Lung Rejection
Patterns and significance of exhaled-breath biomarkers in lung transplant recipients with acute allograft rejection

https://doi.org/10.1016/S1053-2498(01)00343-6Get rights and content

Abstract

Background

Obliterative bronchiolitis (OB) remains one of the leading causes of death in lung transplant recipients after 2 years, and acute rejection (AR) of lung allograft is a major risk factor for OB. Treatment of AR may reduce the incidence of OB, although diagnosis of AR often requires bronchoscopic lung biopsy. In this study, we evaluated the utility of exhaled-breath biomarkers for the non-invasive diagnosis of AR.

Methods

We obtained breath samples from 44 consecutive lung transplant recipients who attended ambulatory follow-up visits for the Johns Hopkins Lung Transplant Program. Bronchoscopy within 7 days of their breath samples showed histopathology in 21of these patients, and we included them in our analysis. We measured hydrocarbon markers of pro-oxidant events (ethane and 1-pentane), isoprene, acetone, and sulfur-containing compounds (hydrogen sulfide and carbonyl sulfide) in exhaled breath and compared their levels to the lung histopathology, graded as stable (non-rejection) or AR. None of the study subjects were diagnosed with OB or infection at the time of the clinical bronchoscopy.

Results

We found no significant difference in exhaled levels of hydrocarbons, acetone, or hydrogen sulfide between the stable and AR groups. However, we did find significant increase in exhaled carbonyl sulfide (COS) levels in AR subjects compared with stable subjects. We also observed a trend in 7 of 8 patients who had serial sets of breath and histopathology data that supported a role for COS as a breath biomarker of AR.

Conclusions

This study demonstrated elevations in exhaled COS levels in subjects with AR compared with stable subjects, suggesting a diagnostic role for this non-invasive biomarker. Further exploration of breath analysis in lung transplant recipients is warranted to complement fiberoptic bronchoscopy and obviate the need for this procedure in some patients.

Section snippets

Materials and methods

This study was conducted during a 10-month period (March to December 1999) among ambulatory lung transplant recipients who attended routine follow-up visits at the Johns Hopkins Medical Institutions Lung Transplantation Program (Baltimore, MD). Patients gave verbal consent to breath sampling (no patients refused). Data from patients who underwent single fiberoptic bronchoscopy (see below) within 7 days of their exhaled-breath sample are presented in this study. For patients who underwent

Results

We obtained 152 breath samples from 44 consecutive patients during the study period. Of these, 21 patients (5 double lung and 16 single lung transplants) met criteria for inclusion in this analysis (histology available from fiberoptic bronchoscopy within 7 days of breath sampling). Table I presents the demographics and key clinical descriptors of the 21 study subjects.

Subjects were grouped into those with histologic evidence of AR (n = 6) and those without AR (n = 15), and their exhaled gas

Discussion

This study reports information on a novel test for AR of lung allografts in humans. We hypothesized that exhaled-breath biomarkers would evidence measurable changes during AR and this was demonstrated for COS. In our study, most patients without AR had undetectable or low exhaled COS levels, whereas only 1 subject with AR had an undetectable level of exhaled COS. If these findings are confirmed in future studies, patients with undetectable COS levels and stable pulmonary function may be

Acknowledgements

This work was supported by NIH Grant P01-HL56091. The authors wish to thank Helena Studer, MD, for her editorial assistance.

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