A Breath Fungal Secondary Metabolite Signature to Diagnose Invasive Aspergillosis

Koo, Sophia; Thomas, Horatio; Daniels, Stephen D.; Lynch, Robert C.; Fortier, Sean M.; Shea, Margaret M.; Rearden, Preshious; Comolli, James C.; Baden, Lindsey R.; Marty, Francisco M.

doi:10.1093/cid/ciu725

Cited by 139 publications

(129 citation statements)

References 36 publications

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“…For example, 2-aminoacetophenone has been detected in the headspace of Pseudomonas aeruginosa cultures (Bean et al 2012) as well as the breath of cystic fibrosis patients chronically colonized with this organism (Scott-Thomas et al 2010). The compounds α- and β-trans-bergamotene have been detected in the headspace of Aspergillus fumigatus cultures, and also in the breath of patients with invasive aspergillosis (Koo et al 2014). Nicotinic acid has been detected in the headspace of Mycobacterium tuberculosis cultures (Syhre and Chambers 2008) and its methylated derivative, methyl nicotinate, has been detected in the breath of M. tuberculosis infected individuals (Syhre et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Volatile metabolic diversity of Klebsiella pneumoniae in nutrient-replete conditions

et al. 2017

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Introduction: Microorganisms catabolize carbon-containing compounds in their environment during growth, releasing a subset of metabolic byproducts as volatile compounds. However, the relationship between growth media and the production of volatile compounds has been largely unexplored to-date. Objectives: To assess the core and media-specific components of the Klebsiella pneumoniae volatile metabolome via growth in four in vitro culture media. Methods: Headspace volatiles produced by cultures of K. pneumoniae after growth to stationary phase in four rich media (brain heart infusion broth, lysogeny broth, Mueller-Hinton broth, and tryptic soy broth) were analyzed using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOFMS). Differences in the composition of headspace volatiles as a function of growth media was assessed using hierarchical clustering analysis (HCA) and principal component analysis (PCA). Results: A total of 365 volatile compounds were associated with the growth of K. pneumoniae across all media, of which 36 (10 %) were common to all growth media, and 148 (41 %) were specific to a single medium. In addition, utilizing all K. pneumoniae-associated volatile compounds, strains clustered as a function of growth media, demonstrating the importance of media in determining the metabolic profile of this organism. Conclusion: K. pneumoniae produces a core suite of volatile compounds across all growth media studied, although the volatile metabolic signature of this organism is fundamentally media-dependent.

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Section: Introductionmentioning

confidence: 99%

Volatile metabolic diversity of Klebsiella pneumoniae in nutrient-replete conditions

et al. 2017

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“…2-Pentylfuran (2-PF) was detected in the breath of patients with A. fumigatus infection (9). It was shown that A. fumigatus produces farnesene when grown in vitro (10), and the use of terpene volatiles for the detection of IA has recently been proposed (11). However, the spectrum of volatile organic compounds (VOCs) produced by A. fumigatus and their synthesis have been poorly described.…”

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confidence: 99%

The Volatome of Aspergillus fumigatus

2014

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bEarly detection of invasive aspergillosis is absolutely required for efficient therapy of this fungal infection. The identification of fungal volatiles in patient breath can be an alternative for the detection of Aspergillus fumigatus that still remains problematic. In this work, we investigated the production of volatile organic compounds (VOCs) by A. fumigatus in vitro, and we show that volatile production depends on the nutritional environment. A. fumigatus produces a multiplicity of VOCs, predominantly terpenes and related compounds. The production of sesquiterpenoid compounds was found to be strongly induced by increased iron concentrations and certain drugs, i.e., pravastatin. Terpenes that were always detectable in large amounts were ␣-pinene, camphene, and limonene, as well as sesquiterpenes, identified as ␣-bergamotene and ␤-trans-bergamotene. Other substance classes that were found to be present in the volatome, such as 1-octen-3-ol, 3-octanone, and pyrazines, were found only under specific growth conditions. Drugs that interfere with the terpene biosynthesis pathway influenced the composition of the fungal volatome, and most notably, a block of sesquiterpene biosynthesis by the bisphosphonate alendronate fundamentally changed the VOC composition. Using deletion mutants, we also show that a terpene cyclase and a putative kaurene synthase are essential for the synthesis of volatile terpenes by A. fumigatus. The present analysis of in vitro volatile production by A. fumigatus suggests that VOCs may be used in the diagnosis of infections caused by this fungus.A spergillus fumigatus is an opportunistic fungal pathogen that causes life-threatening invasive pulmonary infections (invasive aspergillosis [IA]) among immunocompromised patients. A sensitive, rapid, and accurate diagnostic assay for invasive aspergillosis is required to successfully fight this fungal infection (1). It has recently been proposed that the detection of volatiles can be used for the diagnosis of pulmonary infections (2, 3) and lung cancer (4, 5). Several aspergilli, including A. flavus, A. ustus, and A. versicolor, have been identified within the scope of environmental studies, where room air was analyzed to detect fungal pollution in houses (6-8). 2-Pentylfuran (2-PF) was detected in the breath of patients with A. fumigatus infection (9). It was shown that A. fumigatus produces farnesene when grown in vitro (10), and the use of terpene volatiles for the detection of IA has recently been proposed (11). However, the spectrum of volatile organic compounds (VOCs) produced by A. fumigatus and their synthesis have been poorly described. In this work, we characterized the patterns of volatile terpenes produced in vitro by A. fumigatus during growth under saprophytic conditions. In addition, the molecular pathways responsible for the synthesis of terpenoid volatiles were defined. MATERIALS AND METHODS Strains.Aspergillus fumigatus strain FGSC A1163 (ϭ DAL ϭ CBS144.89) was used for wild type strain-based experiments. Gene deletions were obta...

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“…This biomarker was demonstrated to be exhaled by patients and to be produced by A. fumigatus in vitro (46,47). Similarly, recent GC-MS and gas chromatography-solidphase microextraction studies of A. fumigatus in vitro and in vivo demonstrated other candidate VOCs for IA, such as monoterpenes and sesquiterpenes (18,48). Last, the current study strengthens the suggestion that eNose technology can detect such a distinct profile of metabolites produced by A. fumigatus in vivo by means of exhaled breath analysis.…”

Section: Discussionmentioning

confidence: 81%

“…Previously, we showed that patients with PCIN and IA have a distinct exhaled breath profile that can be discriminated by an electronic nose (eNose) (17). Very recently, this was confirmed by using gas chromatography-mass spectrometry (GC-MS), demonstrating exhaled metabolite signatures of Aspergillus fumigatus in vitro and IA in vivo (18).…”

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confidence: 82%

Detection of Airway Colonization by Aspergillus fumigatus by Use of Electronic Nose Technology in Patients with Cystic Fibrosis

et al. 2016

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Currently, there is no noninvasive test that can reliably diagnose early invasive pulmonary aspergillosis (IA). An electronic nose (eNose) can discriminate various lung diseases through an analysis of exhaled volatile organic compounds. We recently published a proof-of-principle study showing that patients with prolonged chemotherapy-induced neutropenia and IA have a distinct exhaled breath profile (or breathprint) that can be discriminated with an eNose. An eNose is cheap and noninvasive, and it yields results within minutes. We determined whether Aspergillus fumigatus colonization may also be detected with an eNose in cystic fibrosis (CF) patients. Exhaled breath samples of 27 CF patients were analyzed with a Cyranose 320. Culture of sputum samples defined the A. fumigatus colonization status. eNose data were classified using canonical discriminant analysis after principal component reduction. Our primary outcome was cross-validated accuracy, defined as the percentage of correctly classified subjects using the leave-one-out method. The P value was calculated by the generation of 100,000 random alternative classifications. Nine of the 27 subjects were colonized by A. fumigatus. In total, 3 subjects were misclassified, resulting in a crossvalidated accuracy of the Cyranose detecting IA of 89% (P ‫؍‬ 0.004; sensitivity, 78%; specificity, 94%). Receiver operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.89. The results indicate that A. fumigatus colonization leads to a distinctive breathprint in CF patients. The present proof-of-concept data merit external validation and monitoring studies.T he diagnosis of invasive pulmonary aspergillosis (IA) in patients with prolonged chemotherapy-induced neutropenia (PCIN) remains a frequently occurring and difficult challenge (1-3). The signs and symptoms are nonspecific (4, 5). Mortality is high, especially in case of a diagnostic delay (3, 6, 7). The Platelia galactomannan assay (Bio-Rad) performed on bronchoalveolar lavage fluid samples is the only test with sufficient sensitivity and specificity to demonstrate or rule out IA (8). Its major drawback is the invasive and highly uncomfortable nature of bronchoalveolar lavage (9-13).The Platelia galactomannan assay was originally developed to be used on serum. Although diagnostic accuracy is significantly lower in this setting, it creates the opportunity to serially monitor patients who are at high risk, such as acute myeloid leukemia (AML) patients treated with intensive induction chemotherapy (14). This might enable earlier diagnosis and thus a better prognosis. This is the topic of a number of ongoing studies. Unfortunately, two already-published studies did not show that serial monitoring of galactomannan leads to an earlier diagnosis (15, 16). Previously, we showed that patients with PCIN and IA have a distinct exhaled breath profile that can be discriminated by an electronic nose (eNose) (17). Very recently, this was confirmed by using gas chromatography-mass spectrometry (GC-MS), dem...

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A Breath Fungal Secondary Metabolite Signature to Diagnose Invasive Aspergillosis

Cited by 139 publications

References 36 publications

Volatile metabolic diversity of Klebsiella pneumoniae in nutrient-replete conditions

Volatile metabolic diversity of Klebsiella pneumoniae in nutrient-replete conditions

The Volatome of Aspergillus fumigatus

Detection of Airway Colonization by Aspergillus fumigatus by Use of Electronic Nose Technology in Patients with Cystic Fibrosis

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