Allergic asthma has traditionally been treated with inhaled and systemic glucocorticosteroids. A continuum of allergic fungal airways disease associated with Aspergillus fumigatus colonization and/or atopic immune responses that encompasses fungal asthma, severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis is now recognized along a phenotypic severity spectrum of T2-high immune deviation lung disease. Oral triazoles have shown clinical, anti-inflammatory and microbiologic efficacy in this setting; in the future inhaled antifungals may improve the therapeutic index. Humanized monoclonal antibody biologic agents targeting T2-high disease also show efficacy and promise of improved control in difficult cases. Developments in these areas are highlighted in this overview.

The prevalence of fungal infections is increasing worldwide, especially that of aspergillosis, which previously only affected people with immunosuppression. Aspergillus fumigatus can cause allergic bronchopulmonary aspergillosis and endangers public health due to resistance to azole-type antimycotics such as fluconazole. Antifungal peptides are viable alternatives that combat infection by forming pores in membranes through electrostatic interactions with the phospholipids as well as cell death to peptides that inhibit protein synthesis and inhibit cell replication. Engineering antifungal peptides with nanotechnology can enhance the efficacy of these therapeutics at lower doses and reduce immune responses. This manuscript explains how antifungal peptides combat antifungal-resistant aspergillosis and also how rational peptide design with nanotechnology and artificial intelligence can engineer peptides to be a feasible antifungal alternative.

Pulmonary aspergillosis is generally categorized into three groups: allergic bronchopulmonary aspergillosis, chronic pulmonary aspergillosis and invasive pulmonary aspergillosis. Aspergillus overlap syndromes (AOS) defined as the occurrence of more than one form of aspergillus disease in a single individual is not common. We present a 62-year-old-male patient with tachypnea, hypoxemia and shock after 4 weeks of cough, expectoration and intermittent hemoptysis, and 2 days of hyperpyrexia. Cardiac arrest occurring during tracheal intubation was resuscitated successfully. Laboratory examination showed acute kidney failure and severe myelosuppression with leukopenia and thrombocytopenia. Chest computed tomography (CT) scan showed the cavity with aspergilloma in the right upper lung lobe, a mass of consolidation in the right lower lung lobe and hyperdense shadow bronchiectasis in the left lower lobe. Bronchoscopy showed lots of sputum occluding the opening of the right airway bronchus. Laboratory examination showed significantly increased C-reactive protein (CRP) and procalcitonin concentration, serum (1,3)-β-D-glucan (BDG) and aspergillus immunoglobulin G (IgG) levels were also elevated. The metagenomic next-generation sequencing and sputum cultures revealed Klebsiella pneumoniae and Aspergillus flavus infection. Pulmonary aspergillosis, invasive aspergillosis infection and severe pneumonia were diagnosed. Initial caspofungin and meropenem followed by piperacillin-tazobactam sodium and voriconazole were administrated in combination. Continuous renal replacement therapy and mechanical ventilation were also performed. The patient's condition gradually recovered. Oral antifungal therapy was continued for 1 year after discharge and CT images gradually improved. Coinfections with K. pneumoniae and A. flavus in a patient with AOS will complicate clinical conditions. A search of PubMed showed few reports of similar cases. Clinicians should pay enough attention to the polymicrobial interactions and improve clinical management strategies, especially in critically ill patient with AOS.

A 56-year-old woman who had allergic bronchopulmonary mycosis (ABPM) with nontuberculous mycobacteriosis (NTM) was treated with prednisone. After treatment, her respiratory symptoms, eosinophil count, and infiltrative shadow diminished. However, when the dosage of prednisone was tapered and finally stopped, the eosinophil count increased and the infiltrative shadow returned. Since there was a risk of exacerbation of NTM, benralizumab without prednisone was administrated, which improved the patient's respiratory symptoms and eosinophil count, while the infiltrative shadow remained. When the dosage of prednisone was restarted, the shadow disappeared. After prednisone discontinuation, no exacerbation of the shadows nor relapse were observed. In recent years, clinical usefulness of biologics like benralizumab for ABPM has been reported, but evidence to support their use is insufficient. Furthermore, it is expected that the number of the combined cases of NTM and ABPM will increase with the increase in NTM; however, reports of biologics for the management of both cases are extremely rare. The risk of complications of infectious diseases, interaction with antifungal drugs, and steroid sparing effects should be considered when deciding the treatment strategy. Accumulation of more cases in the future may lead to the establishment of a treatment method for the combined cases of NTM and ABPM.

A 29-year-old man presented to our hospital with severe eosinophilic asthma. He needed a short OCS burst for exacerbation of asthma once every 1 or 2 months, although he used a high dose of inhaled corticosteroids and a long-acting beta-2 agonists. Chest CT showed multiple mucous plugs with bronchiectasis, but further examination found that he did not meet the diagnostic criteria for allergic bronchopulmonary aspergillosis. After starting dupilumab for his severe eosinophilic asthma, his asthma control improved without exacerbation. Furthermore, most mucus plugs disappeared on chest CT after 16 weeks from initiating dupilumab. This case suggests that dupilumab may be an effective treatment against mucus plugs associated with severe eosinophilic asthma.

Pulmonary aspergillosis may be classified under three categories depending on whether the patient is atopic or immunocompromised: invasive, chronic necrotizing, and allergic bronchopulmonary aspergillosis (ABPA), which is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus spp., manifesting with poorly controlled asthma. ABPA is diagnosed using major and minor criteria. Herein, we present two ABPA cases with endobronchial signs on bronchoscopy. Asthmatic 31-year-old male and 59-year-old female patients were admitted with dyspnea and bilateral rhonchi. Total IgE levels were elevated. Peripheral eosinophilia was also present. Chest computed tomography revealed consolidated areas, peribronchial micronodules, ground-glass appearance, and increased nodular densities. Bronchoscopy showed brownish-yellow membranes on the bronchial mucosa of these patients. Aspergillus spp. growth was observed in bronchial lavage culture. ABPA is a curable disease only if diagnosed correctly. Notwithstanding the large number of cases reported to date, we aimed to emphasize the importance of bronchoscopic examination in endobronchial fungal infections.

As an allergic lung disease caused by Aspergillus species, allergic bronchopulmonary aspergillosis(ABPA) is manifested by asthma and recurrent lung infiltrates, often with signs of bronchiectasis. ABPA is not uncommon, but under-diagnosis/misdiagnosis and inappropriate management are common in clinical practice, due to the varied manifestations, inconsistent diagnostic criteria, and the need of complicated laboratory studies. To improve the diagnosis and treatment of ABPA, experts of the Asthma Group of Chinese Thoracic Society proposed an expert consensus on the diagnosis and treatment of ABPA in 2017 (1 st Edition). Its publication has been well received by the Chinese physicians, and promoted the appropriate management of the disease. In the past 5 years, advances have been made in the investigation into the mechanisms, and in the diagnosis and therapy of ABPA, including novel insight into the pathogenesis, more studies of the diagnostic criteria, and more evidence on the efficacy of glucocorticoid, antifungal and/or biologic therapies. Based on new evidence and the clinical practice in China, experts of the Asthma Group of Chinese Thoracic Society updated the consensus.

When Aspergillus, an ubiquitous, saprophytic fungus, is detected in respiratory tract specimens collected from chronic respiratory disease patients, it is important to determine whether it is a true infection or colonization. We investigated the usefulness of the Bio-Rad Platelia Aspergillus IgG (Platelia Aspergillus IgG) enzyme-linked immunosorbent assay (ELISA) method and the Aspergillus precipitin test to distinguish pulmonary aspergillosis from colonization. Between January 2017 and November 2021, 51 confirmed, untreated pulmonary aspergillosis (33 chronic pulmonary aspergillosis [CPA] and 18 allergic bronchopulmonary aspergillosis [ABPA]) and 77 colonization patients were included in this study. At first, the conventional cutoff value was utilized in assessing the validity of the two antibody tests for distinguishing pulmonary aspergillosis from colonization. The Platelia Aspergillus IgG cutoff value was then reevaluated to fit this situation. Finally, differences in test accuracy dependent on Aspergillus species were assessed for both antibody tests by comparing cases with Aspergillus fumigatus complex and those with non-fumigatus Aspergillus complex. Both antibody tests demonstrated significantly higher positive rates for pulmonary aspergillosis (P < 0.0001) than colonization. The cutoff value should be 15.7 arbitrary units (AU)/mL to best distinguish infection from colonization, which was higher than the conventional value of 10 AU/mL. The diagnostic sensitivity of Platelia Aspergillus IgG for the non-fumigatus Aspergillus complex was inferior to the A. fumigatus complex (P = 0.019). In conclusion, both Aspergillus antibody tests were valid to distinguish infection from colonization, although we should note the higher cutoff value for Platelia Aspergillus IgG and the lower sensitivity in cases of non-fumigatus Aspergillus infection. IMPORTANCE Pulmonary aspergillosis is the most common pulmonary fungal infection. However, Aspergillus is a ubiquitous, saprophytic fungus; it can be detected in respiratory specimens even in the absence of infection. Especially since Aspergillus is detected in respiratory specimens collected from patients with chronic respiratory disease, it is important to determine whether it is true infection or colonization. We investigated the validity of the Platelia Aspergillus IgG ELISA method and the Aspergillus precipitin test to distinguish pulmonary aspergillosis from colonization. Both antibody tests were considered useful in differentiating true infection from colonization in respiratory practice. The appropriate cutoff value for Platelia Aspergillus IgG was higher than the conventional value, and it was also noted that the sensitivity of both antibody tests for non-fumigatus Aspergillus complex was low. This study will be significant in real-world clinical practice of pulmonary aspergillosis using antibody tests in respiratory care.

A man in his 80s with no known comorbidities presented with diffuse swelling on the dorsal aspect of his right forearm for 3 months. Clinical features were suggestive of soft tissue sarcoma of the right forearm. A high resolution CT scan of the thorax showed allergic bronchopulmonary aspergillosis associated with mild mediastinal lymphadenopathy. MRI of the right upper limb showed a suspicious neoplastic/infective aetiology. A core biopsy of the right arm swelling found a granuloma with no malignancy features so an incisional biopsy of the lesion was carried out. This indicated granulomatous inflammation with excessive giant cell reaction and focal panniculitis with the possibility of a mycotic lesion. Bronchoalveolar lavage was negative for tuberculosis and fungal infection. After a multidisciplinary team discussion, the patient was started on antifungal medication. There was a marked reduction in both the size and consistency of the swelling after several weeks of oral itraconazole and potassium iodide solution. The purpose of this report is to increase the awareness of this uncommon treatable condition which, if misdiagnosed, could result in an inappropriate intervention.

Chest computed tomography (CT) of a 76-year-old woman with bronchial asthma showed multiple lung nodules with high CT densities that were compatible with high-attenuation mucoid (HAM) impactions characteristic of allergic bronchopulmonary mycosis (ABPM). Follow-up chest CT revealed increased sizes of multiple lung nodules. However, a left upper lobe nodule showed lower CT density than the other HAM impactions. A transbronchial lung biopsy of that upper lobe nodule revealed lung adenocarcinoma. Measuring the CT density is important for the differential diagnosis of lung nodules when following ABPM patients. Our patient's increased serum carcinoembryonic antigen levels were associated with peripheral blood eosinophilia. Mucoid impaction in the lung was positively stained with carcinoembryonic antigen and showed the distribution of eosinophilic granules.

A male patient in his 20s presented with a cough and a small volume of haemoptysis that lasted a year. He had no other constitutional symptoms and a respiratory examination was suggestive of a consolidation. A chronic infection, such as tuberculosis, was suspected. The routine evaluation showed peripheral eosinophilia with raised serum total IgE. Sputum examination for tuberculosis was negative; hence, a high-resolution CT of the thorax was performed, which revealed bilateral bronchiectasis with high-attenuation mucus plugging. The imaging and blood profiles were in favour of allergic bronchopulmonary aspergillosis, but there was no history suggestive of asthma, and the pulmonary function test was normal. The patient underwent a skin prick test and an allergen-specific IgE test for Aspergillus fumigatus, and both were positive. His bronchoalveolar lavage cultures also grew A. fumigatus, and he responded well to antifungal therapy. This case illustrates the presentation of a rare entity-allergic bronchopulmonary aspergillosis sans asthma.

Mucoid impaction of the bronchi (MIB) is a specific form of proximal bronchiectasis characterized by obstruction and dilation of bronchi usually presented with thick mucoid plug. MIB mostly occurs as the manifestation of a hypersensitivity state in patients with bronchial asthma or in association with allergic bronchopulmonary aspergillosis (ABPA) and clinical overlap between MIB and ABPA can occur. MIB with no history of allergic background is not common and is less reported in the literature. In the following report we discuss a 39-year-old man with no previous history of allergy and atopy who initially presented with fever and shortness of breath. Further assessments demonstrated that the patient had a chronic endobronchial lesion and consolidation of the left lower lobe of the lung. A tissue biopsy reveals no malignant cells. Despite antibiotic therapy, the patient's symptoms persisted, and lobectomy was performed due to no clinical improvement. Even though gross pathology suggested endoluminal impaction, the patient didn't meet the ABPA diagnostic criteria.

Human fungal pathogens cause a broad plethora of infections, spanning cutaneous dermatophytoses to invasive infections in immunocompromised hosts. As eukaryotic pathogens are capable of morphotype switching, they present unique challenges both for drug development and the immunological response. Whilst current antifungal therapies are limited to the orally available triazoles, intravenous echonocandins and polyenes, and flucytosine and terbinafine, there has been recent significant progress in the antifungal armamentorium with ibrexafungerp, a novel orally available terpanoid that inhibits 1,3-beta-D-glucan-approved by Food and Drug Administration in 2021, and fosmanogepix, an orally available pro-drug of manogepix, which targets glycosylphosphatidylinositol-anchored protein maturation entering Phase 3 studies for candidaemia. A number of further candidates are in development. There has been significant use of existing immunotherapies such as recombinant interferon-γ and G-CSF for fungal disease in immunocompromised patients, and there are emerging opportunities for monoclonal antibodies targeting TH2 inflammation. Omalizumab, an anti-IgE monoclonal antibody in asthma, is now used routinely for the treatment of allergic bronchopulmonary aspergillosis, and further agents targeting IL-4 and IL-5 are being evaluated. In addition, T-cell CAR therapy is showing early promise for fungal disease. Thus, we are likely to see rapid advances to our approach to the management of fungal disease in the near future.

Schizophyllum commune is a widely distributed basidiomycete fungus that occasionally causes sinusitis or allergic bronchopulmonary mycosis. The invasive infection mostly occurs in immunocompromised adults. The number of reports on S. commune infection have increased in this decade due to the expansion of diagnostic techniques and awareness in clinical practice. However, S.commune infection in patients with primary immunodeficiencies has not been reported yet. Here, we described S. commune-abscesses developed in the brain and lung of a boy with chronic granulomatous disease (CGD) after allogenic hematopoietic cell transplantation (HCT). A 12-year-old CGD patient developed febrile neutropenia from day 4 after HCT, followed by chest pain on day 23. He had no obvious infection before HCT. Diagnostic imaging revealed disseminated lung and brain abscesses. He received administration of voriconazole, and his symptoms improved after engraftment. Chronic administration of voriconazole had also a favorable therapeutic response to brain lesion. A part of the fungus ball exhaled by the patient was cultured to develop a filamentous fungus. S. commune was identified by the analysis of the 28S rRNA gene. The catalase test was positive for S. commune, indicating that S. commune had virulence in this patient with CGD. The assessment of specific-IgG to S. commune suggested peri-transplant infection, although colonization was not excluded. This rare pediatric case of S. commune infection highlights that CGD patients are vulnerable to invasive infection, especially when undergoing HCT.

Background: Eosinophils have a double-edged role in the human body, being essential in important physiologic functions but whose presence is conspicuous in a variety of diseases characterized by a T2 inflammation phenotype. Eosinophils are exquisitely sensitive to corticosteroids, and the latter have, until recently, represented the cornerstone of treatment of eosinophilic diseases. However, most patients remain dependent on oral corticosteroids, with a notable adverse effect burden and experience a chronic relapsing disease that leads to high morbidity and mortality. Treatment prospects have changed with the advent of biologic drugs that target the eosinotropic cytokine interleukin (IL) 5 or its receptor. The success of the latter drugs in severe eosinophilic asthma has paved the way for their use in other, rarer, eosinophilic lung diseases. Recently, mepolizumab, a humanized monoclonal antibody that works against IL-5, was approved for the add-on treatment of relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis (EGPA) in patients ages ≥ 6 years. Benralizumab, a humanized antibody that binds to the α portion of the IL-5 receptor, is also being tested for its efficacy in EGPA in two clinical trials, after a growing number of case reports and case series supported its use as a steroid-sparing agent in the treatment of EGPA. Methods: In this review, we summarized the scientific literature evaluating the efficacy of benralizumab treatment in patients afflicted with rare primary eosinophilic lung diseases. Results: The literature we found, largely case reports, reported that the use of benralizumab in EGPA, chronic eosinophilic pneumonia (CEP) and allergic bronchopulmonary aspergillosis (ABPA) often led to a depletion of eosinophils, less exacerbations and a decreased systemic corticosteroid burden. No adverse effects were reported. Conclusion: Benralizumab has a prospective role in the treatment of rare eosinophilic lung diseases, which needs to be further elucidated in randomized controlled trials.

Biologics targeting the molecules associated with type 2 inflammation have significantly improved the outcomes of patients with severe eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Chronic eosinophilic airway/lung diseases including chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic bronchitis, and eosinophilic granulomatosis with polyangiitis share clinical features with eosinophilic asthma and CRPwNP, which are mostly adult-onset and may develop simultaneously or consecutively. These eosinophilic airway/lung diseases respond well to initial treatment with systemic corticosteroids, but often recur when the corticosteroids are tapered. The management of these "refractory" cases is an unmet need for clinicians. We first reviewed the standard treatments for these chronic eosinophilic airway/lung diseases, followed by the definition and prevalence of refractory diseases and the role of biologics in their management. The available evidence varies from case reports and case series to randomized control trials, depending on the type of disease; however, these studies provide not only a direction for clinical practice, but also insights into the pathophysiology of each disease. Physicians should discuss the efficacy and costs of biologics in patients with refractory eosinophilic airway/lung diseases to minimize not only the current symptoms, but future risks as well.