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Monitor Bowel Inflammation on the Go

Making Home Faecal Calprotectin Test a Reality to Revolutionise IBD Treatment.

by Dr Allen Lai, Dr David Ong, Dr Thomson Lim,
Dr Webber Chan, and Dr Kristine Paridaens

Smartphone-enabled point of care from home is the next big thing to improve health service delivery. Such a change is ideal now due to the COVID-19 pandemic, as patients and caregivers are advised to reduce their hospital visits. This movement towards telemedicine has expedited the paradigm shift for diagnostics from conventional hospital-based testing to home-based diagnostics using mobile applications.

For most inflammatory bowel disease (IBD) patients who require long-term disease monitoring, an endoscopy is not always possible. A simple and non-invasive biomarker to detect and monitor intestinal inflammation in patients with IBD is desired. Faecal calprotectin (FC) is such a test.

In this article, medical experts in gastroenterology will describe FC testing in IBD as an example to highlight the opportunities and what the future holds for home FC tests to become a reality in IBD diagnosis and monitoring.

 

Inflammatory Bowel Disease: Prevalence, Diagnosis, and Unmet Needs

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic idiopathic disorder causing inflammation of the gastrointestinal tract. It affects over 2 million individuals in North America, 3.2 million in Europe, and millions more worldwide.1

At the turn of the 21st century, epidemiologic studies from the Western world indicated a changing pattern in the incidence of IBD. Western countries reported stabilization of incidence, and even decreasing incidence in some regions.2 Meanwhile, epidemiologic studies from newly industrialized countries in Asia and Latin America,3,4 reported an increasing incidence and prevalence of IBD, and it is believed that numbers would continue to surge in the next decade.

The diagnosis of IBD can be challenging and requires a comprehensive assessment, including clinical history, physical examination, and diagnostic tests, such as endoscopy, histological evaluation of tissue, cross-sectional images, and blood biochemical and faecal biomarkers. In the Asia-Pacific region, accurate diagnosis of IBD is made more challenging because of various infections and diseases that mimic IBD, such as intestinal tuberculosis,5 and Behçet’s disease.6

The gold standard in detecting gastrointestinal inflammation is to perform an endoscopy with biopsy.7 However, endoscopy is an expensive and invasive procedure with risks such as bleeding and perforation. A non-invasive surrogate biomarker is needed and comes in the form of faecal calprotectin, which is a test that can be used for monitoring inflammatory load.

 

Faecal Calprotectin and its Involvement in the Diagnosis and Monitoring of IBD

Calprotectin is a protein found in human white cells involved in many physiological functions. Calprotectin contributes mainly to the body’s immune regulation and inflammatory processes. Hence, it can be found throughout the human body, for example, in saliva, faeces, and urine.

Inflammation in the gut leads to increased permeability of the gut mucosa and migration of white cells towards the bowel.8 This subsequently causes the release of calprotectin and other immune mediators from these white cells into the intestinal lumen, resulting in the increase of the amount of calprotectin in faeces.

In the case of IBD, faecal calprotectin (FC) increases in acute inflammation whereas during IBD remission, FC concentration decreases. Persistent high FC levels during therapy may indicate necessity for dose optimisation or endoscopic assessment. For IBD patients after colectomy, FC testing informs patients and doctors of treatment efficacy or flare, predicting post-surgical recurrence in asymptomatic IBD patients.9 Using an enzyme-linked immunosorbent assay (ELISA), FC concentrations associate well with the severity of gastrointestinal tract inflammation.10 This is because faeces have direct contact with intestinal mucosa, and an increased amount of calprotectin is secreted by white cells into the intestine during the inflammatory process.11

 

The use of FC has its advantages:

First, FC test is stable in room temperature for up to 7 days. FC is resistant to degradation by intestinal secretions or digestive enzymes. It demonstrates stability in stool at room temperature for up to one week.12 It is also homogeneously distributed in stool, making it a good surrogate biomarker to measure inflammatory activity in the bowel.

Second, FC test is simple and sensitive. It is simple because IBD patients can simply collect their stools in a specimen container and return it to the clinic or laboratory before their next clinic appointment. Moreover, FC test is highly sensitive to detect disease occurrence, relapse, and response to treatment, because it correlates very well with endoscopic indices.13 For example, an asymptomatic IBD patient with a high calprotectin level has an 80 percent chance of a clinical relapse in the next 2 to 3 months, whereas only 20 percent of patients with a low calprotectin level will develop a clinical flare.14

Third, COVID-19 pandemic. As patients are advised to reduce their clinic visits and endoscopic assessment during COVID-19 pandemic period, use of FC tests help patients decrease their exposure to the hospital environment with its inherent risks of COVID-19 and other infections. A systemic review shows FC levels were elevated in a significant number of patients with COVID-19, resulting from SARS-CoV-2 gastrointestinal inflammation.15 Hence, FC tests can inform IBD patients in a timely manner to seek further evaluation whether they have diarrhoea from an IBD flare or COVID-19 infection.

Hence, FC is frequently used in clinical settings as a surrogate marker for intestinal inflammation for IBD patients. As more evidence accumulates, clinical guidelines in the EU and US espouse the use of FC test for screening and monitoring of IBD.16 In practice, it enables both physicians and patients to make an objective clinical decision to escalate or de-escalate IBD therapy.

As such, FC has been proven to be one of the preferred biomarkers of choice for IBD management. Of note, ELISA-based FC test is mainly conducted in batches at central labs in tertiary healthcare institutions or commercial reference laboratories. Sample testing can take up to two hours, but the time taken for total sample processing and results varies from days to weeks.

 

The Eureka Moment: Home-based Faecal Calprotectin Tests

At present, there are three test methods of faecal calprotectin (Table 1). In 1990s, the first commercial kit of lab-based FC test was launched by Calpro in the EU, followed by several kits approved by the US FDA, such as Phical Test, CalPrest, and Quanta Lite. Based on ELISA technique mostly, results of lab-based FC testing can take up from days to weeks.

In 2008, the first POC FC test (Quantum Blue fCal™) was introduced for clinical use by Bühlmann laboratories, a diagnostic company based in Switzerland. Other POC tests, such as Calprotectin Rapid Test Card, Quanta Flash, followed suit and got approved in EU and the US.

Using chromatographic immunoassays with testing results available within 30 minutes, doctors and patients are able to make an informed decision in the same clinic visit. Thereafter, more assay developers, such as Calprosmart in the EU and Inova in the US, joined to provide POC FC tests in the market.

Between 2015 and 2018, tremendous efforts have been made to commercialize POC FC testing as a home-based in-vitro diagnostics device. In 2019, Haisma et al. conducted the first head-to-head method comparison study investigating three calprotectin home tests and their companion ELISA tests. The research showed the majority of measurements performed with a lateral flow immunoassay and smartphone readers agreed sufficiently with the ELISA-based quantification of the same manufacturer, provided calprotectin levels are below 500 µg/g.17

The superiority of home FC tests. What makes the home-based FC test unique is not just a shorter turnaround time (from weeks to 15 minutes on average) and more cost savings, but that the results can be obtained no matter where patients are, given that the sample can be self-collected, then analysed by a mobile application.

Simultaneously, the FC test results can be uploaded to patients’ respective encrypted folder and shared with physical portals authorized by patients. It also grants patients access to their own database anywhere, anytime, with just one click.

Home-based FC test allows IBD patients to save at least one hospital trip to either turn in their samples or retrieve their test results. Consequently, home tests may reduce healthcare resources and improve patients’ adherence to therapeutics, which is critical in treatment outcomes.

With test results immediately available at home or at the same clinic visit, step-up treatment such as dosage optimization, or call for an endoscopic check-up can be decided promptly. Home FC test can supplement endoscopic assessment, and at times, even replace the procedure that can only be performed in clinical settings.

In short, home FC tests give patients more ownership and flexibility to tele-monitor their own disease activity while allowing their physicians to keep track of disease progression. This is extremely useful for patients, especially for those living in remote locations or traveling out-of-town. How can we further unleash the potential of home FC tests in IBD management?

 

Making Home FC Tests a Reality

Home-based FC tests are potential to be cost-effective and make reasonable sense during a pandemic situation to reduce patients’ visits to hospitals. Since its development in 2015, home tests have received inconsistent feedback from scientific communities, largely due to the nature of FC tests. Table 2 provides an overview of three home-based test kits that are currently available in the market, especially in Europe. One may notice in this table that each test kit is characterized by different specificities, such as limit of detection, specificity and sensitivity. Hence the reliability of this measurement is very much dependent upon the manufacturer.

To make home-based FC tests a reality, we do need to address a number of issues as follows:

The sensitivity and specificity of FC tests in IBD activity. FC, a neutrophil-derived protein, is a very sensitive marker for intestinal inflammation.18, 19 Calprotectin can predict imminent clinical relapse with an 80 percent sensitivity and accuracy in patients with established, relatively asymptomatic IBD.14 The correlation between the laboratory and home tests is quite good.20

However, as a quantitative measure of bowel inflammation, the FC test is not disease-specific, but inflammation-specific. This means FC test results can also be increased in stool for other intestinal pathologies, such as bacterial or viral infection. There are drugs (e.g., non-steroidal anti-inflammatory drugs) associated with low-grade intestinal inflammation with average FC levels between 50 and 300 μg/g. That is, elevation of FC can result from any inflammation in the gut and is not specific to IBD.21

When it comes to Crohn’s disease (CD), FC tests fail to perform as satisfactorily as for ulcerative colitis.18 The correlation with histology in CD is less satisfactory due to the patchy nature of CD, and the fact that the small bowel is not assessed histologically.

Intra-individual and inter-assay variability. It is widely known that the results of an FC test vary between bowel motions in patients over the course of a day or several days. Thus, it is advised to sample stools from the first bowel action in the morning to potentially reduce this variability. On the other hand, assays from different manufacturers differ in specifications, and the normal ranges of calprotectin will differ accordingly. Lack of standardization between various commercially available kits makes finding the optimal cut-off value to distinguish between inflammatory bowel disease and non-inflammatory disease challenging. This brings us to the next challenge of FC tests – cut-off value.

Cut-off value for further investigations and interventions. Most studies report the range of normal FC value to be 10 to 50 or 60 µg/g. However, this reference range is based mainly on historical data from when the first calprotectin kit was introduced in developed countries. The normal range of calprotectin may differ depending on a patient’s socioeconomic group. Patients from developing countries experiencing poor sanitation and frequent intestinal infections, such as salmonellosis and amoebiasis, may be found to have much higher FC values. For instance, screening FC values between 50 and 200 μg/g are often considered normal in London, especially among people from African-Caribbean descent, who may inherently have a higher normal limit to FC test.

With further clinical studies on FC validation in different geographic regions and racial groups, the utility of home FC tests for disease monitoring is destined to be far-reaching. A strategy of establishing the individual level of FC in remission and using it as a personal level to guide treatment would be preferable.22 To address this concern, the cut-off value has to be modified continuously to increase testing sensitivity and specificity.

It is also advised to establish an intermediate range of FC for values that are above the reference range, but not clinically significant in assessing possible IBD (to avoid unnecessary referrals and to improve patient selections for reviews). Individuals with intermediate-range FC levels may be advised to repeat FC test several weeks later, and if their calprotectin level is persistently slightly elevated, a conservative approach to monitor FC levels on an outpatient basis may be employed.

Home FC tests show significant value for money. Though there is no formal cost-effectiveness study of home FC tests, there should be significant cost savings for healthcare systems when FC tests are compared with conventional laboratory tests and endoscopic assessment. This is because the FC test occasionally allows patients to avoid endoscopic procedures, which in general are more expensive and more invasive than the test.

 

Conclusion

It is evident that measuring FC to evaluate IBD activity is useful, as shown from the method’s increased use in clinical trials and the real-world setting. With a home-based, non-invasive, quantitative measurement of FC, it makes patients report their disease parameters at ease. Moreover, they have more control in tracking their IBD, reducing trips to hospitals and invasive endoscopic assessments, which is especially critical during the COVID-19 pandemic. With more real-time FC results collected and analysed via smartphone apps, as well as randomized control trials integrating home FC testing, doctors will be better able to optimize dosing regimens and tailor treatment strategies. In doing so, we are one step closer to make home FC tests a reality to revolutionize IBD treatment. [APBN]

Acknowledgement: The authors would like to express an immense gratitude to Fredrik Andersson and Jonathan Plumb for their feedback and comments for this article.

References

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About the Authors

Dr. Allen Lai, Medical Director, Southeast Asia, Ferring Pharmaceuticals, Singapore

 

 

 

Dr. David Ong, Senior Consultant, Head of Div. Gastroenterology & Hepatology, National University Hospital, Singapore

 

 

Dr. Thomson Lim, Associate Consultant, Gastroenterology & Hepatology, Singapore General Hospital, Singapore

 

 

 

Dr. Webber Chan, Senior Consultant, Director of Inflammatory Bowel Disease Service, Singapore General Hospital, Singapore

 

 

Dr. Kristine Paridaens, Senior Medical Director, Global Medical Affairs, Ferring Pharmaceuticals, Switzerland