Article

An evaluation of nebulised amphotericin B deoxycholate (Fungizone ® ) for treatment of pulmonary aspergillosis in the UK National Aspergillosis Centre

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Abstract

Antifungal treatment options for allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS) are largely limited to itraconazole based on the outcome of randomised controlled trials. It is unclear if nebulised amphotericin B deoxycholate (Fungizone® ) is a viable therapeutic option. We evaluated the safety and efficacy of nebulised Fungizone® in the long-term treatment of various forms of pulmonary aspergillosis. We assessed the records of 177 patients with various forms of pulmonary aspergillosis attending the National Aspergillosis Centre in Manchester who had received Fungizone® . Patients first received a challenge test with nebulised Fungizone® in hospital with spirometry pre/post-Fungizone® and nebulised salbutamol given pre-Fungizone® . Tolerability and changes in Aspergillus IgE, Aspergillus IgG and total IgE were evaluated. Sixty-six per cent (117/177) were able to tolerate the test dose of Fungizone® and in all cases, the reason for discontinuation of the first test dose was worsening breathlessness. Twenty six (21%) stopped therapy within 4-6 weeks, and the commonest reason cited for discontinuation of therapy was increased breathlessness, hoarseness and cough. Eighteen (10.2%) patients continued the Fungizone® for >3 months of which 5 (27.8%) recorded an improvement in total IgE, Aspergillus-specific IgE and Aspergillus IgG. Eleven had ABPA, four had SAFS, two had Aspergillus bronchitis and one had Aspergillus sensitisation with cavitating nodules. Among these 18 patients, sputum fungal culture results went from positive to negative in five patients, became positive in one patient, remained positive in three patients, and remained negative in seven patients. Nebulised Fungizone® appears to be a poorly tolerated treatment for pulmonary Aspergillosis with high dropout rates. There appears to be both clinical and serological benefits following sustained treatment with nebulised Fungizone® in some patients.

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... 57 Aunque se considera el estándar para manejo de la entidad, no existe un consenso acerca de la dosis y la duración del tratamiento, y se acostumbra la disminución gradual de la dosis, demostrándose que con un tratamiento efectivo, los títulos séricos de acs IgE total disminuirían en alrededor del 25%, luego de un mes, y en alrededor de un 60%, luego de 2 meses. 4,71,72,74,104 En general, las dosis recomendadas para las exacerbaciones agudas de ABPA, incluyen una fase de inducción con dosis de 0.5-1.0 mg/ kg de prednisona (PDN) o su equivalente diario (por 1 a 2 semanas), seguido de una fase de mantenimiento con una dosis de 0.5 mg/ kg, interdiario (durante 6 a 12 semanas), y una fase de disminución gradual (al menos 6 a 12 meses), sin embargo, en algunos pacientes (especialmente pacientes con FQ) no es posible este destete con éxito, ya que requieren una dosis de mantenimiento diaria relativamente baja (<10 mg). ...
... 51.El consenso no recomienda en el paciente con diagnóstico de ABPA, en el contexto de asma o FQ, el inicio de un tratamiento antifúngico con AmB nebulizada. (recomendación débil, baja calidad de la evidencia).71,72 b. ...
... 63,7151.El consenso no recomienda en el paciente con diagnóstico de ABPA, en el contexto de asma o FQ, el inicio de un tratamiento antifúngico con AmB nebulizada. (recomendación débil, baja calidad de la evidencia).71,72 ...
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Despite the ubiquity of Aspergillus species, and the fact that a person may inhale hundreds of conidia daily, only a small proportion of patients develop an infectious disease. Aspergillus spp. can cause a wide spectrum of diseases, depending on the patient’s underlying immune function; these range from an allergic syndrome, (which does not represent a true infection), a hypersensitivity reaction (ABPA), a chronic process (CPA) or invasive aspergillosis (IA). All diseases associated with Aspergillus spp. have the potential to be misdiagnosed because symptoms and/or clinical findings overlap with each other, or with other non-fungal conditions. Greater clinical recognition of the different pulmonary syndromes is needed to identify those patients who could benefit from an appropriate therapeutic approach. Multidisciplinary management is required, where the role of antifungal therapy is only established for symptomatic and/or progressive disease management, taking into account the potential for azole resistance, which adds to the complexity of treatment and, in some cases, limits therapeutic options.
... Nebulized AmB may increase the risk of bronchospasm [134,135]. Patients diagnosed with ABPA may face a higher risk due to their underlying diseases (bronchiectasis/cystic fibrosis) [134,135]. The first dose should, therefore, be administered in a hospital setting [135]. ...
... Nebulized AmB may increase the risk of bronchospasm [134,135]. Patients diagnosed with ABPA may face a higher risk due to their underlying diseases (bronchiectasis/cystic fibrosis) [134,135]. The first dose should, therefore, be administered in a hospital setting [135]. ...
... Patients diagnosed with ABPA may face a higher risk due to their underlying diseases (bronchiectasis/cystic fibrosis) [134,135]. The first dose should, therefore, be administered in a hospital setting [135]. L-AmB may also be safer than D-AmB within this setting [63,136]. ...
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... Some of the proposed benefits of nebulised amphotericin include its potential to achieve higher lung tissue concentrations with minimal systemic distribution and treat azoleresistant strains of Aspergillus (Chrdle et al., 2012;Otu et al., 2019). Liposomal amphotericin B also contains phospholipids and cholesterol, which may play a role in improving pulmonary compliance as seen in natural surfactant (Otu et al., 2019). ...
... Some of the proposed benefits of nebulised amphotericin include its potential to achieve higher lung tissue concentrations with minimal systemic distribution and treat azoleresistant strains of Aspergillus (Chrdle et al., 2012;Otu et al., 2019). Liposomal amphotericin B also contains phospholipids and cholesterol, which may play a role in improving pulmonary compliance as seen in natural surfactant (Otu et al., 2019). ...
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... Administration of aerosolized amphotericin B formulations has been associated with adverse effects, most notably nausea, bad taste, cough, dizziness, chest tightness, mild bronchospasm and sputum production [67]. This is most notable with aAmBd [26, 53,68] and likely due (at least in part) to sodium deoxycholate as the solubilizing agent [28]. In patients with ABPA and/or asthma, aAmBd is poorly tolerated [68,69]. ...
... This is most notable with aAmBd [26, 53,68] and likely due (at least in part) to sodium deoxycholate as the solubilizing agent [28]. In patients with ABPA and/or asthma, aAmBd is poorly tolerated [68,69]. Overall, aABLC tolerability has best been characterized among lung transplant recipients. ...
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... The antifungal treatment benefit in ABPA may not be restricted to itraconazole -in a retrospective study of patients with ABPA and SAFS, clinical response to voriconazole was observed in 12/16 (75%) and in 7/9 (78%) for posaconazole [13]. Further evidence for the benefit of antifungal intervention in ABPA has been evidenced by positive therapeutic benefit with the use of inhaled amphotericin [11,12,60]. In a recent prospective study of 21 ABPA patients, authors compared treatment with nebulised amphotericin and budesonide versus budesonide alone [12]. ...
... The study did not report measurement of fungal load in sputum. A number of retrospective studies have highlighted the high incidence of bronchospasm with inhaled amphotericin which restricts widespread utility in this population [11,60]. ...
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... In a case series study of 177 patients with pulmonary aspergillosis that received inhaled amphotericin B, 66% of patients were able to tolerate an initial dose, however, 21% stopped therapy in the following 6 weeks. Only 10% of patients continued with therapy for more than 3 months, with 28% of those patients showing improvement in IgE levels [81]. Similarly, in a small clinical study of 21 adult asthmatics with SAFS and ABPA, who had failed previous antifungal therapy, 18 subjects either failed initial dosing or discontinued therapy in the following 12 months [56]. ...
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Aspergillus spp. are spore forming molds; a subset of which are clinically relevant to humans and can cause significant morbidity and mortality. A. fumigatus causes chronic infection in patients with chronic lung disease such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). In patients with CF, A. fumigatus infection can lead to allergic disease, such as allergic bronchopulmonary aspergillosis (ABPA) which is associated with high rates of hospitalizations for acute exacerbations and lower lung function. ABPA results from TH2 immune response to Aspergillus antigens produced during hyphal growth, marked by high levels of IgE and eosinophil activation. Clinically, patients with ABPA experience difficulty breathing; exacerbations of disease and are at high risk for bronchiectasis and lung fibrosis. Oral corticosteroids are used to manage aspects of the inflammatory response and antifungal agents are used to reduce fungal burden and lower the exposure to fungal antigens. As the appreciation for the severity of fungal infections has grown, new therapies have emerged that aim to improve treatment and outcomes for patients with CF.
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Background: Allergic diseases caused by fungi are common. The best understood conditions are allergic bronchopulmonaryaspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS). Our knowledge of the fungal microbiome (mycobiome) is limited to a few studies involving healthy individuals, asthmatics and smokers. No study has yet examined the mycobiome in fungal lung disease. Objectives: The main aim of this study was to determine the mycobiome in lungs of individuals with well characterised fungal disease. A secondary objective was to determine possible effects of treatment on the mycobiome. Methods: After bronchoscopy, ITS1 DNA was amplified and sequenced and fungal load determined by RT-PCR. Clinical and treatment variables were correlated with the main species identified. ABPA (n=16), SAFS (n=16), severe asthma not sensitised to fungi, (n=9), mild asthma patients(n=7) and 10 healthy controls were studied. Results: The mycobiome was highly varied with severe asthmatics carrying higher loads of fungus. Healthy individuals had low fungal loads, mostly poorly characterised Malasezziales.The most common fungus in asthmatics was Aspergillus fumigatus complex and this taxon accounted for the increased burden of fungus in the high level samples. Corticosteroid treatment was significantly associated with increased fungal load (p<0.01). Conclusions: The mycobiome is highly variable. Highest loads of fungus are observed in severe asthmatics and the most common fungus is Aspergillusfumigatus complex. Individuals receiving steroid therapy had significantly higher levels of Aspergillus and total fungus in their BAL.
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Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.
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In susceptible individuals, inhalation of Aspergillus spores can affect the respiratory tract in many ways. These spores get trapped in the viscid sputum of asthmatic subjects which triggers a cascade of inflammatory reactions that can result in Aspergillus-induced asthma, allergic bronchopulmonary aspergillosis (ABPA), and allergic Aspergillus sinusitis (AAS). An immunologically mediated disease, ABPA, occurs predominantly in patients with asthma and cystic fibrosis (CF). A set of criteria, which is still evolving, is required for diagnosis. Imaging plays a compelling role in the diagnosis and monitoring of the disease. Demonstration of central bronchiectasis with normal tapering bronchi is still considered pathognomonic in patients without CF. Elevated serum IgE levels and Aspergillus-specific IgE and/or IgG are also vital for the diagnosis. Mucoid impaction occurring in the paranasal sinuses results in AAS, which also requires a set of diagnostic criteria. Demonstration of fungal elements in sinus material is the hallmark of AAS. In spite of similar histopathologic features, co-existence of ABPA and AAS is still uncommon. Oral corticosteroids continue to be the mainstay of management of allergic aspergillosis. Antifungal agents play an adjunctive role in ABPA as they help reduce the fungal load. Saprophytic colonization in cavitary ABPA may lead to aspergilloma formation, which could increase the severity of the disease. The presence of ABPA, AAS, and aspergilloma in the same patient has also been documented. All patients with Aspergillus-sensitized asthma must be screened for ABPA, and AAS should always be looked for.
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The clinical presentation of Aspergillus lung disease is determined by the interaction between fungus and host. Invasive aspergillosis develops in severely immunocompromised patients, including those with neutropenia, and increasingly in the non-neutropenic host, including lung transplant recipients, the critically ill patients and patients on steroids. A high index of suspicion is required in patients without the classical risk factors as early presentation is usually silent and non-specific, pyrexia uncommon and timely treatment is crucial for survival. Invasive aspergillosis has also been diagnosed in normal hosts after massive exposure to fungal spores. Chronic pulmonary aspergillosis affects patients without obvious immune compromise, but with an underlying lung condition such as COPD or sarcoidosis, prior or concurrent TB or non-tuberculous mycobacterial disease. Aspergillus bronchitis may be responsible for persistent respiratory symptoms in patients with Aspergillus detected repeatedly in sputum without evidence of parenchymal Aspergillus disease, especially in patients with bronchiectasis and cystic fibrosis. Allergic bronchopulmonary aspergillosis affects patients with asthma and cystic fibrosis, and is important to recognise as permanent lung or airways damage may accrue if untreated. Changes in the classification of Aspergillus allergic lung disease have been proposed recently. Cases of extrinsic allergic alveolitis and chronic pulmonary aspergillosis have been observed after Aspergillus exposure. Asymptomatic colonisation of the respiratory tract needs close monitoring as it can lead to clinical disease especially with ongoing immunosuppression. The various syndromes should be viewed as a semicontinuous spectrum of disease and one form may evolve into another depending on the degree of ongoing immunosuppression.
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Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis. There are estimated to be in excess of four million patients affected world-wide. The importance of recognizing ABPA relates to the improvement of patient symptoms, and delay in development or prevention of bronchiectasis, one manifestation of permanent lung damage in ABPA. Environmental factors may not be the only pathogenetic factors because not all asthmatics develop ABPA despite being exposed to the same environment. Allergic bronchopulmonary aspergillosis is probably a polygenic disorder, which does not remit completely once expressed, although long-term remissions do occur. In a genetically predisposed individual, inhaled conidia of A. fumigatus germinate into hyphae with release of antigens that activate the innate and adaptive immune responses (Th2 CD4+ T cell responses) of the lung. The Inter- national Society for Human and Animal Mycology (ISHAM) has constituted a working group on ABPA complicating asthma (www.abpaworkinggroup.org), which convened an international conference to summarize the current state of knowledge, and formulate con- sensus-based guidelines for diagnosis and therapy. New diagnosis and staging criteria for ABPA are proposed. Although a small number of randomized controlled trials have been conducted, long-term management remains poorly studied. Primary therapy consists of oral corticosteroids to control exacerbations, itraconazole as a steroid-sparing agent and optimized asthma therapy. Uncertainties surround the prevention and management of bronchiectasis, chronic pulmonary aspergillosis and aspergilloma as complications, con- current rhinosinusitis and environmental control. There is need for new oral antifungal agents and immunomodulatory therapy.
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Background. Systemic steroids and adjunctive antifungal therapy are the cornerstone in treating allergic bronchopulmonary aspergillosis (ABPA) in the context of CF. Aim. Evaluate the use of inhaled amphotericin B (iAMB) as antifungal agent in this context. Methods. Report of 7 CF patients with recurrent or difficult to treat ABPA and failure to taper systemic corticosteroids treated with AMB deoxycholate (AMB-d) (Fungizone 25 mg 3× a week) or AMB lipid complex (ABLC) (Abelcet 50 mg twice weekly). Successful therapy was defined as steroid withdrawal without ABPA relapse within 12 months. Results. Therapy was successful in 6 of 7 patients treated with iAMB. In 5/6, lung function improved. The patient with treatment failure has concomitant MAC lung infection. Conclusion. Inhaled AMB may be an alternative to commonly used adjunctive antifungal therapy in the treatment of ABPA. More data are needed on safety and efficacy.
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Aims and objectives To describe the experience of screening patients with asthma for allergic bronchopulmonary aspergillosis (ABPA) presenting to a chest clinic. The clinical, serologic, radiologic, and treatment aspects including outcome of ABPA are also described. Methods All consecutive patients with asthma presenting to the chest clinic over a period of 2 years were screened with an Aspergillus skin test. Patients who were found to be positive were further investigated for ABPA. Patients were also arbitrarily classified as ABPA-seropositive (ABPA-S), ABPA with central bronchiectasis (ABPA-CB), and ABPA-CB with other radiologic findings (ABPA-CB-ORF) based on the high-resolution CT findings. Results Five hundred sixty-four patients were screened using an Aspergillus skin test; 223 patients (39.5%) were found to be positive, and ABPA was diagnosed in 126 patients (27.2%). There were 34 patients (27%) with ABPA-S, 42 patients with ABPA-CB, and 50 patients with ABPA-CB-ORF. Fifty-nine patients (46.8%) had received antitubercular therapy in the past. The vast majority of patients had bronchiectasis at presentation to our hospital. High-attenuation mucous impaction was noted in 21 patients (16.7%). There was no significant difference between the stages of ABPA and the duration of illness, the severity of asthma, and the serologic findings (ie, absolute eosinophil count, IgE levels [total] and IgE levels [for Aspergillus fumigatus]). The median duration of follow-up was 13 months (range, 9 to 38 months). All patients went into “remission” at 6 weeks. Twenty-five patients had a “relapse” during the course of their treatment. One hundred nine patients had “complete remission,” 17 patients were classified as having “glucocorticoid-dependent ABPA,” and 7 patients were classified as having “end-stage ABPA.” Conclusions There is a high prevalence of ABPA in asthmatic patients presenting at our hospital. The disease entity is still underrecognized in India; the vast majority of patients have bronchiectasis at presentation, and almost half are initially misdiagnosed as having pulmonary tuberculosis. There is a need to redefine the definitions of ABPA and the optimal dose/duration of glucocorticoid therapy. This study reinforces the need for the routine screening of asthmatic patients with an Aspergillus skin test.
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Allergic bronchopulmonary aspergillosis is a hypersensitivity disorder that can progress from an acute phase to chronic disease. The main treatment is systemic corticosteroids, but data from uncontrolled studies suggest that itraconazole, an orally administered antifungal agent, may be an effective adjunctive therapy. We conducted a randomized, double-blind trial of treatment with either 200 mg of itraconazole twice daily or placebo for 16 weeks in patients who met immunologic and pulmonary-function criteria for corticosteroid-dependent allergic bronchopulmonary aspergillosis. A response was defined as a reduction of at least 50 percent in the corticosteroid dose, a decrease of at least 25 percent in the serum IgE concentration, and one of the following: an improvement of at least 25 percent in exercise tolerance or pulmonary-function tests or resolution or absence of pulmonary infiltrates. In a second, open-label part of the trial, all the patients received 200 mg of itraconazole per day for 16 weeks. There were responses in 13 of 28 patients in the itraconazole group (46 percent), as compared with 5 of 27 patients in the placebo group (19 percent, P=0.04). The rate of adverse events was similar in the two groups. In the subsequent open-label phase, 12 of the 33 patients who had not had a response during the double-blind phase (36 percent) had responses, and none of the patients who had a response in the double-blind phase of the trial had a relapse. For patients with corticosteroid-dependent allergic bronchopulmonary aspergillosis, the addition of itraconazole can lead to improvement in the condition without added toxicity.
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There is current evidence to demonstrate a close association between fungal sensitisation and asthma severity. Whether such an association is causal remains to be confirmed, but this is explored by means of a detailed literature review. There is evidence from two randomised controlled trials that, in the example of allergic bronchopulmonary aspergillosis (ABPA), treatment with systemic antifungal therapy can offer a therapeutic benefit to approximately 60% of patients. ABPA is only diagnosed if a combination of clinical and immunological criteria is achieved. It is not known whether such cases are a discrete clinical entity or part of a spectrum of the pulmonary allergic response to fungi or fungal products. This paper describes the epidemiological evidence that associates severity of asthma with fungi and discusses possible pathogenetic mechanisms. Many airborne fungi are involved, including species of Alternaria, Aspergillus, Cladosporium and Penicillium, and exposure may be indoors, outdoors or both. The potential for a therapeutic role of antifungal agents for patients with severe asthma and fungal sensitisation is also explored. Not only are many patients with severe asthma desperately disabled by their disease, but, in the UK alone, asthma accounts for 1,500 deaths per yr. The healthcare costs of these patients are enormous and any treatment option merits close scrutiny. Within this report, the case for the consideration of a new term related to this association is put forward. The current authors propose the term "severe asthma with fungal sensitisation". However, it is recognised that enhanced and precise definition of fungal sensitisation will require improvements in diagnostic testing.
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Invasive pulmonary aspergillosis (IPA) is a significant problem in patients with chemotherapy-induced prolonged neutropenia. Because pulmonary deposition of conidia is the first step in developing IPA, we hypothesized that inhalation of liposomal amphotericin B would prevent IPA. We performed a randomized, placebo-controlled trial of patients with hematologic disease with expected neutropenia for >or=10 days. Patients were randomized to receive liposomal amphotericin B or placebo inhalation twice a week, using an adaptive aerosol delivery system, until neutrophil counts increased to >300 cells/mm3. In subsequent neutropenic episodes, the assigned treatment was restarted. The primary end point was the occurrence of IPA according to European Organization for Research and the Treatment of Cancer-Mycoses Study Group definitions. Kaplan-Meier curves were compared with log-rank tests for intent-to-treat and on-treatment populations. A total of 271 patients were studied during 407 neutropenic episodes. According to the intent-to-treat analysis, 18 of 132 patients in the placebo group developed IPA versus 6 of 139 patients in the liposomal amphotericin B group (odds ratio, 0.26; 95% confidence interval, 0.09-0.72; P=.005). According to the on-treatment analysis, 13 of 97 patients receiving placebo versus 2 of 91 receiving liposomal amphotericin B developed IPA (odds ratio, 0.14; 95% confidence interval, 0.02-0.66; P=.007). Some adverse effects, but none serious, in the liposomal amphotericin B group were reported, most frequently coughing (16 patients vs. 1 patient; P=.002). In high-risk patients, prophylactic inhalation of liposomal amphotericin B significantly reduced the incidence of IPA.
Article
Allergic bronchopulmonary aspergillosis (ABPA) is a complicated inflammatory condition characterized by an allergic response to the fungus Aspergillus colonizing in the bronchus. It occurs most frequently in patients with asthma or cystic fibrosis. Oral corticosteroids are the standard therapy for ABPA. Antifungal drugs can clear the fungi in the airway, reduce the body's antigen load, decrease the body's allergic reaction, and reduce corticosteroid requirement. Total serum IgE should be used as an index for efficacy assessment during treatment and follow-up.
Article
Background and aim: Nebulized amphotericin B (NAB) has been used in the management of acute stage and exacerbations of allergic bronchopulmonary aspergillosis (ABPA). Whether NAB can prevent exacerbations of ABPA is not known. Herein, we evaluate the efficacy and safety of NAB in subjects with ABPA complicating asthma. Methods: Consecutive subjects of ABPA with recurrent exacerbations were randomized to receive either NAB plus nebulized budesonide (NEB) or NEB alone. The primary outcome was the time to first exacerbation of ABPA. The secondary outcomes were the number of subjects with ABPA exacerbations, ACQ7 scores, lung function, IgE levels and adverse effects of treatment. Results: Twenty-one subjects (14 men; mean age, 32.3 years) were randomized to either the NAB (n=12) or the NEB (n=9) arm. The baseline characteristics were similar in the two groups. The time to first exacerbation was similar in the two groups. At one year, the numbers of patients experiencing exacerbation were significantly lower in the NAB arm (1/12 [8.3%] vs. 6/9 [66.7%]; p=0.016). The other secondary endpoints were not different between the two groups. There were no major adverse events leading to discontinuation of any of the study drugs. Three patients experienced bronchospasm after first dose of NAB; however, the subsequent doses were well tolerated. Conclusions: Nebulized amphotericin B seems to be beneficial in decreasing the frequency of exacerbations in patients with ABPA complicating asthma. Larger trials are required to confirm our study results. [clinicaltrials.gov:NCT01857479].
Article
The role of total and specific IgE in monitoring treatment responses in allergic bronchopulmonary aspergillosis (ABPA) remains poorly studied. Here in, we evaluate the utility of total and Aspergillus fumigatus specific IgE in the follow-up of ABPA. Eighty-one consecutive treatment-naïve patients of ABPA (acute stage) with pulmonary infiltrates and bronchiectasis underwent measurement of total and A. fumigatus specific IgE at baseline, after 8 weeks of glucocorticoid therapy, and during exacerbations. There was clinical and radiological improvement after treatment with median decline of total IgE by 51.9%. The total IgE declined by at least 35%, 25% and 20% in 69 (85.2%), 76 (93.6%) and 78 (96.3%) patients, respectively. On the other hand, the A. fumigatus specific IgE increased in 42 (51.9%) subjects, and the mean increase was 1.4%, after 8 weeks. Among 13 patients with exacerbation, 12 (92.3%) had a rise of total IgE by >50%. The A. fumigatus specific IgE increased in only five (38.5%) subjects during exacerbation. Thus, the total IgE is a useful test in monitoring treatment responses in ABPA while A. fumigatus specific IgE has limited utility.
Article
Background and rationale: Antifungal therapy for severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA) remains poorly studied. We assessed the efficacy and safety of NAB as second and third line therapy in SAFS and ABPA. Methods: 21 adult asthmatics with SAFS (n = 11) and ABPA (n = 10) who had either failed itraconazole (n = 8), voriconazole proceeded by itraconazole (n = 5) or developed adverse events (AEs) to either agent (n = 7) were treated with 10mg of NAB (Fungizone) twice daily. We audited clinical and immunological response, using the Asthma Quality of Life Questionnaire (AQLQ-J) scores, asthma control, FEV1, healthcare utilisation and IgE. Patients were followed up for 12 months. Results: Twenty-one patients were treated (SAFS, n = 11) and (ABPA, n = 10), M: F = 8:12, median age 65 years (range, 24-78). The median duration of therapy was 30 days (0-1825). Clinical benefit was observed in three (14.3 %) in which overall mean AQLQ-J score improved by + 2.9, mean FEV1 improved by 0.5 L and there was improvement in overall asthma control. Seven (33%) failed initial dose (bronchospasm). Eleven (52.4%) discontinued within 12 months of therapy due to delayed bronchospasm (n = 3, within 4 weeks), equipment problems (n = 2, within 4 weeks) and lack of clinical benefit (n = 4, within 16 weeks). Conclusion: Our data suggest that the overall efficacy of NAB in this group of patients is poor and associated with bronchospasm. However, the excellent response in 3 patients, suggest it may be considered when other alternatives have been exhausted. Overcoming the initial bronchospasm may improve tolerability.
Article
Aspergillus bronchitis is poorly understood and described. We extracted clinical data from more than 400 referred patients with persistent chest symptoms who did not fulfill criteria for allergic, chronic, or invasive aspergillosis. Symptomatic patients with a positive culture or real-time PCR for Aspergillus spp. were reviewed. Seventeen patients fulfilled the selected criteria. Fourteen were women, with a mean age of 57 years (range 39-76). Sixteen of the patients had productive cough, eight had voluminous tenacious sputum, and seven had recurrent chest infections. Eight patients had Medical Research Council dyspnea scores of 4-5; 12 had bronchiectasis; and 13 patients grew A. fumigatus, 3 A. niger, and 1 A. terreus. Twelve of the 17 patients (71%) had elevated Aspergillus IgG (47-137 mg/L, mean 89.2) and 5 (29%) had elevated Aspergillus precipitins. Six of 12 (50%) had a major response to antifungal therapy and five of 12 (42%) patients relapsed, requiring long-term therapy. Aspergillus bronchitis is a discrete clinical entity in patients with structural lung disease but who are not significantly immunocompromised. It is distinct from asymptomatic fungal colonization and other forms of aspergillosis, and may respond to antifungal therapy.
Article
While allergic bronchopulmonary aspergillosis (ABPA) is well recognized as a fungal complication of asthma, severe asthma with fungal sensitization (SAFS) is not. In ABPA the total immunoglobulin E (IgE) is usually >1,000 IU/mL, whereas in SAFS it is <1,000 IU/mL, and either skin prick tests or fungus-specific IgE tests are positive. ABPA may present with any severity of asthma, and occasionally with no asthma or cystic fibrosis, the other common underlying disease. SAFS is a problem in patients with poorly controlled asthma and occasionally presents in the intensive care unit (ICU). Production of mucous plugs and coughing paroxysms is more common in ABPA. Certain underlying genetic defects seem to underpin these remarkable phenotypic differences. From a management perspective both ABPA and SAFS respond to both high doses of corticosteroids and oral antifungal agents, with ∼60% response rate in both ABPA and SAFS with itraconazole. In 50% of patients itraconazole boosts inhaled corticosteroid exposure, sometimes leading to cushingoid features. Second-line therapy data are scant, but we have shown that 70 to 80% of patients who tolerate either voriconazole or posaconazole also respond. Other useful therapies include nebulized hypertonic saline to aid expectoration of thick sputum and long-term azithromycin for its anti-inflammatory effect on the airways. Omaluzimab is useful in some patients with SAFS and occasionally in ABPA. Complications of ABPA include bronchiectasis, typically central in distribution, and chronic pulmonary aspergillosis. Most patients with ABPA and SAFS can be stabilized for long periods with inhaled corticosteroids and itraconazole or another antifungal agent. Novel immunotherapies are on the horizon.
Article
Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus fumigatus that occur frequently in patients with cystic fibrosis (CF). Recurrent episodes of bronchial obstruction, inflammation, and mucoid impaction occur in ABPA and results in bronchiectasis, fibrosis, and respiratory failure. The treatment of ABPA includes corticosteroids to reduce the acute inflammation and intraconazole to reduce the fungal colonization load in order to reduce lung injury. This case discusses the successful use of aerosolized amphotericin B for the treatment of ABPA in a 14-year-old patient with CF listed for lung transplant. The patient required fewer hospitalizations, and both oral corticosteroids and anti-fungal therapy were eventually stopped.
Article
Allergic bronchopulmonary aspergillosis (ABPA) is a complex clinical entity that results from an allergic immune response to Aspergillus fumigatus, most often occurring in a patient with asthma or cystic fibrosis. Sensitization to aspergillus in the allergic host leads to activation of T helper 2 lymphocytes, which play a key role in recruiting eosinophils and other inflammatory mediators. ABPA is defined by a constellation of clinical, laboratory, and radiographic criteria that include active asthma, serum eosinophilia, an elevated total IgE level, fleeting pulmonary parenchymal opacities, bronchiectasis, and evidence for sensitization to Aspergillus fumigatus by skin testing. Specific diagnostic criteria exist and have evolved over the past several decades. Staging can be helpful to distinguish active disease from remission or end-stage bronchiectasis with progressive destruction of lung parenchyma and loss of lung function. Early recognition allows treatment with corticosteroids, which are effective but may be required indefinitely. There is some evidence to support the use of newer antifungal azoles as corticosteroid-sparing agents. Patients must be followed closely for recurrent disease. ABPA should be considered in all patients with asthma or cystic fibrosis, but especially in those with difficult to control disease.
Article
The main problem with using nebulized liposomal amphotericin (n-LAB) as prophylaxis for Aspergillus infection after lung transplantation is the lack of knowledge of its pharmacokinetics and its possible adverse effects. The aim of this study was to measure post-inhalation amphotericin B concentration in the respiratory tract and serum of lung transplant patients and assess the effects of n-LAB on respiratory function. Thirty-two consecutive bronchoscopies were performed on 27 lung transplant patients at two hospitals. Amphotericin B concentration in the first and third aliquot of bronchoalveolar lavage material was measured in steady state. The first aliquot approximates most closely the true amphotericin B concentrations in the proximal airway, whereas the third aliquot provides an optimum sample from the distal airway. At 2 days, mean amphotericin B concentrations were 11.1 microg/ml (95% confidence interval [CI]: 16.5 to 5.7 microg/ml) and 9.0 microg/ml (95% CI: 14.3 to 3.8 microg/ml) in the first and third aliquot, respectively. Thereafter, concentrations declined progressively. At 14 days, concentrations were 3.0 microg/ml (95% CI: 4.4 to 1.5 microg/ml) in the first aliquot and 4.1 microg/ml (95% CI: 6.1 to 2.1 microg/ml) in the third aliquot (p = not statistically significant). Traces of amphotericin B (0.1 microg/ml) were found in serum samples from only 1 of 27 patients. Mean value of forced expiratory volume in the first second (FEV(1)) was similar before and after n-LAB. Amphotericin B concentrations after n-LAB remained high for 14 days, at adequate concentrations for prophylaxis of Aspergillus infection. No significant systemic absorption of amphotericin B was detected and no effect was observed on respiratory function. This promising prophylactic regimen warrants assessment in future clinical studies.
Article
Invasive pulmonary aspergillosis (IPA) is a leading cause of mortality in immunocompromised patients, with the highest risk observed in patients with acute leukaemia or lung transplantation. IPA-prophylactic strategies include administration of aerosolized amphotericin-B. Liposomal amphotericin-B (L-AmB) is one of the formulations available, although few data exist on safety and tolerability. Data on tolerability, systemic toxicity and effects of aerosolized L-AmB on pulmonary function were recorded in a subgroup out of 271 haematological patients enrolled in a placebo-controlled trial on the efficacy of aerosolized L-AmB for the prevention of IPA. Using an adaptive aerosol-delivery system, nebulization of L-AmB or placebo was performed during chemotherapy-induced neutropenia for 30 min/day on 2 consecutive days/week with a maximum of 6 weeks. Thirty-eight patients (41 episodes) received L-AmB, 39 patients (49 episodes) received placebo. Proportions of patients with >20% post-nebulization decline in forced expiratory volume in 1s (FEV(1)) or forced vital capacity (FVC) did not differ between groups. Also 26/38 L-AmB patients (68%) versus 31/39 patients (79%) on placebo had no significant decline during the entire treatment (p=0.20). Coughing was significantly more reported in L-AmB patients (p<0.0001). No differences were observed when baseline and post-nebulization serum levels of renal function and hepatic enzymes were compared. Short-term prophylactic nebulization of L-AmB was well tolerated and not associated with decline in pulmonary function or systemic adverse effects.
Serum IgE and IgG antibody activity against Aspergillus fumigatus was measured in 3 groups of subjects by 2 different immunologic methods. Group A consisted of 23 patients with allergic bronchopulmonary aspergillosis (ABPA). Group B was composed of 19 patients with extrinsic asthma who had marked immediate type skin reactivity to A. fumigatus (prick skin test, 3 or 4+) but no other manifestation of ABPA. Group C, the control group, was composed of 12 healthy subjects. Two immunological methods, including a solid-phase polystyrene tube radioimmunoassay and an iodine-125-labeled, A. fumigatus antigen radioimmunoassay, were used to study each patient's serum sample, so as to demonstrate IgE antibody activity against A. fumigatus (IgE-Af) and IgG antibody activity against A. fumigatus (IgG-Af). Both IgE-Af and IgG-Af were significantly greater among patients in Group A than among those in Group B and Group C, as measured by both methods (P is less than 0.001). The results of this study suggest that either method can be used as a diagnostic aid for ABPA. These methods may provide a laboratory test permitting diagnosis of ABPA in its early stages before bronchial or pulmonary destruction occurs.
Article
Clinical and immunologic characteristics are reported in a series of 20 patients with allergic bronchopulmonary aspergillosis seen by physicians in one consulting service during a period of 9 years. Seventeen of these patients have been identified in the past 2 years, reflecting the increasing recognition of the entity. Fifteen of the 20 patients are believed to have proven diagnoses; the other five are strongly suspected. Asthma, pulmonary infiltrates, and eosinophilia are the usual presenting symptoms. Serum immunoglobulin E was markedly elevated in all patients, and serum immunoglobulin D was normal in four out of five patients sampled. Bronchograms were abnormal in all cases in which they could be done. Lymphocyte transformation may be present in some cases but is not a diagnostic feature. The average age at time of diagnosis was 25.5 years, and seven of the 15 proven patients were 20 or younger.
Article
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.
Article
Allergic bronchopulmonary aspergillosis (ABPA), an immunologically mediated lung disease, occurs predominantly in patients with asthma. This chronic relapsing disorder ranges clinically from mild asthma to fatal destructive lung disease and is caused by hypersensitivity to colonized Aspergillus fumigatus (Af). The immunopathogenesis of the disease is yet to be understood clearly. Specific IgE-Af and IgG-Af, the serological markers, contribute to the diagnosis. Radiologically, ABPA is characterized by fleeting pulmonary infiltrates often confused with pulmonary tuberculosis. However, central bronchiectasis on computed tomography is considered to be the hallmark of the disease. Early diagnosis and therapy with prednisolone, the cornerstone of management, could alter the course of the disease and prevent the development of end-stage lung fibrosis.
Article
Allergic bronchopulmonary aspergillosis (ABPA) complicates chronic asthma and results from hypersensitivity to the fungus Aspergillus fumigatu s, causing an intense systemic immune response and progressive lung damage. We sought to determine whether treatment with the antifungal agent itraconazole reduced eosinophilic airway inflammation in subjects with ABPA. A randomized, double-blind, placebo-controlled trial was performed in stable subjects with ABPA (n = 29). Subjects received 400 mg of itraconazole per day (n = 15) or placebo (n = 14) for 16 weeks. All subjects were reviewed monthly with history, spirometry, and sputum induction to measure airway inflammation, serum total IgE and IgG levels to A fumigatu s, and blood eosinophil counts. By using regression analysis in a random-effects model, subjects receiving itraconazole had a decrease in sputum eosinophils of 35% per week, with no decrease seen in the placebo arm (P <.01). Sputum eosinophil cationic protein levels decreased with itraconazole treatment by 42% per week compared with 23% in the placebo group (P <.01). Itraconazole reduced systemic immune activation, leading to a decrease in serum IgE levels (310 IU/mL) compared with levels seen in the placebo group (increase of 18 IU/mL, P <.01) and a decrease in IgG levels to A fumigatu s (15.4 IU/mL) compared with levels seen in the placebo group (increase of 3.7 IU/mL, P =.03). There were fewer exacerbations requiring oral cortico-steroids in those treated with itraconazole compared with in the placebo group (P =.03). Itraconazole treatment of subjects with stable ABPA reduces eosinophilic airway inflammation, systemic immune activation, and exacerbations. These results imply that itraconazole is a potential adjunctive treatment for ABPA.
Article
Aspergillus fumigatus is a filamentous fungal saprophyte that is ubiquitous in the environment. It is also a human pathogen and induces allergenic response, negatively impacting health care and associated costs significantly around the world. Much of the basic biology of this organism is only poorly understood, but the recent completion and publication of its genome sequence provides an excellent tool for researchers to gain insight into these processes. In this review we will summarize some of the more salient features revealed by analysis of the genome, including the search for candidate pathogenicity genes and the switch to a pathogenic lifestyle, allergen proteins, DNA repair, secondary metabolite gene clusters that produce compounds both useful and toxic, a theoretical capability of this asexual organism to reproduce sexually, signalling, and transcription. A. fumigatus was compared with the food biotechnology fungus Aspergillus oryzae and sexual fungus Aspergillus nidulans, as well as other fungi, in an attempt to discern key differences between these organisms.
Tolerability of prophylactic aerosolized liposomal amphotericin‐B and impact on pulmonary function: data from a randomized placebo‐controlled trial
  • L Slobbe
  • E Boersma
  • BJ Rjinders
Pharmacology and Therapeutics for Dentistry
  • N Park
  • K Shin
  • M Kang