• Cystic Fibrosis
• Gastroenterology
• Paediatrics

Cystic fibrosis (CF) is a well-characterised genetic disease caused by reduced function or absence of cystic fibrosis transmembrane regulator (CFTR) protein. In the 1930s–1950s, the gastrointestinal (GI) manifestations were the most life-threatening—the term ‘cystic fibrosis’ was a description first used by Dorothy Andersen related to the characteristic postmortem histology of the pancreas, and death before school age was common, with severe malnutrition due to pancreatic exocrine insufficiency a major contributor. The introduction of pancreatic enzyme replacement therapy resulted in the focus of clinical management moving to the lungs.

The landscape of CF care is now once again dramatically changing with the introduction of CFTR modulator drugs.1 These medications act directly to improve the function of the mutant protein and in older children and adults have been shown to significantly improve lung function, body mass index and quality of life, reduce pulmonary exacerbation by up to 78%, as well as reduce sweat chloride to normal or borderline levels. Life expectancy is expected to increase significantly. In the UK, elexacaftor/tezacaftor/ivacaftor triple-combination CFTR modulator is now available from the age of 2 years for those with phe508del and other responsive CFTR mutations and ivacaftor from 1 month of age for those with gating mutations of CFTR. As a result, the predominant and most burdensome symptoms of CF may now be switching back to the GI tract, although it should be noted that 5–10% of people with CF have genetic variants unresponsive to CFTR modulators, and many people with CF live in countries without current access to these high-cost drugs.

Even with the introduction of CFTR modulators, GI symptoms (such as nausea, abdominal pain, flatulence and bloating) are common in CF and rated within the top three priorities by the James Lind Alliance Priority Setting partnership involving wide representation from people with CF.2 Looking forward to adult health, it is known that adults with CF have a fourfold to fivefold increased risk of GI cancers including colon cancers, and it may be that with increased understanding, paediatricians may be able to help reduce this future risk. Other recognised GI issues for a proportion of children and adults with CF include distal intestinal obstruction syndrome, fibrosing colonopathy and gastro-oesophageal reflux—the latter often contributing to respiratory symptoms and complications. In preschool children, CFTR modulator use has been associated with improvements in pancreatic exocrine function, with faecal elastase reaching normal concentrations in a proportion—whether this improvement is maintained in the long term remains to be determined.

It is thus to be welcomed that Roca and colleagues have studied the relationship between faecal calprotectin, quality of life, GI symptoms and pulmonary function in school-age children with CF.3 Although the research was conducted in the pre-CFTR modulator era, it remains important and demonstrates some important findings. First, increased concentrations of faecal calprotectin were significantly associated with increased GI symptoms (for diarrhoea and for total Modified PedsQL-GI questionnaire score). They showed that faecal calprotectin concentrations rise over time and show an inverse relationship to lung function—raising the possibility that sputum-containing inflammatory mediators, which are present in larger volumes as lung function declines, may be swallowed and contribute to the faecal calprotectin concentrations directly and/or indirectly by causing increased levels of gut inflammation. They also showed that faecal calprotectin concentrations vary significantly over time, raising the question whether other biomarkers of gut inflammation may be more useful. This pre-CFTR modulator study can be usefully compared with changes in faecal calprotectin in a prospective randomised placebo controlled clinical trial of lumacaftor/ivacaftor (LUM/IVA) CFTR modulator in a younger preschool cohort of children 2–5 years old.4 Faecal calprotectin concentrations were elevated at baseline in both active and placebo groups compared with children without CF. By week 48, faecal calprotectin concentrations fell towards normal levels in the LUM/IVA group, but remained stable and elevated in the placebo group. Notably, there was also a fall in pulmonary exacerbation in the LUM/IVA group compared with the placebo group, again raising the question raised by Roca and colleagues whether measured faecal calprotectin is primarily related to gut inflammation or more impacted by inflammatory mediators from swallowed sputum. Calprotectin is predominantly derived from neutrophils and thus any neutrophilic inflammation will be associated with a rise in calprotectin concentrations.

Other aspects of GI function that are known to be impaired by reduced CFTR protein function include bicarbonate secretion into the intestine from the gastroduodenal epithelium and pancreas, orocaecal transit time and the gut microbiome. Much work is going on to try and elucidate which of these mechanisms is the most important driver of gut symptomatology, including functional gut MRI studies.5 Use of validated GI symptom questionnaires relevant to people with CF will be an important part of this work.

It seems the following aspects will be critical to us making progress in this area:

1. Future studies of gut inflammation in CF should collect data on pulmonary exacerbation and inflammatory mediators (including calprotectin) in serum and sputum, as well as stool, where possible. While serum concentrations are relatively straightforward, getting consistent sputum samples not variably diluted with saliva or lavage fluid is more challenging. It will also be important to determine concentrations of faecal inflammatory markers when lung health is stable compared with during pulmonary exacerbation. This may help determine the most specific faecal inflammatory marker specific to GI complications of CF.

2. How does swallowed sputum affect gut symptomatology directly and how much do intrinsic gut factors such as reduced bicarbonate and slower transit time impact on symptoms?

3. What about the impact of antibiotics (commonly used to treat or prevent pulmonary exacerbation in CF) and/or probiotics on faecal calprotectin and gut flora?

4. Will we see an increase in rates of acute pancreatitis in children with pancreatic exocrine-insufficient CF treated with CFTR modulators? There are theoretical concerns that an increase in pancreatic exocrine function in the presence of existing pancreatic ductal obstruction may increase the risk of acute pancreatitis, and paediatricians will need to consider this on the list of reasons why children with CF may present to emergency departments.

5. Will the risk of distal intestinal obstruction syndrome reduce in children receiving CFTR modulator treatment?