Exhaled biomarkers and gene expression at preschool age improve asthma prediction at 6 years of age

Am J Respir Crit Care Med. 2015 Jan 15;191(2):201-7. doi: 10.1164/rccm.201408-1537OC.


Rationale: A reliable asthma diagnosis is difficult in wheezing preschool children.

Objectives: To assess whether exhaled biomarkers, expression of inflammation genes, and early lung function measurements can improve a reliable asthma prediction in preschool wheezing children.

Methods: Two hundred two preschool recurrent wheezers (aged 2-4 yr) were prospectively followed up until 6 years of age. At 6 years of age, a diagnosis (asthma or transient wheeze) was based on symptoms, lung function, and asthma medication use. The added predictive value (area under the receiver operating characteristic curve [AUC]) of biomarkers to clinical information (assessed with the Asthma Predictive Index [API]) assessed at preschool age in diagnosing asthma at 6 years of age was determined with a validation set. Biomarkers in exhaled breath condensate, exhaled volatile organic compounds (VOCs), gene expression, and airway resistance were measured.

Measurements and main results: At 6 years of age, 198 children were diagnosed (76 with asthma, 122 with transient wheeze). Information on exhaled VOCs significantly improved asthma prediction (AUC, 89% [increase of 28%]; positive predictive value [PPV]/negative predictive value [NPV], 82/83%), which persisted in the validation set. Information on gene expression of toll-like receptor 4, catalase, and tumor necrosis factor-α significantly improved asthma prediction (AUC, 75% [increase of 17%]; PPV/NPV, 76/73%). This could not be confirmed after validation. Biomarkers in exhaled breath condensate and airway resistance (pre- and post- bronchodilator) did not improve an asthma prediction. The combined model with VOCs, gene expression, and API had an AUC of 95% (PPV/NPV, 90/89%).

Conclusions: Adding information on exhaled VOCs and possibly expression of inflammation genes to the API significantly improves an accurate asthma diagnosis in preschool children. Clinical trial registered with www.clinicaltrial.gov (NCT 00422747).

Trial registration: ClinicalTrials.gov NCT00422747.

Keywords: children; exhaled breath condensate; gene expression; volatile organic compounds; wheeze.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Resistance / genetics
  • Airway Resistance / physiology
  • Asthma / diagnosis*
  • Asthma / genetics
  • Asthma / physiopathology
  • Biomarkers / metabolism
  • Breath Tests*
  • Catalase / blood
  • Catalase / genetics
  • Child
  • Child, Preschool
  • Diagnosis, Differential
  • Female
  • Gene Expression Profiling / methods*
  • Humans
  • Inflammation / diagnosis*
  • Inflammation / etiology
  • Inflammation / genetics
  • Logistic Models
  • Male
  • Netherlands
  • Predictive Value of Tests
  • Prospective Studies
  • ROC Curve
  • Respiratory Sounds / diagnosis*
  • Respiratory Sounds / genetics
  • Toll-Like Receptor 4 / blood
  • Toll-Like Receptor 4 / genetics
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Volatile Organic Compounds / analysis


  • Biomarkers
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Volatile Organic Compounds
  • Catalase

Associated data

  • ClinicalTrials.gov/NCT00422747