Aspergillus Species and Other Molds in Respiratory Samples from Patients with Cystic Fibrosis: a Laboratory-Based Study with Focus on Aspergillus fumigatus Azole Resistance

Mortensen, Klaus Leth; Hare, Rasmus Krøger; Johansen, Helle Krogh; Skov, Marianne; Pressler, Tacjana; Howard, Susan J.; Leatherbarrow, Howard; Mellado, Emilia; Arendrup, Maiken Cavling

doi:10.1128/jcm.00213-11

Cited by 159 publications

(166 citation statements)

References 51 publications

(66 reference statements)

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“…The Aspergillus cyp51A gene encodes cytochrome P450 sterol 14a-demethylase and is the target for azole drugs. Between 5% and 20% of CF patients exposed to recent itraconazole courses were found to be either colonised or infected with azole-resistant A. fumigatus in recent studies, while, in another study, 4% of A. fumigatus respiratory isolates from a variety of different patient groups (including CF, chronic obstructive pulmonary disease, intensive care unit cases and ABPA) were itraconazole-resistant [104,105,108]. In some instances, azole cross-resistance has also been documented.…”

Section: Antifungal Therapy In Abpa and Safsmentioning

confidence: 97%

“…It has not yet been clearly demonstrated that the beneficial effects of azoles in ABPA and SAFS are due to their antifungal activity as opposed to alterations in concomitantly administered glucocorticosteroid metabolism or independent anti-inflammatory azole effects [43,51]. Most troubling, however, is the emerging evidence that increased azole usage for various medical conditions and (at least in some geographical regions) agricultural applications is leading to a higher prevalence of azole resistance in clinical A. fumigatus isolates, most commonly due to point mutations in the cyp51A gene [100][101][102][103][104][105][106][107][108]. The Aspergillus cyp51A gene encodes cytochrome P450 sterol 14a-demethylase and is the target for azole drugs.…”

Section: Antifungal Therapy In Abpa and Safsmentioning

confidence: 99%

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Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Moss

2013

European Respiratory Journal

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Severe asthma with fungal sensitisation and allergic bronchopulmonary aspergillosis encompass two closely related subgroups of patients with severe allergic asthma. Pulmonary disease is due to pronounced host inflammatory responses to noninvasive subclinical endobronchial infection with filamentous fungi, usually Aspergillus fumigatus. These patients usually do not achieve satisfactory disease control with conventional treatment of severe asthma, i.e. high-dose inhaled corticosteroids and long-acting bronchodilators. Although prolonged systemic corticosteroids are effective, they carry a substantial toxicity profile. Supplementary or alternative therapies have primarily focused on use of antifungal agents including oral triazoles and inhaled amphotericin B. Immunomodulation with omalizumab, a humanised anti-IgE monoclonal antibody, or "pulse" monthly high-dose intravenous corticosteroid, has also been employed. This article considers the experience with these approaches, with emphasis on recent clinical trials. @ERSpublications Treatment of fungal asthma includes glucocorticoids, azoles, amphotericin and anti-IgE. Trial validation is needed.

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Section: Antifungal Therapy In Abpa and Safsmentioning

confidence: 97%

Section: Antifungal Therapy In Abpa and Safsmentioning

confidence: 99%

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Moss

2013

European Respiratory Journal

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“…1-3 Aspergillus fumigatus (Af) is the most commonly isolated fungus in CF with a prevalence of up to 60%. 4 The fungus is associated with a range of manifestations in CF, most commonly allergic bronchopulmonary aspergillosis (ABPA) and less commonly, aspergillomas and invasive pulmonary aspergillosis. [5][6][7] ABPA affects between 2%-15% of patients with CF (PWCF) and recurrent episodes impact pulmonary function.…”

Section: Abbreviationsmentioning

confidence: 99%

The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis

Mirković

Lavelle

Azim

et al. 2016

Journal of Allergy and Clinical Immunology

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“…In this study, 47 of 921 patients (5.1%) were diagnosed with TR34-L98H and 13 (1.4%) with the TR46-Y121F-T289A mutations. Other mutations have also been described (13)(14)(15)(16). Infections with azole-resistant strains are associated with a very high mortality rate (17).…”

mentioning

confidence: 99%

Validation of a New Aspergillus Real-Time PCR Assay for Direct Detection of Aspergillus and Azole Resistance of Aspergillus fumigatus on Bronchoalveolar Lavage Fluid

Chong

Sande

Dingemans³

et al. 2015

J Clin Microbiol

133

112

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A spergillus fumigatus is the most frequent cause of invasive mold infections in immunocompromised patients. The mortality rate from these infections varies substantially and depends on patient characteristics and the extent of disease. Mortality in intensive care unit (ICU) patients with invasive aspergillosis (IA) can be as high as 90% (1). In hematology patients, a relatively low mortality is observed when the diagnosis is made early and treatment with voriconazole, the current standard of care (2), is initiated promptly (3). In 2002, the landmark study by Herbrecht et al. (4) showed that the treatment of IA with voriconazole resulted in improved survival. However, a series of recent publications described the appearance of azole resistance in A. fumigatus (5-10). This resistance is caused by a mutation in the CYP51A gene of A. fumigatus at position 98 (L98H), together with a 34-bp tandem repeat (TR) in the promoter region (TR34). CYP51A encodes cytochrome p450 sterol 14␣-demethylase, the target of azoles. The majority of these mutated strains were cultured from patients who were never exposed to azoles. It is assumed that resistance development is caused by environmental azole exposure (11). More recently, van der Linden et al. (12) described a second mutation, a 46-bp TR combined with the point mutations Y121F and T289A (12). In this study, 47 of 921 patients (5.1%) were diagnosed with TR34-L98H and 13 (1.4%) with the TR46-Y121F-T289A mutations. Other mutations have also been described (13-16). Infections with azole-resistant strains are associated with a very high mortality rate (17).Currently, the absence of a non-culture-based, fast, and readily available azole susceptibility testing method compromises the identification of azole resistance. This is a major limitation, as the mortality of IA increases substantially when the initiation of adequate therapy is delayed (18). Furthermore, most Aspergillus infections are diagnosed indirectly using galactomannan (or ␤-1,3-D-glucan) testing, because cultures remain negative in most patients. Therefore, even if culture-based azole resistance testing became broadly available, this would be helpful in only a subset of patients.This study describes the laboratory and first clinical validation of the AsperGenius, a new Aspergillus real-time PCR assay that detects Aspergillus species directly from bronchoalveolar lavage

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Aspergillus Species and Other Molds in Respiratory Samples from Patients with Cystic Fibrosis: a Laboratory-Based Study with Focus on Aspergillus fumigatus Azole Resistance

Cited by 159 publications

References 51 publications

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis

The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis

Validation of a New Aspergillus Real-Time PCR Assay for Direct Detection of Aspergillus and Azole Resistance of Aspergillus fumigatus on Bronchoalveolar Lavage Fluid

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