Elsevier

Tuberculosis

Volume 90, Issue 2, March 2010, Pages 145-151
Tuberculosis

Diagnostics
Breath biomarkers of active pulmonary tuberculosis

https://doi.org/10.1016/j.tube.2010.01.003Get rights and content

Summary

Background

Volatile organic compounds (VOCs) in breath may contain biomarkers of active pulmonary tuberculosis derived from the infectious organism (metabolites of Mycobacterium tuberculosis) and from the infected host (products of oxidative stress).

Methods

We analyzed breath VOCs in 226 symptomatic high-risk patients in USA, Philippines, and UK, using gas chromatography/mass spectroscopy. Diagnosis of disease was based on sputum culture, smear microscopy, chest radiography and clinical suspicion of tuberculosis (CSTB). Chromatograms were converted to a series of 8 s overlapping time slices. Biomarkers of active pulmonary tuberculosis were identified with a Monte Carlo analysis of time-slice alveolar gradients (abundance in breath minus abundance in room air).

Results

Breath VOCs contained apparent biomarkers of active pulmonary tuberculosis comprising oxidative stress products (alkanes and alkane derivatives) and volatile metabolites of M. tuberculosis (cyclohexane and benzene derivatives). Breath biomarkers identified active pulmonary tuberculosis with C-statistic (area under curve of receiver operating characteristic) = 0.85 (i.e. 85% overall accuracy, sensitivity = 84.0%, specificity = 64.7%) when sputum culture, microscopy, and chest radiography were either all positive or all negative. Employing a single criterion of disease, C-statistic = 0.76 (smear microscopy), 0.68 (sputum culture), 0.66 (chest radiography) and 0.65 (CSTB).

Conclusion

A breath test identified apparent biomarkers of active pulmonary tuberculosis with 85% accuracy in symptomatic high-risk subjects.

Section snippets

Patients at high risk of active pulmonary TB

226 technically satisfactory breath samples and sputum cultures were obtained from high-risk patients at four sites: the University of California San Diego, California (38). The University of Santo Tomas, Manila, Philippines (100), De La Salle University Hospital, Cavite, Philippines (66), and The East London Tuberculosis Service, London, England (22). Patients aged 13 yr or older were defined as “high-risk” and included in the study if they had one or more symptoms or radiographic findings

Human subjects

Table 1 displays demographics, prevalence of symptoms, results of chest radiography, sputum culture, and sputum microscopy, and subjects assessed as positive or negative for active pulmonary TB. No subject reported any adverse effects associated with breath sample donation.

Concordance between tests for active pulmonary TB

Table 3 displays concordance between results of smear microscopy, sputum culture and chest radiography. Kappa values and results of McNemar's test16 indicate low agreement between these three diagnostic methods, except for

Discussion

Analysis of breath VOCs demonstrated apparent volatile biomarkers of active pulmonary TB, in an international multicenter study of high-risk patients. The VOC biomarkers may have been derived from the infective organism, the host, or from both.

These findings were consistent with the results of an earlier pilot study because the breath VOC biomarkers were similar to those previously observed in human breath, and also to the volatile metabolites of M. tuberculosis observed in vitro.15 The breath

Acknowledgements

This research was supported by SBIR award R44 AI52504-03 from NIH/NIAID. Michael Phillips is President and CEO of Menssana Research, Inc.; he had access to and takes responsibility for the integrity of the data and the accuracy of the data analysis. Other coauthors have no financial interest in the subject matter or any conflict of interest. Michael Phillips designed and supervised the study and drafted the manuscript. Victoria Basa-Dalay, Graham Bothamley, Phung Kim Lam, and Maria Piedad R.

References (38)

  • S. Michiels et al.

    Prediction of cancer outcome with microarrays: a multiple random validation strategy

    Lancet

    (2005)
  • S. Kwiatkowska et al.

    Increased serum concentrations of conjugated diens and malondialdehyde in patients with pulmonary tuberculosis

    Respir Med

    (1999)
  • E.M. Gatner et al.

    Correlation of the results of X-ray and sputum culture in tuberculosis prevalence surveys

    Tubercle

    (1980)
  • J.T. Wilcke et al.

    Diagnostic strategy for pulmonary tuberculosis in a low-incidence country: results of chest X-ray and sputum cultured for Mycobacterium tuberculosis

    Respir Med

    (1997)
  • T.A. Lasko et al.

    The use of receiver operating characteristic curves in biomedical informatics

    J Biomed Inform

    (2005)
  • M. Phillips et al.

    Variation in volatile organic compounds in the breath of normal humans

    J Chromatogr B Biomed Sci Appl

    (1999)
  • Anon

    World TB Day – March 24, 2008

    MMWR

    (2008)
  • M.D. Perkins et al.

    Facing the crisis: improving the diagnosis of tuberculosis in the HIV era

    J Infect Dis

    (2007)
  • A.K. Pavlou et al.

    Sniffing out the truth: clinical diagnosis using the electronic nose

    Clin Chem Lab Med

    (2000)
  • Cited by (209)

    • Detection of tuberculosis-associated compounds from human skin by GCxGC-TOFMS

      2023, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
    • Odors and cancer: Current status and future directions

      2022, Biochimica et Biophysica Acta - Reviews on Cancer
    • Interaction studies of tuberculosis biomarker vapours on novel beta arsenene sheets – A DFT insight

      2021, Computational and Theoretical Chemistry
      Citation Excerpt :

      Before going into the discussion, we designate the adsorption site of different configurations on As-NS. M. Phillips et al. studied pulmonary tuberculosis biomarkers [44]. From the report, we came to know that four VOC are the prominent biomarker for TB, namely hexylcyclohexane, 4-methyldodecane, oxetane, 3-(1-methylethyl), tridecane.

    View all citing articles on Scopus
    h

    Tel.: +63 46 416 0226x238.

    i

    Tel.: +44 (0) 20 8510 7814.

    j

    Tel.: +1 973 643 5464.

    k

    Tel.: +1 619 543 5550; fax: +1 619 543 3276.

    l

    Tel.: +63 (02) 731 3001.

    m

    Tel.: +1 973 733 2225.

    View full text