Exhaled Endogenous VOCs Help Differentiate Between Asthma Phenotypes

Eosinophil Scan
Eosinophil Scan
Investigators characterized exhaled endogenous volatile organic compounds through sputum from a discovery study and subsequent replication study of >500 patients with asthma.

Among people with asthma, detection of 4 different exhaled endogenous volatile organic compounds (VOCs) helped investigators successfully differentiate between bronchial inflammation subtypes, distinguishing eosinophilic and neutrophilic asthma phenotypes at levels meeting or exceeding the discriminatory abilities of more established methodologies, according to a report in the American Journal of Respiratory and Critical Care Medicine.

The ability to phenotype asthma by inflammatory mechanisms allows for more targeted therapies. While sputum induction remains the gold standard for this purpose, it is not widely available and often impractical. Investigators, in a first of its kind attempt, sought to use noninvasive exhaled VOCs to identify eosinophilic and neutrophilic asthma subtypes for the purposes of comparing this method with other surrogate markers for eosinophilic asthma and establishing biomarkers for neutrophilic asthma that were heretofore lacking.

A total of 521 patients with asthma were enrolled in a prospective cross-sectional trial that was divided into a discovery study (n=276) and a replication study (n=245), independently recruiting participants from 2010 to 2014 and from 2014 to 2018, respectively. All patients gave blood samples and underwent sputum induction, VOC measurement, and spirometry to calculate the fraction of exhaled nitric oxide (FeNO), in addition to completing questionnaires. At follow-up a week later, all patients refrained from bronchodilator use before being given a methacholine challenge.

Sputum granulocytic count classified participants into 1 of 3 inflammatory phenotypes: eosinophilic, neutrophilic, or paucigranulocytic. Pairwise comparisons were made between the first 2 phenotypes, as well as between the first and third and between the second and third phenotypes. Discriminatory power was assessed using area under the receiver operating characteristic curve (AUROC).

The discovery study involved 122 patients with eosinophilic asthma (mean age, 53 years; 55% women), 50 patients with neutrophilic asthma (mean age, 52 years; 72% women) and 90 patients with paucigranulocytic asthma (mean age, 44 years; 58% women). The replication study involved 90 patients with eosinophilic asthma (mean age, 54 years; 50% women), 53 patients with neutrophilic asthma (mean age, 59 years; 49% women) and 90 patients with paucigranulocytic asthma (mean age, 52 years; 58% women).

In the discovery study, gas chromatography with mass spectrometry was used to identify 7 potential biomarkers, while the replication study used 2-dimensional gas chromatography with high-resolution time-of-flight mass spectrometry to confirm 4 VOCs as potential biomarkers to differentiate inflammatory asthma phenotypes.

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In classifying eosinophilic asthma, hexane and 2-hexanone performed best, demonstrating comparable accuracy to that seen with FeNO and blood eosinophils. When the 2 VOCs were combined with these other surrogate markers, the combination accurately predicted this asthma subtype (AUROC 0.9). For classification of neutrophilic asthma, where markers were lacking, hexane, 1-propanol and nonanal combined to predict this inflammatory subtype at levels comparable to that seen with blood eosinophils or FeNO in eosinophilic inflammation (AUROC 0.71). The levels of all 3 of these VOC biomarkers were higher in neutrophilic asthma and lower in eosinophilic asthma.

There was no effect of age on any results, and the various VOCs used were not able to discriminate between classes of smokers, nor were they capable of differentiating according to inhaled steroid use or lack thereof.

One study limitation identified was sputum cell count use as a gold standard for asthma inflammatory phenotype classification.

“We believe that the four compounds identified may become a powerful biochemical signature to discriminate between inflammatory phenotypes,” noted the authors. They recommended that future research explore the utility of VOC monitoring for purposes of tracking responsiveness to maintenance therapies.


Schleich FN, Zanella D, Stefanuto P-H, et al. Exhaled volatile organic compounds are able to discriminate between neutrophilic and eosinophilic asthma [published online April 11, 2019]. Am J Respir Crit Care Med. doi:10.1164/rccm.201811-2210OC