lung disease. CPA is more common than was realized two decades ago. Recognition remains poor, despite recent studies from many countries highlighting the high prevalence in at-risk populations. In low- and middle-income countries, CPA may be misdiagnosed and treated as tuberculosis (TB). In addition, CPA may develop following successful TB treatment. The coronavirus disease pandemic has resulted in significant disruption to provision of TB care, likely leading to more extensive lung damage, which could increase the risk for CPA.Although CPA refers to various syndromes, the classic presentation is that of chronic cavitary pulmonary aspergillosis, which manifests as one or more progressive cavities with or without a fungal ball, accompanied by systemic and respiratory symptoms for at least 3 months. Diagnosis relies on Aspergillus immunoglobulin G in serum, as sputum culture lacks sensitivity. Differential diagnosis includes mycobacterial infection, bacterial lung abscess or necrotizing pneumonia, lung cancer, and endemic fungi.The aim of antifungal treatment in CPA is to improve symptoms and quality of life, and to halt progression, and possibly reverse radiological changes. Current recommendations suggest treatment for 6 months, although in practice many patients remain on long-term treatment. Improvement may manifest as weight gain and improvement of symptoms such as productive cough, hemoptysis, and fatigue. Surgical management should be considered in cases of diagnostic uncertainty, in significant hemoptysis, and when there is concern for lack of response to therapy. Itraconazole and voriconazole are the first-line azoles, with more experience now accumulating with posaconazole and isavuconazole. Side effects are frequent and careful monitoring including therapeutic drug monitoring is essential. Intravenous antifungals such as echinocandins and amphotericin B are used in cases of azole intolerance or resistance, which often develop on treatment. Relapse is seen after completion of antifungal therapy in around 20% of cases, mostly in bilateral, high-burden disease.Several research priorities have been identified, including characterization of immune defects and genetic variants linked to CPA, pathogenetic mechanisms of Aspergillus adaptation in the lung environment, the contribution of non-fumigatus Aspergillus species, and the role of new antifungal agents, immunotherapy, and combination therapy.

Left Lung High-Density Shadow Combined with Elevated NSE Ultimately Confirmed as Pulmonary Aspergillosis.

BACKGROUND: Detection of serum neuron specific enolase (NSE) has high sensitivity and specificity in the diagnosis of lung cancer, especially small cell lung cancer, but sometimes serum NSE provides limited help. We report a case of high-density shadow of the left lung and elevated serum NSE which mimicked lung cancer. It was ultimately confirmed to be pulmonary aspergillosis (PA) by bronchoscopic alveolar lavage fluid (BALF) and next-generation sequencing (NGS). METHODS: Appropriate laboratory tests, chest computed tomography (CT) scan, bronchoscopic alveolar lavage fluid, and next-generation sequencing were used to explore latent causes. RESULTS: NSE level was elevated, chest CT scan showed high-density shadow of the left lung, bronchoscopy showed flesh-colored new organisms in the lower lobe of the left lung, BALF and NGS revealed the presence of Aspergillus. CONCLUSIONS: Elevated NSE is not a typical manifestation of lung cancer, and we should perform BALF and NGS early to determine whether there is infection with special pathogenic bacteria.

The Utility of Galactomannan and Polymerase Chain Reaction Assays in Bronchoalveolar Lavage for Diagnosis of Chronic Pulmonary Aspergillosis.

The diagnosis of chronic pulmonary aspergillosis (CPA) is established by combined clinic-radio-microbiological criteria. Out of the different microbiological criteria, a positive serology for Aspergillus-specific IgG levels is the cornerstone of diagnosis. Alternatively, other microbiological evidence are sometimes sought viz., positive Aspergillus antigen (broncho-alveolar lavage fluid, i.e., BALF galactomannan ≥ 1.0), histopathological demonstration of the fungi following lung biopsy or resection, demonstration of hyaline septate hyphae in direct microscopy resembling Aspergillus spp. or its growth on a respiratory specimen. However, the exact roles of BALF- GM and the newer BALF-PCR have not been confirmed by studies till date. This study enrolled 210 patients with suspected CPA. Of the participants, 88 patients met the criteria for CPA, whereas 122 patients had an alternative diagnosis. The sensitivity-specificity of AsperGenius® PCR and "in-house" PCR were 52.27(36.69-67.54) %-33.78 (23.19-45.72) % and 36.36 (22.41-52.23) %-39.19 (28.04-51.23) % respectively. The sensitivity/specificity of BALF (> 1.0) and serum galactomannan (> 1.0) were 46.55% (33.34-60.13)/64.08% (54.03-73.3) and 29.82% (22.05-37.6)/86.84% (81.1-92.59) respectively. The optimal cut-off values for BALF-Galactomannan and serum galactomannan in diagnosing CPA were found to be 0.69 (sensitivity: 64%; specificity: 53%) and 0.458 (sensitivity: 67%; specificity: 64%) respectively. This results of this study suggests that Aspergillus PCR from BAL may not be a good "rule-in" test for diagnosing CPA. While the performances of GM in BAL and serum may be better than PCR, it should be best used in conjunction with other clinical, radiological, and other microbiological characteristics.

Lady Windermere syndrome with haemoptysis: suspected pulmonary aspergilloma and MAC pulmonary disease.

We present a case of a woman in her 70s, with a history of Mycobacterium avium complex (MAC) pulmonary disease, pectus excavatum, s-shaped thoracolumbar scoliosis, bronchiectasis of the right middle lobe, lingula of left upper lobe, and malnutrition with low body mass index of 14 kg/m2, who presented to the hospital due to worsening shortness of breath and small volume haemoptysis over 2 weeks. The patient was diagnosed with pulmonary MAC infection for the first time in 1999 without known history of pulmonary disease. Later on, it was complicated by massive haemoptysis requiring bronchial artery embolisation; however, she was unable to complete an oral antibiotic regimen due to gastrointestinal adverse reactions. Chest CT identified a newly found mass in the left upper lobe bulla, consistent with a radiological finding of aspergilloma. We present a rare symptoms constellation, described as 'Lady Windermere syndrome' and chronic untreated MAC infection progressing from reticulonodular changes to fibrocavitary lung disease and suspected aspergilloma formation.

Prevalence and predictors of Aspergillus seropositivity and chronic pulmonary aspergillosis in an urban tertiary hospital in Sierra Leone: A cross-sectional study.

BACKGROUND: In the World Health Organization Global Tuberculosis (TB) Report 2022, 37% of pulmonary TB patients were clinically diagnosed and thus many people were treated for TB without evidence of the disease. Probably the most common TB misdiagnosis is chronic pulmonary aspergillosis (CPA). In this study, we aimed to assess the prevalence and predictors of Aspergillus seropositivity and CPA in patients with chronic respiratory symptoms in an urban tertiary hospital in Sierra Leone. METHODOLOGY/PRINCIPAL FINDINGS: We used a cross-sectional study design to recruit adults (≥18 years) from the Chest Clinic of Connaught Hospital, Freetown between November 2021 and July 2022. Aspergillus antibody was detected using LDBio Aspergillus IgM/IgG. Logistic regression was performed to assess the independent predictors of Aspergillus seropositivity and CPA. Of the 197 patients with chronic respiratory symptoms, 147 (74.6%) were male. Mean age was 47.1 ± 16.4 years. More than half (104, 52.8%) had been diagnosed with TB in the past, while 53 (26.9%) were on TB treatment at the time of recruitment. Fifty-two (26.4%) patients were HIV positive, 41 (20.8%) were seropositive for Aspergillus and 23 (11.6%) had CPA, 2 (3.8%) with current TB and 18 (17.3%) with past TB. Common radiologic abnormalities reported were localized fibrotic changes 62 (31.5%), consolidation 54 (27.4%), infiltrates 46 (23.4%), hilar adenopathy 40 (20.3%) and pleural effusion 35 (17.85) and thickening 23 (11.7%). Common symptoms were weight loss 144 (73.1%), cough 135 (68.5%), fever 117 (59.4%) and dyspnea 90 (45.7%). Current or past TB infection {aOR 3.52, 95% CI (1.46, 8.97); p = 0.005} was an independent predictor of Aspergillus seropositivity and CPA. CONCLUSIONS/SIGNIFICANCE: We report a high prevalence of Aspergillus antibody seropositivity and CPA, underscoring the need to integrate the prevention and management of pulmonary fungal infections with TB services and asthma care in order to reduce unnecessary morbidity and mortality.

Diagnostic Laboratory Features and Performance of an Aspergillus IgG Lateral Flow Assay in a Chronic Pulmonary Aspergillosis Cohort.

Chronic pulmonary aspergillosis (CPA) is a chronic and progressive fungal disease with high morbidity and mortality. Avoiding diagnostic delay and misdiagnosis are concerns for CPA patients. However, diagnostic practice is poorly evaluated, especially in resource-constrained areas where Aspergillus antibody testing tools are lacking. This study aimed to investigate the diagnostic laboratory findings in a retrospective CPA cohort and to evaluate the performance of a novel Aspergillus IgG lateral flow assay (LFA; Era Biology, Tianjin, China). During January 2016 and December 2021, suspected CPA patients were screened at the Center for Infectious Diseases at Huashan Hospital. A total of 126 CPA patients were enrolled. Aspergillus IgG was positive in 72.1% with chronic cavitary pulmonary aspergillosis, 75.0% with chronic necrotizing pulmonary aspergillosis, 41.7% with simple aspergilloma, and 30.3% with Aspergillus nodule(s). The cavitary CPA subtypes had significantly higher levels of Aspergillus IgG. Aspergillus IgG was negative in 52 patients, who were finally diagnosed by histopathology, respiratory culture, and metagenomic next-generation sequencing (mNGS). Sputum culture was positive in 39.3% (42/107) of patients and Aspergillus fumigatus was the most common species (69.0%, 29/42). For CPA cohort versus controls, the sensitivity and specificity of the LFA were 55.6% and 92.7%, respectively. In a subgroup analysis, the LFA was highly sensitive for A. fumigatus-associated chronic cavitary pulmonary aspergillosis (CCPA; 96.2%, 26/27). Given the complexity of the disease, a combination of serological and non-serological tests should be considered to avoid misdiagnosis of CPA. The novel LFA has a satisfactory performance and allows earlier screening and diagnosis of CPA patients. IMPORTANCE There are concerns on avoiding diagnostic delay and misdiagnosis for chronic pulmonary aspergillosis due to its high morbidity and mortality. A proportion of CPA patients test negative for Aspergillus IgG. An optimal diagnostic strategy for CPA requires in-depth investigation based on real-world diagnostic practice, which has been rarely discussed. We summarized the clinical and diagnostic laboratory findings of 126 CPA patients with various CPA subtypes. Aspergillus IgG was the most sensitive test for diagnosing CPA. However, it was negative in 52 patients, who were finally diagnosed by non-serological tests, including biopsy, respiratory culture, and metagenomic next-generation sequencing. We also evaluated a novel Aspergillus IgG lateral flow assay, which showed a satisfactory performance in cavitary CPA patients and was highly specific to Aspergillus fumigatus. This study gives a full picture of the diagnostic practice for CPA patients in Chinese context and calls for early diagnosis of CPA with combined approaches.

Cavitary lung metastases of mixed metaplastic breast cancer mimicking aspergilloma.

We report a case of a 57-year-old woman with pulmonary metastasis of breast cancer presenting with a characteristic cavitary shadow resembling aspergilloma. The primary tumor and metastases showed multiple histopathologic components, including squamous cell carcinoma. Although a fungal ball-like shadow may indicate the presence of a pulmonary aspergilloma, a comprehensive examination, including bronchoscopy, should be considered.

Instillation of Amphotericin B by bronchoscopy combined with systemic voriconazole in advanced non-small cell lung cancer patients with chronic cavitary pulmonary aspergillosis: A case series and literature review.

Although the treatment of aspergillosis has been studied for years, the optimal nonsurgical treatment of chronic cavitary pulmonary aspergillosis (CCPA) remains unsatisfactory, especially in lung cancer. We report two advanced non-small cell lung cancer (NSCLC) patients who recovered from CCPA following instillation of Amphotericin B (AmB) by bronchoscopy combined with systemic voriconazole. The first patient was diagnosed with lung adenocarcinoma after right upper lobe resection and was treated with anaplastic lymphoma kinase-targeted therapy. Chest computed tomography (CT) revealed a right pulmonary cavity containing solid materials. The second patient was diagnosed with squamous cell carcinoma and received immunotherapy following surgery, chemotherapy, and radiotherapy. Chest CT tomography revealed a mass in the right lung cavity. Both patients' cultures and next-generation sequencing of their bronchoalveolar lavage (BAL) samples revealed presence of Aspergillus fumigatus. In addition, the galactomannan test of both patients BAL samples was positive. Systemic voriconazole was prescribed based on in vitro susceptibility testing. The chest images and clinical symptoms of both patients did not improve after one month of voriconazole therapy within the therapeutic blood concentration. Considering the low local concentrations of antifungals against CCPA, AmB instillation by bronchoscopy combined with systemic voriconazole was utilized. The chest CT images and clinical symptoms of both patients markedly improved in the following third month. Instillation of AmB combined with systemic voriconazole may be a promising treatment option for NSCLC patients with CCPA who fail voriconazole monotherapy.

Challenges, Characteristics, and Outcomes of Chronic Pulmonary Aspergillosis: A 11-Year Experience in A Middle-Income Country.

OBJECTIVES: Chronic pulmonary aspergillosis (CPA) is a research priority in fungal diseases with a need for new studies to reduce misdiagnosis with more common diseases, discuss improvement in diagnostic methods and better characterize gaps in antifungal and surgical treatments to improve clinical outcomes. METHODS: In this retrospective study, we reviewed medical records of patients diagnosed with CPA from January 2010 to June 2021 at University of São Paulo, São Paulo, Brazil. We evaluated clinical characteristics, radiological findings, serology, treatment, and outcomes. RESULTS: The study included 91 participants, with 43 (47.3%) patients who underwent surgery and 69 (75.8%) received antifungal therapy. We found a predominance of middle-aged adults (median 51 years), males (n = 58, 64%) with lower BMI (median 21.3 kg/m2). The most common underlying lung disease was pulmonary tuberculosis (n = 70, 76.9%). The commonest symptoms were cough (n = 67, 74%), haemoptysis, and dyspnea (n = 63, 70%). The most common chest computerized tomography abnormalities were cavity (n = 86, 94.5%), with a predominance of mycetomas (n = 78, 91%). The serology was positive in 81% (61/75). The one-year mortality was low (3.3%). Clinical improvement and stability occurred in 89% of participants for constitucional symptoms and 86% for pulmonary symptoms. While serological improvement and stability occurred in 71%. Radiological improvement and stability occurred in 75%. CONCLUSION: We observed a good outcome after 1-year follow-up, in which the majority had improvement or stability of pulmonary and constitutional symptoms, decrease in CIE titers and low mortality.

Coexistence of human immunodeficiency virus, active pulmonary tuberculosis, and aspergilloma: A rare entity.

Tuberculosis (TB) constitutes a significant burden of infectious diseases worldwide. TB and human immunodeficiency virus (HIV) coinfection potentiate each other, which has a negative impact on the disease progression. Aspergillus colonizing a preexisting parenchymal tubercular cavity is referred to as aspergilloma. Aspergilloma occurring in a patient with active TB is unusual. We report the case of a 50-year-old male who presented to us with complaints of cough and recurrent hemoptysis for 3 months. Clinical and radiological examination revealed right upper lobe aspergilloma. A right upper lobectomy was done and a histopathological examination showed evidence of active TB. The patient was started on antitubercular therapy (ATT) followed by antiretroviral therapy (ART). The presence of active TB should not be overlooked in a patient with aspergilloma, especially in immune-compromised individuals such as people living with HIV, as definitive treatment with surgical resection, and ATT along with ART has better outcomes.