Aspergillus fumigatus Strain-Specific Conidia Lung Persistence Causes an Allergic Broncho-Pulmonary Aspergillosis-Like Disease Phenotype.

Aspergillus fumigatus is a filamentous fungus which can cause multiple diseases in humans. Allergic broncho-pulmonary aspergillosis (ABPA) is a disease diagnosed primarily in cystic fibrosis patients caused by a severe allergic response often to long-term A. fumigatus colonization in the lungs. Mice develop an allergic response to repeated inhalation of A. fumigatus spores; however, no strains have been identified that can survive long-term in the mouse lung and cause ABPA-like disease. We characterized A. fumigatus strain W72310, which was isolated from the expectorated sputum of an ABPA patient, by whole-genome sequencing and in vitro and in vivo viability assays in comparison to a common reference strain, CEA10. W72310 was resistant to leukocyte-mediated killing and persisted in the mouse lung longer than CEA10, a phenotype that correlated with greater resistance to oxidative stressors, hydrogen peroxide, and menadione, in vitro In animals both sensitized and challenged with W72310, conidia, but not hyphae, were viable in the lungs for up to 21 days in association with eosinophilic airway inflammation, airway leakage, serum IgE, and mucus production. W72310-sensitized mice that were recall challenged with conidia had increased inflammation, Th1 and Th2 cytokines, and airway leakage compared to controls. Collectively, our studies demonstrate that a unique strain of A. fumigatus resistant to leukocyte killing can persist in the mouse lung in conidial form and elicit features of ABPA-like disease.IMPORTANCE Allergic broncho-pulmonary aspergillosis (ABPA) patients often present with long-term colonization of Aspergillus fumigatus Current understanding of ABPA pathogenesis has been complicated by a lack of long-term in vivo fungal persistence models. We have identified a clinical isolate of A. fumigatus, W72310, which persists in the murine lung and causes an ABPA-like disease phenotype. Surprisingly, while viable, W72310 showed little to no growth beyond the conidial stage in the lung. This indicates that it is possible that A. fumigatus can cause allergic disease in the lung without any significant hyphal growth. The identification of this strain of A. fumigatus can be used not only to better understand disease pathogenesis of ABPA and potential antifungal treatments but also to identify features of fungal strains that drive long-term fungal persistence in the lung. Consequently, these observations are a step toward helping resolve the long-standing question of when to utilize antifungal therapies in patients with ABPA and fungal allergic-type diseases.

Allergic bronchopulmonary aspergillosis (ABPA) sans asthma: A distinct subset of ABPA with a lesser risk of exacerbation.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex immunological disorder complicating asthma. Uncommonly, ABPA presents without underlying asthma. Herein, we describe the outcomes of ABPA with and without asthma. Of the 530 subjects (median follow-up, 39 months), 37 (7%) were ABPA sans asthma. Bronchiectasis was more frequent (97.3% vs. 83.2%, P = .02), and the lung function was significantly better in ABPA sans asthma. The incidence-rate of ABPA exacerbation was higher in those with asthma than without (112 vs. 242 per 1000 person-years, P = .0001). ABPA sans asthma appears to be a distinct subset of ABPA, with a better lung function and fewer exacerbations.

[Invasive pulmonary aspergillosis and chronic pulmonary aspergillosis]. / Aspergillose pulmonaire invasive et aspergilttose pulmonaire chronique.

Aspergillus pulmonary infection causes a spectrum of diverse diseases according to host immunity. The two major entities are invasive pulmonary aspergillosis and chronic pulmonary aspergillosis. The later can be divided into aspergilloma, then into chronic cavitary, more or less fibrosing aspergillosis, and finally into chronic necrotizing aspergillosis, or semiinvasive aspergillosis. The present article reviews this complex classification, which is necessary to reflect the diverse clinical aspect of the disease. Allergic broncho-pulmonary aspergillosis (ABPA), which is more a hypersensitivity reaction than an infectious process, will not be discussed here.

Caso clínico: aspergilosis pulmonar invasiva tratada con Voriconazol en paciente con Síndrome de Inmunodeficiencia Adquirida / Clinical case: invasive pulmonary aspergillosis treated with Voriconazol in an AIDS patient

Se reporta un caso clínico de aspergilosis pulmonar invasiva en un paciente de 29 años VIH(+) en etapa SIDA, sin antecedentes mórbidos conocidos, con diagnóstico inicial de neumonía por Pneumocystis jirovecii. Fue tratado con éxito, pero sin asistir a controles posterior a su alta . Tres meses después ingresa al servicio de Urgencias del Hospital Gustavo Fricke con tos productiva mucopurulenta, disnea progresiva, fiebre intermitente y compromiso del estado general. La radiografía de tórax sugirió neumonía atípica, detectándose en los exámenes Pneumocystis jirovecii y Enterobacter aerógenes , por lo que se inicia tratamiento con Cotrimoxazol y Ertapenem. En los cultivos en agar Sabouraud se detectó abundante desarrollo de Aspergillus fumigatus , por lo que se empieza tratamiento con anfotericina B en dosis crecientes hasta alcanzar 50 mg/día, sin embargo, por reacciones adversas severas se decidió tratamiento con Voriconazol intravenoso y luego oral, con buena respuesta clínica, radiológica y de laboratorio. Es dado de alta con tratamiento con Voriconazol oral, además de profilaxis secundaria para P. jirovecii y Mycobaterium avium.

A clinical case of an invasive pulmonary aspergillosis in a 29 aged VIH (+) patient, at an AIDS stage, lacking any known morbid data, and bearing an initial diagnosis of pneumonia by Pneumocystis jirovecii is herein described. Was successfully treated even though he failed to attend subsequent health controls. Three months later he is admitted in the Hospital Gustavo Fricke, showing productive mucupurulent cough, progressive disnea, intermittent fever and his overall health condition resulting deeply compromised. Thorax X-ray revealed an atypical pneumonia together with the presence of P. jirovecii and Enterobacter aerogenes, and decided to treat him with Cotrimoxazol and Ertapenem. Meanwhile in agar cultures a heavy development of Aspergillus fumigatus was detected, thus the patient was given Anfotericina B in increasing doses up to reach 50mg/day; however due to some severe adverse reactions, the treatment with intravenous and later oral Voriconazol, which rendered satisfactory clinical, radiological and laboratory responses was ultimately preferred. The patient is discharged from the hospital and advised to continue with oral Voriconazol besides undergoing secondary profilaxis for P. jirovecii and Mycobaterium avium.

Isolation of Aspergillus spp. from the respiratory tract in critically ill patients: risk factors, clinical presentation and outcome.

INTRODUCTION: Our aims were to assess risk factors, clinical features, management and outcomes in critically ill patients in whom Aspergillus spp. were isolated from respiratory secretions, using a database from a study designed to assess fungal infections. METHODS: A multicentre prospective study was conducted over a 9-month period in 73 intensive care units (ICUs) and included patients with an ICU stay longer than 7 days. Tracheal aspirate and urine samples, and oropharyngeal and gastric swabs were collected and cultured each week. On admission to the ICU and at the initiation of antifungal therapy, the severity of illness was evaluated using the Acute Physiology and Chronic Health Evaluation II score. Retrospectively, isolation of Aspergillus spp. was considered to reflect colonization if the patient did not fulfil criteria for pneumonia, and infection if the patient met criteria for pulmonary infection and if the clinician in charge considered the isolation to be clinically valuable. Risk factors, antifungal use and duration of therapy were noted. RESULTS: Out of a total of 1756 patients, Aspergillus spp. were recovered in 36. Treatment with steroids (odds ratio = 4.5) and chronic obstructive pulmonary disease (odds ratio = 2.9) were significantly associated with Aspergillus spp. isolation in multivariate analysis. In 14 patients isolation of Aspergillus spp. was interpreted as colonization, in 20 it was interpreted as invasive aspergillosis, and two cases were not classified. The mortality rates were 50% in the colonization group and 80% in the invasive infection group. Autopsy was performed in five patients with clinically suspected infection and confirmed the diagnosis in all of these cases. CONCLUSION: In critically ill patients, treatment should be considered if features of pulmonary infection are present and Aspergillus spp. are isolated from respiratory secretions.

Categorization of eosinophilic chronic rhinosinusitis.

PURPOSE OF REVIEW: The presence of eosinophilia histopathologically in sinusitis is frequently associated with greater disease objectively and a decreased likelihood of surgical success. Eosinophilic chronic rhinosinusitis encompasses a wide variety of etiologies and associations that can be grouped under this umbrella term. In addition, this term can be further divided into those patients with no polyps and those with polyps. The purpose of this review is to detail the epidemiology of eosinophilic chronic rhinosinusitis, to define known and potential subcategories, and to discuss targeted therapeutic interventions. Eosinophilia is frequently, but not exclusively, caused by IgE-mediated hypersensitivity and is dominated by the associated cytokine milieu of Th2 inflammation. Thus, allergic rhinitis or allergy is a subcategory and not synonymous with eosinophilic chronic rhinosinusitis. RECENT FINDINGS: Recent findings supporting mechanisms that promote eosinophilic infiltration are discussed and include the following subcategories: super antigen-induced eosinophilic chronic rhinosinusitis, allergic fungal sinusitis, nonallergic fungal eosinophilic chronic rhinosinusitis, and aspirin-exacerbated eosinophilic chronic rhinosinusitis. Undoubtedly there are other mechanisms and categorizations of eosinophilic chronic rhinosinusitis as yet unknown. It is possible, and in fact probable, that some patients may have overlapping mechanisms for eosinophilia. Corticosteroid therapy is an important treatment across all eosinophilic disorders and a profoundly potent but nonspecific antiinflammatory agent. Within each subcategory a specific antibacterial, antifungal, or immune modulation may be indicated. SUMMARY: The subcategories of eosinophilic chronic rhinosinusitis are discussed in light of recent findings and treatment recommendations.

Mild, moderate, and severe forms of allergic bronchopulmonary aspergillosis: a clinical and serologic evaluation.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disorder induced by Aspergillus species colonizing the bronchial tree. There are patients with asthma who fulfill the diagnostic criteria of ABPA by serologic evaluation (specific IgE/IgG to Aspergillus fumigatus), bronchography, CT, and or conventional linear tomography. OBJECTIVE: To identify different forms of ABPA based on various diagnostic criteria. METHODS: Eighteen patients with asthma fulfilling the criteria of ABPA were evaluated in the present study. Six patients each received a diagnosis of ABPA serologic positive (ABPA-S), ABPA with central bronchiectasis (ABPA-CB), and ABPA with central bronchiectasis and other radiologic features (ABPA-CB-ORF). RESULTS: The spirometric changes in the ABPA-S group (group 1) were mild, in the ABPA-CB group (group 2) were moderate, and in the ABPA-CB-ORF group (group 3) were severe. Absolute eosinophil count was raised in each group but was maximum (1,233 micro L) in severe form of disease (group 3). Specific IgE against A fumigatus was raised in each group, and the maximum was 47.91 IU/mL in ABPA-CB-ORF. CT scan findings of the ABPA-S group were normal without central bronchiectasis. The exacerbation in symptoms was maximum in group 3 compared to other groups. CONCLUSION: The present observations suggest that ABPA includes mild (ABPA-S), moderate (ABPA-CB), and severe (ABPA-CB-ORF) forms of disease. It is recommended, therefore, that the disease should be diagnosed early, treated at the mild form of disease (ABPA-S), and prevented from leading to ABPA-CB or ABPA-CB-ORF.

Chronic pulmonary aspergillosis: current classification and therapy.

A type of non-acute pulmonary aspergilloses, defined as 'semi-invasive' and 'chronic necrotizing aspergillosis', respectively, was described by Geffer, and later by Binder in the 1980s. Subsequently, a terminological uncertainty prevailed, favored by a preference in choosing the predisposing diseases. The simple term 'chronic pulmonary aspergillosis', as well as a classification based on the pulmonary anatomy, is proposed in this review. The most significant Medline and Embase indexed papers published between 1966 and the present day, including coverage of classification, diagnosis and treatment of aspergillosis are analyzed. In addition, an open study, carried out on 23 patients treated with terbinafine is reported. The results obtained suggest the need for further randomized studies.

[Allergic bronchopulmonary aspergillosis (ABPA)].

The entity of allergic pulmonary aspergillosis includes various diseases of the lung which are caused by not only allergic reactions to aspergillus but also destructive inflammations due to saprophytic infection of aspergillus in lower respiratory tracts. We focus our discussion on ABPA with our own experience of 11 cases and overview of the disease. First of all, We propose that the entity of ABPA should be expanded from one that has been defined by the diagnostic criteria established by Rosenberg et al in 1977. We have to consider stage of ABPA, the existence of ABPA without asthma and ABPA complicated with chronic bacterial infection in lower respiratory tracts and the progression of ABPA to infectious and invasive aspergillosis. It is important for the diagnosis of ABPA to study not only allergic reactions to aspergillus but also chest HRCT which reveals the central bronchiectasis and mucus plugging that are thought characteristic of the disease. Systemic steroid therapy is indispensable in the acute stage of the disease. Bronchial toileting for the removal of mucoid impaction is also important. In the chronic stage of the disease, antifungal drugs and inhaled steroid therapy should be considered in intractable cases on recurrence to prevent the disease progression and lung injuries.

Diagnosis and management of allergic bronchopulmonary aspergillosis.

Early diagnosis and treatment is essential for patients afflicted with bronchopulmonary aspergillosis (ABPA). Inflammatory damage to the airways may be significantly reduced through use of corticosteroids. Without treatment, bronchiectasis causing permanent anatomic alteration of the airways may occur. ABPA should be considered in any asthmatic who requires oral corticosteroids and has recurrent pulmonary infiltrates. Evaluation should include determination of total serum IgE, which generally exceeds 1000 ng/mL in patients with ABPA. Disease categorization of ABPA patients may be made according to radiographic and clinical considerations into five stages. The treatment choice for ABPA is prednisone, although inhaled corticosteroids including beclomethasone dipropionate may also be used in long-term asthma management. Successful therapy of ABPA is typically associated with a decline in total serum IgE, subsequent exacerbations often being associated with elevation in total serum IgE. Allergen avoidance is essential for the ABPA patient, as exposure to heavy concentrations of fungi may precipitate disease exacerbation.

Aspergilosis pulmonar, aspectos clínico-radiológicos

Se realizó un estudio descriptivo, retrospectivo, en 31 pacientes con aspergiloma pulmonar observados en un período de 12 años; 25 de ellos tenían radiografías. Se analizaron sus características clínicas, de laboratorio y radiológicas al momento del diagnóstico y durante el seguimiento del tratamiento con itraconazol. La condición preexistente más frecuente fue la tuberculosis (61.3 por ciento); el síntoma más común al momento de la consulta fue la tos productiva (83.9 por ciento); 21 pacientes (66.7 por ciento) presentaron hemoptisis,la cual disminuyó en frecuencia (21.4 por ciento) con el tratamiento (p>0.05). La alta positividad (64 por ciento) de las pruebas serológicas al comienzo del estudio, cayó posteriormente a 7 por ciento (p>0.05). En 23 pacientes (91 por ciento) las radiografías de tórax mostraron engrosamiento pleural y patrón intersticial anormal. Se demostró, además, cómo cuatro de los siete aspergilomas clásicos disminuyeron o desaparecieron con el tratamiento. Se concluye que la forma de presentación del aspergiloma en nuestro medio es similar a la descrita en otros países y que el itraconazol oral es una opción terapéutica aceptable

The spectrum of pulmonary aspergillosis.

Aspergillus species can produce a wide range of pulmonary disorders. Classically, pulmonary aspergillosis has been categorized into invasive, saprophytic, and allergic forms, all of which differ in their manifestations and therapy. More recently, however, other types of infection by this fungus have been recognized that do not fit into these traditional categories; an example is semi-invasive (chronic necrotizing) aspergillosis. In fact, these forms have features that are intermediate between those of the invasive and saprophytic types. The various types of aspergillosis can be regarded as constituting a continuous spectrum, ranging from invasive disease in the severely immunosuppressed patient to hypersensitivity reactions such as allergic bronchopulmonary aspergillosis (and bronchocentric granulomatosis) in the hyperreactive patient. Between these extremes are chronic necrotizing disease seen in midly immunocompromised hosts, and the noninvasive aspergilloma, which is due to saprophytic growth within a previously diseased area of lung in an otherwise normal host. Other intermediate forms may be encountered, their behavior being determined by the host immune status in combination with the underlying lung morphology. The radiographic and clinical features of these various forms of pulmonary aspergillosis are reviewed, including the more recently reported forms of infection such as Aspergillus tracheobronchitis and aspergillosis associated with acquired immunodeficiency syndrome and cystic fibrosis. The proposed concept of a disease spectrum is emphasized.

Allergic bronchopulmonary aspergillosis. Natural history and classification of early disease by serologic and roentgenographic studies.

Eighty-four patients with allergic bronchopulmonary aspergillosis (ABPA) were evaluated for a total of 294 patient-years with a mean observation period of 3.7 years and classified by the stage of ABPA. The largest percentage of patients were in the stage IV (corticosteroid-dependent asthma stage) group. The next largest percentage were in the stage V (fibrotic, end-stage lung disease) group. Of the latter 24 patients, eight had died. In addition, we describe 13 patients with all serologic characteristics of ABPA but without central bronchiectasis. We propose that these patients have seropositive ABPA and represent the earliest cases of it that can be diagnosed in contrast with ABPA with central bronchiectasis in which lung damage is already present.

Unusual manifestations of pulmonary aspergillosis.

Pulmonary aspergillosis is being diagnosed with increasing frequency, particularly in larger referral centers. The spectrum of lung pathology can be classified into 3 major groups: A) non-invasive mycetoma; B) allergic bronchopulmonary aspergillosis and C) invasive aspergillosis. Five patients with pulmonary aspergillosis are presented, illustrating unusual features of each major group. Transthoracic needle aspiration biopsy was diagnostic in 3 patients. It is important to differentiate a mycetoma developing in a pre-existing cavity from a cavitating Aspergillus abscess. The radiologic appearances may be similar, but evolution of the 2 lesions is entirely different.