A breath fungal secondary metabolite signature to diagnose invasive aspergillosis

Clin Infect Dis. 2014 Dec 15;59(12):1733-40. doi: 10.1093/cid/ciu725. Epub 2014 Oct 22.


Background: Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection.

Methods: Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples.

Results: The monoterpenes camphene, α- and β-pinene, and limonene, and the sesquiterpene compounds α- and β-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, β-trans-bergamotene, a β-vatirenene-like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%-98%) and 93% specificity (95% CI, 79%-98%).

Conclusions: In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia.

Keywords: aspergillosis; breath; diagnostics; fungal infection; volatile organic compounds.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aspergillosis / diagnosis*
  • Aspergillosis / metabolism*
  • Aspergillus fumigatus / metabolism*
  • Aspergillus fumigatus / pathogenicity*
  • Bicyclic Monoterpenes
  • Bridged Bicyclo Compounds / analysis
  • Cyclohexenes / analysis
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Humans
  • Limonene
  • Male
  • Middle Aged
  • Monoterpenes / analysis
  • Prospective Studies
  • Sesquiterpenes / analysis
  • Terpenes / analysis


  • Bicyclic Monoterpenes
  • Bridged Bicyclo Compounds
  • Cyclohexenes
  • Monoterpenes
  • Sesquiterpenes
  • Terpenes
  • beta-pinene
  • Limonene
  • camphene
  • alpha-pinene