Breath-Based Diagnosis of Infectious Diseases

Key points

Introduction

Breath has been proposed to hold diagnostic clues to pathophysiologic processes since ancient times. Ancient Greek physicians described a sweet smell in patients with diabetes and a fishlike odor emanating from patients with what is now known to be kidney disease. ¹

The modern era of breath analysis started when biochemist Linus Pauling characterized the landscape of volatile organic compounds (VOCs) in human breath using methods available to him at the time, finding these VOCs to originate from numerous endogenous biochemical processes, including aldehydes and alkanes from lipid oxidation and ketones from carbohydrate and fatty acid metabolism. 2345 Gas-phase metabolites and breakdown products originating from these processes are carried through the circulatory system and rapidly excreted through the lungs.

These VOCs are diluted in a bulk matrix of nitrogen, oxygen, carbon dioxide, water vapor, and inert gases, and typically present in trace concentrations in the breath. Although a few highly abundant compounds, such as acetone, are present in the low parts-per-million range, most VOCs are present in the low parts-per-billion (ppb) to parts-per-trillion (ppt) range. The low concentration of these analytes is one of the challenges in reliably identifying metabolic changes in the breath that indicate disease processes, with the need for methods to concentrate these metabolites before analysis on most analytical instrumentation. Other challenges include the natural variability of breath compounds diurnally and with varying age and sex; the potential for exogenous VOCs from the patient’s environment in the breath sample; the chemical complexity of breath samples, which can contain hundreds to a thousand VOCs; and the lack of standardized methods for breath collection, which in aggregate may lead to findings that are not generalizable. ⁶

Furthermore, the term breath analysis is primarily used when referring to the analysis of VOCs, which are truly volatile or semivolatile and found in the gas phase of the breath sample, but it is also sometimes used to refer to the analysis of larger molecules, including nucleic acids and proteins, suspended in aerosols and droplets in the liquid component of the breath. To analyze this fraction of the breath, the breath is generally collected in a cooled container and the condensate examined for these analytes.

With the development of effective preconcentration methods and increasingly sensitive analytical instruments capable of identifying and quantifying analytes at ultratrace levels, various analytes in the exhaled breath have been assessed for the identification of pathophysiologic processes, including infectious diseases. The ultimate objective of identifying and validating breath biomarkers of various infections is to identify these processes at an earlier stage than currently possible with existing culture, antigen, and molecular methods; to facilitate early, appropriate antimicrobial prescribing; to reduce unnecessary antimicrobial exposure; and to improve clinical outcomes in patients with these infections.