Monitoring Pulmonary Exacerbation in Cystic Fibrosis: The Hunt for Urine-based Biomarkers Begins

The buildup of mucus in the lungs is an ongoing challenge faced by people with cystic fibrosis, and knowing whether they should seek medical attention is not always clear.

Recently, Mologic - a developer of personalized diagnostics - have developed a tool which they hope will help guide people with cystic fibrosis so they can avoid unnecessary stays in hospital.

The app-embedded algorithm converts data collected from a urinary test to a traffic light result, which indicates whether a patient is stable or in need of medical intervention.

Recently, Mologic, announced that they are launching a clinical trial to assess the company's urine-based diagnostic tool, 'HeadsUp'.

To learn more about how this point-of-care diagnostic tool could help improve healthcare for people with cystic fibrosis, we spoke with Gita Parekh, Head of R&D at Mologic.

How do you define pulmonary exacerbation, and why is it important that it is monitored in people with cystic fibrosis?

There is currently no universally agreed definition of pulmonary exacerbations, nor is there consensus about the diagnostic criteria, although there are a lot of commonalities across the different definitions in the public domain.

Clinical features of an exacerbation generally include increased cough, increased sputum production (or a change in color), shortness of breath, chest pain, loss of appetite, loss of weight, and lung function decline.

The main difference of opinion is whether the physician’s decision to treat with additional or new antibiotic therapy should be considered as one of the key criteria, with the variability in clinician’s approach to treatment being the primary reason for potentially excluding this.

Pulmonary exacerbations typically require treatment with antibiotics, with intravenous (IV) therapy commonly required to treat more severe exacerbations.

Most courses of IV therapy require hospital admission, with an average inpatient stay of 10-14 days at a typical cost of £675- £1,100 per night. Pulmonary exacerbations can also contribute to long-term deterioration in lung function in people with cystic fibrosis.

A monitoring system which is able to provide early warning or confirmation of an exacerbation will enable appropriate treatment to be started earlier, reducing the need for hospitalisation, and minimising long-term damage to the patient. 

Research scientists at Mologic have been working to develop a simple, non-invasive test that helps patients suffering from chronic lung disease to understand, monitor and manage their condition at home. Credit: Mologic.

Can you give us an overview of what methods are currently used to identify and monitor pulmonary exacerbation? 

Currently there are no home cystic fibrosis exacerbation diagnostic tests. Treatment of patients is through hospital visits and telephone support.

There are some home cystic fibrosis monitoring Apps which are limited to inputting symptoms and/or spirometry measurement of lung function, both of which are late indicators of exacerbation and suffer from variability in test performance and symptom identification.

In the UK, the Standards for Care recommend regular routine outpatient reviews every 6-8 weeks which include a physical examination, culture of sputum, spirometry, chest X-ray, and a review by a physiotherapist and dietitian. There is also an annual review which includes a detailed assessment of the patient’s treatment and condition to identify areas where treatment could be improved. 

None of the above provides early warning of exacerbation. There is a large unmet need for better disease management and pre-emptive medication because significant, irreversible losses of lung function occur with every exacerbation. 

The cystic fibrosis HeadsUp device was developed using the same technique which underlies the standard pregnancy test.

Which biomarkers do you intend to measure, and what do they represent? 

The five biomarkers used need to be selected from a current panel of 15. We’ve already shown that these biomarkers change when symptoms are first seen, but we’re looking to select a combination of five (or fewer) biomarkers that can predict the diagnosis of an exacerbation even earlier.

This selection will be confirmed during the first phase of the clinical trial. The biomarkers that are being evaluated are all known markers of inflammation, and they include:

• Signalling molecules that recruit neutrophils to the inflammation site
• Degranulation molecules including proteases released by the neutrophils to fight off the infection that can become self-destructive
• Protease inhibitors that usually regulate the proteases that are impaired thus causing a further imbalance
• Degradation molecules that are a consequence of the damage caused by the proteases to the lung structure such as elastin and collagen
• Other additional biomarkers which are contributed by the kidneys themselves as a result of the downstream damage

How will data be collected in this clinical trial? How do you hope this information will be used to inform medical decisions and improve healthcare?

In Phase 1 of this two-phase study, 40 subjects will be performing a number of daily tests for four  months, as well as taking a daily urine sample which will be sent to Mologic for testing with the biomarker panel to confirm the selection of the final five.

In Phase 2, the patients will be performing the HeadsUp test on a daily basis for a further four months, both validating the final selection of biomarkers and providing information about the usability of the test system. 

The introduction of HeadsUp as a home use test will enable earlier detection of pulmonary exacerbation, and therefore the initiation of prompt treatment leading to improved patient outcomes, and a reduction in healthcare costs.

Earlier detection and intervention will also help to reduce the loss of lung function.

The trial is designed to validate the use of this novel point-of-care test for patient's self monitoring of their condition.

Is there a story behind the name of the diagnostic test, ‘HeadsUp’? 

The name came about for two reasons. HeadsUp means giving advance warning of something, and of course this is exactly what the test does – gives advance warning of an exacerbation.

We also like to think that it helps people with cystic fibrosis to hold their heads up, helping to improve their quality of life.

Gita Parekh, Head of R&D at Mologic, was speaking to Michele Wilson, Science Writer for Technology Networks.