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Breath Analysis: Revolutionizing Diagnosis and Monitoring of Cystic Fibrosis

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Cystic fibrosis is a genetic disorder that causes a build-up of thick, viscous mucus in organs, most commonly the gastrointestinal and pulmonary systems. Affecting over 80,000 people worldwide, cystic fibrosis occurs in approximately 1 in 3,500 births per year.

Although the disease can affect multiple organ systems, its effects on the pulmonary system are the leading cause of patient death. Current diagnostic and monitoring techniques for cystic fibrosis can be uncomfortable for the patients, a challenge that breath analysis, an inexhaustible source with a comfortable and non-invasive sampling method, could overcome.

Understanding the complexities of cystic fibrosis: from genetic mutations to diagnostic challenges

Cystic fibrosis is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene. The CFTR protein normally produced by this gene forms a channel to transport ions such as sodium and chloride through the membranes of cells throughout the body, including the lungs.

The transport of these ions helps control the movement of water in tissues, which is necessary to produce thin (normal) mucus. When mutations occur, sodium and chloride become trapped in cells and cannot attract the fluids needed to hydrate cells, and mucus becomes dehydrated and sticky.

Cilia, tiny hairs along the walls of the airways, and mucus work together to trap unwanted bacteria and microbes and stop us from getting sick. However, in people with cystic fibrosis, the mixture of thick, sticky mucus and altered ion transport can allow bacteria such as Pseudomonas and Staphylococcus aureus to colonize the respiratory tract, causing an inflammatory response. An infection tied with inflammation can lead to airway constriction with this being the main cause of death in 80–95% of patients.

Thirty years ago, the average person with cystic fibrosis would live to the age of 30, but now life expectancy has risen to 50 years, with some patients living well into their 80s. This increase is likely due to therapeutic interventions administered before the onset of cystic fibrosis symptoms having a greater long-term benefit. All babies born in the UK are screened for cystic fibrosis, enabling presymptomatic diagnosis, and potentially preventing irreversible pulmonary damage.

Routine monitoring and assessment are crucial in providing effective long-term care to cystic fibrosis patients. Some patients require pulmonary monitoring via regular sputum sampling, potentially weekly for higher-risk patients. Patients must cough hard to expel sputum, which can be very uncomfortable, especially with repetition for ongoing monitoring.

Despite a recent treatment breakthrough, there remains an unmet need for disease monitoring

Patients diagnosed with cystic fibrosis require extensive follow-up and management, with chest radiographs being the most common tool to monitor disease progression. There is no cure for cystic fibrosis, but a range of treatments can help control symptoms, reduce complications and improve patient quality of life.

Patients with cystic fibrosis are prone to bacterial infections due to mucus buildup; sputum samples allow healthcare professionals to detect and identify bacterial species present and prescribe the most effective antibiotics.

Medicines like mucolytic medications that make the mucus thinner and easier for clearance in the lungs are effective for cystic fibrosis patients. However, not all patients can benefit from these medicines due to varied treatment responses, which are largely influenced by factors such as the patient’s genetic background, disease severity and the presence of other lung complications.

In 2019, the Food and Drug Administration (FDA) approved a breakthrough new drug, Trikafta®, for cystic fibrosis treatmentTrikafta combines three major chemical compounds: tezacaftor, ivacaftor and elexacaftor. Tezacaftor helps correct the folding of the CFTR protein, while ivacaftor and elexacaftor bind to different locations on the CFTR protein, increasing chloride transport. This normalization of CFTR protein function reduces the accumulation of thick and sticky mucus, preventing airway blockage and decreasing the risk of bacterial infections.

However, like other available mucolytic medications, many patients who have taken Trikafta experience reduced sputum production, meaning it becomes less clear if changes in sputum biomarkers are due to medication taking effect on the cystic fibrosis, or the patient’s ability to produce sputum. Some patients may struggle to produce any sputum at all, rendering sputum sampling impossible, highlighting the need for alternative biomarkers for cystic fibrosis.


The benefits of breath analysis and its potential in cystic fibrosis disease management

Breath sampling and analysis offer several advantages over other monitoring technologies. Given its non-invasive nature, breath sampling is more comfortable for patients and offers the potential for at-home breath tests, saving time compared to clinic visits and reducing the risk of contracting pathogens.

Breath contains volatile organic compounds (VOCs), including metabolites produced by various physiological processes, which have the potential to serve as biomarkers for disease diagnosis and treatment monitoring.

In cystic fibrosis, airway inflammation is a common pathophysiology that results in oxidative stress. The elevation of reactive oxygen species (ROS) can break down cell membranes through lipid peroxidation, resulting in the production of VOCs. If the levels of these VOCs are found to be different in the exhaled breath of diseased subjects compared to healthy controls, they can be validated as biomarkers of inflammation.

A study conducted by Barker et al has demonstrated the differences in breath volatile metabolites between cystic fibrosis patients and healthy controls (aged 8–29), with compounds indicative of inflammation, in particular pentane, showing higher levels in cystic fibrosis patients than healthy controls. Even higher levels of pentane were detected in those experiencing pulmonary exacerbations, a sudden worsening of conditions in cystic fibrosis, as well as in those with chronic Pseudomonas infection, a well-known stimulant of neutrophilic airway inflammation.

The identification of breath biomarkers indicative of specific types of inflammation resulting from certain bacterial infections can replace the necessity of sputum biomarkers for treatment monitoring.

Additionally, exhaled breath volatile compounds can encompass metabolites such as sulfur-containing compounds like dimethyl sulfide and ketones like 2-pentanone, which are known to be produced by bacteria. This indicates the potential applications for breath analysis in detecting bacterial colonization or infection.

With an understanding of specific volatile compounds produced by certain bacterial strains, unique breath signatures can help clinicians rapidly identify bacterial species present, enabling faster selection of antibiotic treatments. The convenience of breath sampling not only enables early detection of bacterial infections, preventing exacerbation episodes but also facilitates easier treatment monitoring of medications like Trikafta.

Breath analysis emerges as a promising non-invasive solution, offering personalized insights into disease conditions and treatment responses. With its numerous benefits in biological sampling and the opportunity for validation of volatile compounds indicative of inflammation and/or bacterial infections as biomarkers, breath analysis has the potential to be a revolutionary tool for cystic fibrosis management.

About the authors:

Lucy Godbeer is a scientific marketing associate at Owlstone Medical, assisting with written content for the company. Lucy graduated with a degree in Biology and has an MSc in Biomedical Science. 

Dr. Tina Chou is a senior biomarker scientist at Owlstone Medical, where she is responsible for supporting customers in study design, data interpretation, report delivery and manuscript writing. She is also involved in scientific content writing as part of the company’s technical sales and marketing efforts. Tina holds a PhD in Plant Science from the University of Connecticut and has several years of post-doctoral experience working with omics data in the broader biology field at North Carolina State University before joining Owlstone in late 2021.