10.1.6.1. Oral calorie supplementation

10.1.6.2. Enteral tube feeding

10.1.6.3. Appetite stimulants

10.1.6.4. Nutrition education/dietary advice

10.1.6.5. Psychological and behavioural interventions

10.1.6.6. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

10.1.7.1. Relative value placed on the outcomes considered

The aim of this review was to determine the clinical and cost effectiveness of nutritional interventions in improving health outcomes for people with cystic fibrosis.

The committee chose change in weight, height, body mass index (BMI), z score or other indices of nutrition or growth, lung function (FEV₁) and quality of life as critical outcomes for decision making. Changes to body composition detected by anthropometric measures, pulmonary exacerbations, patient and parent or carer satisfaction and adverse effects (including diarrhoea, reduced appetite, abdominal bloating and episodes of distal intestinal obstruction syndrome) were rated as important. For appetite stimulants, the following adverse effects were also rated as important outcomes high blood glucose and adrenal insufficiency.

10.1.7.2. Consideration of clinical benefits and harms

People with cystic fibrosis often suffer from undernutrition due to faecal fat loss, increased energy requirements caused by chronic infections and malabsorption due to pancreatic insufficiency. It is well established that nutrition is important for lung function and overall health, therefore, different nutritional interventions to improve the nutritional status and growth of people with cystic fibrosis should be considered. Because nutrition is such an important component of overall health and a considerable problem among people with cystic fibrosis, the committee agreed that dietitians should be an integral part of the multidisciplinary team caring for the person with cystic fibrosis and review the patient regularly. This should be from an individualised basis considering a myriad of factors, including current diet, salt and water intake, bowel habit in relation to pancreatic enzyme use as well as family circumstances and needs and capabilities before recommending any nutritional intervention.

If there are nutrition concerns, the committee recommended, based on their clinical experience and expertise, to encourage people to increase portion size and eat high-energy foods in order to increase calorie intake and counterbalance increased energy requirements and malabsorption.

The committee noted that the available evidence showed that oral calorie supplements are not effective in improving nutrition or growth in people in cystic fibrosis. Therefore, the committee agreed not to recommend them as a routine intervention for the general population of people with cystic fibrosis. They discussed whether to recommend them if there are nutrition concerns. They noted that out of 3 studies on oral nutritional supplements, the population in 2 studies (Hanning 1993 and Kalnins 2005) was small (between 15 and 20 participants) and did not represent the population that dietitians would actually consider offering nutrition interventions to because inclusion criteria were either unclear (Hanning 1993) or used relatively high thresholds for weight (Kalnins 2005) to define the study populations. Only one study (Poustie 2006, 102 participants) showed no effectiveness of oral nutritional supplements in a population defined by inclusion criteria that were similar to the thresholds for additional nutritional support outlined in the CF Trust consensus document on nutritional management of cystic fibrosis. The committee agreed that supplements, if effective, would be preferable, from a patient’s perspective, to enteral tube feeding, which is an invasive technique, or to appetite stimulant drugs which may be associated with adverse effects. Therefore, based on their clinical experience and expertise, they agreed that oral nutritional supplements should be considered on a trial basis for people requiring additional nutrition who had not responded to dietary advice before considering more invasive interventions.

The committee noted that the evidence showed enteral tube feeding to be effective in improving nutrition and growth in people with cystic fibrosis. The committee agreed that the capacity and the capabilities of the person and family should always be carefully considered before embarking on this.

The committee looked at appetite stimulants as an alternative to enteral tube feeding. The committee noted that evidence on megestrol acetate and cyproheptadine hydrochloride shows that they can improve nutritional status and growth. However, the committee noted that the evidence was based on studies with small sample size and discussed whether appetite stimulants can have adverse effects such as hyperglycaemia and adrenal insufficiency. There was no evidence available on adverse effects of cyproheptadine hydrochloride and limited evidence available on adverse effects of megestrol acetate, which was limited to either 3 or 6 months follow-up. This evidence showed no clinically significant difference in constipation at 6 months and no difference in fasting blood glucose levels at 3 months (clinical significance could not be calculated) between participants receiving megestrol acetate and those receiving placebo. According to the evidence, some participants had decreased morning cortisol levels after receiving megestrol acetate, however, in one study with 3 months follow-up values in the control group were not reported, while in the other study with 6 months follow-up there was no clinically significant difference with the control group, and values increased after the intervention group stopped receiving megestrol acetate. The committee discussed that although many people with cystic fibrosis considering appetite stimulants might already have diabetes, and in their clinical experience, adrenal insufficiency is not very often observed, they agreed to recommend them only in adults, short-term (for example up to 3 months) and after all other options had been fully explored. Moreover, possible adverse effects should be explained so that an informed decision can be made. The committee discussed whether the appetite stimulants for which the evidence was reviewed (megestrol acetate and cyproheptadine hydrochloride) should be named in the recommendations. However, they agreed not to endorse these specifically because of the limitations of the evidence. The decision about these treatments should be based on the whole clinical picture as well as the patient’s preferences and capabilities.

The committee agreed that oral calorie supplements, enteral feeding and appetite stimulants should be closely monitored and discontinued if there are no positive outcomes.

10.1.7.3. Consideration of economic benefits and harms

The committee advised that oral supplements should not be routinely offered to all people with cystic fibrosis as dietary modifications are at least as effective and do not take away from NHS resources. Moreover, the cost of oral supplementation could be substantial over the longer term, especially if they are used to substitute rather than complement a healthy diet. A single measure could cost £2.45 (BNF August 2016, Scandishake® oral powder 85g sachet), but the specific supplement would depend on the person’s deficiencies which could require a more expensive preparation.

However, the committee agreed that oral supplements should be used to complement a person’s diet for acute use, during periods of ill health, such as an exacerbation, when they are nutritionally unwell and have the scope to benefit from oral supplementation when their normal diet is insufficient. Following this, the committee agreed that a research recommendation to assess the clinical and cost-effectiveness of oral supplementation in people with cystic fibrosis who are nutritionally unwell, would assess if the benefits from the acute use of oral supplementation can justify the costs to reduce current uncertainty in this area. However, a research recommendation was not prioritised, given that the findings would not contradict a recommendation to consider a trial of oral nutritional supplements if dietary modifications are not effective.

Conversely, in the longer term, the committee stated that optimal nutrition can prevent a decline in lung function. This iterates that the studies included in the clinical evidence review were too short to demonstrate the differences seen in clinical practice over several years. As a result, longer term studies would be needed to justify the additional cost of interventions compared to usual care when the aim is to maintain lung function.

The high upfront cost of tube feeding and the initial monitoring schedule was recognised by the committee. They acknowledged that tube feeding is associated with adverse effects (incurring a treatment cost and disutility) and can negatively impact social interactions during meal times. Despite this, the committee considered a role for tube feeding in the event of failure of efficacy or intolerance of alternative interventions where the benefits could outweigh the costs. The committee also added that the most appropriate type of tube feeding would be determined through a discussion with the dietitian, the person with cystic fibrosis and their family, to ensure their quality of life is maximised.

The committee advised that appetite stimulants are associated with severe side effects such as high blood glucose and adrenaline insufficiency. They should not be offered as a first-line option as the expected cost to manage those complications could outweigh the benefits from an increased appetite. Moreover, the cost of appetite stimulants could soon overtake the cost of tube feeding when they are prescribed on a long-term basis (BNF NHS Drug Tariff price, August 2016; cyproheptadine hydrochloride 4mg 4 times daily, £24.28/month; megace 480mg/day, £59.34/month).

Overall, the committee agreed that appropriate dietary modifications should be considered, before initiating oral supplements, tube feeding or appetite stimulants. Therefore, options associated with the least cost and resource use would be considered first. The committee were reluctant to specify the second-line intervention in their recommendations as this would depend on the capabilities and preferences of the person with cystic fibrosis and their family or carers. The committee added that there would need to be a decline in health, or faltering growth, before an intervention more costly and invasive than advice is considered.

10.1.7.4. Quality of evidence

The quality of the evidence presented in this review range from very low to high as assessed by GRADE.

For the domain risk of bias, the studies were assigned the same risk of bias as in the Cochrane reviews and were not individually reviewed. The main biases that lead to downgrading the quality of the evidence included randomisation, allocation concealment, and reporting bias.

Sample sizes of the studies are relatively small and statistical power might therefore be too low to show an effect. Another problem with the studies are that the intervention time and the follow-up time are not necessarily adequate to detect an effect in some outcomes (for example change in weight).

No serious issues were found regarding inconsistency (heterogeneity), as most comparisons included only one study.

Some issues regarding indirectness were also identified. The committee discussed that the participants in some of the studies on nutrition interventions among people with cystic fibrosis do not represent the population that dietitians would actually consider offering nutrition interventions to, instead the studies might include all people at a cystic fibrosis clinic, not just the ones with faltering growth or undernutrition.

10.1.7.5. Other considerations

The committee agreed that studies with longer follow-up are needed (over 18 months) as the aim of nutritional interventions is to prevent long term deterioration in lung function rather than improving it in the short term.

They also discussed that a possible explanation for interventions not proving to be effective is the lack of adherence.

At the time of publication (October 2017), there are no medicines available in the UK specifically licensed as appetite stimulants. However, there are clinical situations in which the off-label use of a medicine may be judged by the prescriber to be in the best clinical interests of the patient. As a result, the committee agreed they could recommend the off-label use of those medicines because the clinical need cannot be met by a licensed product and there is sufficient evidence and/or experience of using the medicines to demonstrate their safety and efficacy to support this.

No equality issues were identified by the committee for this review question.

The committee agreed that a research recommendation was not a priority in this area although it was noted that there was a lack of studies about nutritional interventions and children with faltering growth.

10.1.7.6. Key conclusions

The committee concluded that a dietitian should be an integral part of the multidisciplinary team caring for the person with cystic fibrosis. The evidence showed that enteral tube feeding and appetite stimulants are effective in improving nutritional status and growth in people with cystic fibrosis. However, because of the invasive nature of enteral tube feeding and the concern for potential adverse effects of appetite stimulants, dietary modifications through nutritional advice should always be considered as the first choice of treatment for a person with cystic fibrosis with undernutrition or faltering growth. The committee did not recommend routine use of oral calorie supplements for people with cystic fibrosis because no evidence was found to justify this. However, they did recommend that if there are signs that raise nutrition concerns, a trial of oral supplementation should be considered before proceeding to more invasive approaches.

10.2.4.1. Acid suppressing agents as adjuvant therapy to PERT

Table 153

Summary clinical evidence profile: Comparison 1.2. PERT + Ranitidine versus PERT alone in children.

Table 154

Summary clinical evidence profile: Comparison 1.3. PERT + Omeprazole versus PERT alone in adults.

Table 155

Summary clinical evidence profile: Comparison 1.4. PERT + Ranitidine versus PERT alone in adults.

10.2.4.2. High-dose PERT versus low-dose of PERT

Table 156

Summary clinical evidence profile: Comparison 2.1. High dose PERT versus low dose PERT in children.

10.2.6.1. Comparison 1. Acid suppressing agents as adjuvant therapy to PERT

10.2.6.2. Comparison 2. High versus low dose of PERT

10.2.6.3. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

10.2.7.1. Relative value placed on the outcomes considered

The aim of this review was to evaluate the effectiveness of PERT given with an acid neutralising or suppressing agent in comparison with PERT alone and to evaluate the effectiveness of a high dose of PERT in comparison with a low dose of PERT in the treatment of exocrine pancreatic insufficiency.

The critical outcomes specified by the committee were reduction of steatorrhoea using measures such as faecal fat excretion (total or as a percentage of fat consumption) and the coefficient of fat absorption (the percentage of consumed fat absorbed, based on the difference between fat consumed and fat excreted in the stool), weight, BMI (also % weight for height if available) and resolution of symptoms of malabsorption. Quality of life, satisfaction and drug related side effects were rated as important outcomes.

10.2.7.2. Consideration of clinical benefits and harms

The committee noted that pancreatic enzyme insufficiency is a common disorder among people with cystic fibrosis that prevents digestion and absorption of nutrients. This results in nutrient malabsorption and other symptoms such as diarrhoea. These, in turn, can affect quality of life and, eventually, result in malnutrition. Based on this, the committee agreed that all people with cystic fibrosis should be offered a test if there are signs or symptoms suggestive of malabsorption. This recommendation was based on their clinical knowledge and experience.

The committee discussed the technique that should be used to assess exocrine pancreatic insufficiency. They agreed direct pancreatic stimulation tests (such as the direct pancreatic stimulation test) are invasive, uncomfortable for the person and costly. Instead, they recommended the use of non-invasive techniques, such as stool elastase estimation, as it is a non-invasive easy to perform alternative. They noted there are other alternatives, such as the analysis of the percentage of fat absorbed or excreted, but they agreed they are uncomfortable for the person, as a 72-hours stool collection is needed, and they rely on the person accurately recording food intake.

The committee agreed that the use of PERT is well-established in clinical practice as it is known that PERT treatment is useful in overcoming enzyme deficiency in people with cystic fibrosis. However, they noted there is uncertainty regarding the optimal doses of enzymes needed.

The committee acknowledged the evidence presented comparing different treatment dosages, but they agreed it was of limited use because it was rated as of very low quality.. They noted that although normalisation of fat absorption and thus prevention of steatorrhoea would ideally be achieved with PERT, demonstrating this was in practice difficult. The reasons for this, as indicated above, are the measurement of stool fat entails stool collection and measurement of dietary fat intake over a period of days in order to calculate the coefficient of fat absorption. This approach is rarely done other than in a research context, as it is considered troublesome and impractical.

The committee acknowledged that the evidence suggested improved fat absorption with higher doses of pancreatic enzyme replacement therapy. However, dosage was likely to vary on an individual basis since the severity of pancreatic insufficiency was not uniform in people with cystic fibrosis. Optimal dose might differ depending on body size and dietary composition and intake. Infants and young children have a higher intake of fat proportionately than older children, young people and adults.

Based on this, the committee agreed to recommend to offer PERT to people with cystic fibrosis with pancreatic insufficiency and that the dose should be adjusted for each person in order to minimise symptoms of malabsorption. This recommendation is consistent with clinical practice and aligned with the CF Trust Consensus recommendations (CF Trust, Nutritional Management of Cystic Fibrosis 2016).

The committee agreed that evidence regarding the effectiveness of PERT dose and acid suppression in relation to resolution of malabsorption symptoms, improvement in weight and improvement in patient satisfaction or health-related quality of life was very limited and of very low quality or completely lacking. They noted that the normal clinical approach to determining individual need was an empirical one, for instance titrating the PERT dose in terms of units of lipase against the amount of fat being ingested. A standard dose, related to age in children, was usually given and adjustment then made based on the clinical response in terms of trying to achieve a normal bowel habit and the resolution of any malabsorption symptoms. They recommended that, in people with confirmed pancreatic exocrine insufficiency, the dose was titrated against symptoms and regularly reviewed. High enzyme concentration products would aid treatment optimisation where there was a higher dose requirement.

The committee noted that trials were of short duration and therefore it was not possible to assess whether prescribing high dose PERT treatment or adding an antacid had an impact on weight. They also noted the dosages used are very low compared to those used in clinical practice. In addition, most trials included a very small sample size and were underpowered to detect differences between treatment arms.

10.2.7.3. Consideration of economic benefits and harms

Based on their clinical expertise, the committee agreed PERT should be tested when symptoms or signs suggesting malabsorption occur, as the results of the test in those individuals would be used to improve their management strategy. For this reason, the committee made a recommendation to reinforce best practice to test for PERT using a noninvasive technique. Following this, the committee discussed if the test should be repeated annually in children and young people. However, they agreed the test would not add any additional information to a clinical assessment if the person is asymptomatic. Therefore, to prevent a cost-ineffective use of resources, a frequency was not recommended. Instead, the test should be repeated if symptoms or signs suggesting malabsorption occur, at any age.

When the committee discussed the management of PERT, it was noted that the dose-response may justify the additional cost of high-concentration PERT over low-concentration PERT. With regards to acid suppression, the committee agreed the clinical evidence was too uncertain to justify the costs for intermittent malabsorption. However, in people with cystic fibrosis with persistent symptoms of malabsorption, the committee believed the benefits from acid suppression would justify the costs. Overall, the committee agreed clinical judgement is necessary to provide the most cost-effective treatment as the optimal dose and concentration of enzymes is individualised based on weight and drug adherence.

10.2.7.4. Quality of evidence

The quality of the evidence presented in this report ranged from very low to high as assessed by GRADE. The main reasons that lead to downgrading the quality of the evidence were the following.

For the domain risk of bias, the 6 trials included in the review were assessed as having unclear or high risk of bias regarding randomisation and concealment methods. All of the trials were of cross-over design, but given the nature of the intervention it is not expected that treatments have a carry-over effect.

The committee noted that there were issues regarding indirectness of the intervention as the dosage used in some of the studies was much lower than current practice. In addition, they noted that measuring fat excretion or fat absorption as grams per 24 hours is inaccurate as it does not take into account daily intake.

Most trials were underpowered to detect a difference between both treatment groups.

Finally, there were some concerns regarding the statistical analysis used and the type of data reported. Due to this limitation most of the results could not be meta-analysed.

Imprecision could not be assessed when results were provided in medians.

10.2.7.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee agreed that a research recommendation was not prioritised for this topic because clinical practice is already established. Additionally, there are treatments which are known, based on clinical expertise, to be useful in the treatment of pancreatic exocrine insufficiency.

At the time of publication (October 2017), cimetidine is the only H2 receptor antagonist licensed for this indication. In addition, none of the proton pump inhibitors available in the UK are licensed for this indication. However, there are clinical situations in which the off-label use of a medicine may be judged by the prescriber to be in the best clinical interests of the patient. As a result, the committee agreed they could recommend the off-label use of acid suppression agents because the clinical need may not be met by a licensed product and there is sufficient evidence and/or experience of using the medicines to demonstrate their safety and efficacy to support this.

10.2.7.6. Key conclusions

The committee concluded that people with cystic fibrosis with pancreatic insufficiency should be offered oral pancreatic enzyme replacement therapy. Although the evidence showed some indication that high-dose PERT treatment may have a beneficial impact in both faecal fat excretion and fat absorption when compared to standard or low-dose treatment, without an increase in side effects, the committee agreed that the dose should be adjusted to minimise symptoms of malabsorption.

In addition, the committee noted that there was some indication that addition of acid suppressants to PERT treatment may reduce faecal fat excretion and therefore the use of an acid suppressant agents can be considered in people with cystic fibrosis who have persistent symptoms of malabsorption despite optimal PERT therapy.

10.3.7.1. Relative value placed on the outcomes considered

The aim of this review was to identify the most effective strategies for the primary treatment and secondary prevention of DIOS.

For the primary treatment, when a person presented with acute abdominal pain and other symptoms due to DIOS, the committee identified the following outcomes as critical reduction in clinical manifestations, adverse events from treatment and treatment failure. Patient satisfaction and duration of hospital stay were rated as important outcomes.

For the secondary prevention of DIOS, the committee identified the following outcomes as critical reduction in clinical manifestations, adverse events from treatment and recurrence of DIOS. Patient satisfaction was rated as an important outcome.

10.3.7.2. Consideration of clinical benefits and harms

The committee noted the absence of trials in the review. They agreed that there are difficulties in undertaking RCTs of treatments for those presenting with DIOS. In particular, the clinical presentation varies considerably. Some people have relatively minor symptoms (for example abdominal pain) while others might have symptoms of intestinal obstruction with vomiting. The approach to managing these patients would be tailored to their individual difficulties. Given the lack of evidence, the list of recommendations as part of this topic are derived from both current good practice and the committee expert opinion. In addition, the committee emphasised the variability in practice and the need to define a correct treatment.

10.3.7.3. Consideration of economic benefits and harms

The committee considered imaging studies to reduce the number of false positives as some people with cystic fibrosis have potentially serious conditions such as appendicitis or intussusception that might mimic the symptoms of DIOS. For this reason, the committee agreed imaging studies would be a cost-effective use of NHS resources as they would minimise the foregone risks and additional treatment costs associated with unidentified cases.

The committee also added that DIOS can be a serious and costly condition that negatively impacts a person’s health-related quality of life if incorrectly managed. Therefore, it would be necessary to manage suspected DIOS in a specialist cystic fibrosis centre, with supervision from specialists who have expertise in recognising and treating the condition and its complications, in order to minimise the number of incorrectly managed cases. As a result, a recommendation was prioritised to ensure resource allocations in this area are maintained.

According to the committee people with acute onset of DIOS symptoms can respond to an intravenous fluids to regain adequate hydration or osmotic laxative containing polyethylene glycol. These treatments are relatively inexpensive treatment at a cost of less than £10 per month. However, the committee noted that the more expensive treatment, diatrizoate, is often chosen as the first-line treatment in current clinical practice based on experience that it is the most effective first-line treatment with the potential for fewer side effects. Moreover, cheaper alternatives would overtake the cost of diatrizoate when they are required for longer durations to achieve the same effects.

Following this, the committee also agreed that the cost and distress incurred by a surgical procedure would be overtaken by pharmacological treatments that require ongoing costs and treatment burden. As a result, the committee made a recommendation to consider surgery if prolonged pharmacological treatment is not effective.

When making their recommendations, the committee referred to previous guidance (Colombo 2011) that recommends a stepwise approach to DIOS treatment. This involves using the least invasive options first and surgery only as a last resort. As a result, the committee believed guideline recommendations are not likely to represent a change in current practice and resource use.

10.3.7.4. Quality of evidence

Not applicable, as no studies were identified for inclusion in this review.

10.3.7.5. Other considerations

The guideline committee were not aware of any published trial and it was their clinical experience that the choice of a treatment over another was mainly empirically based. Current good practice guidance (Colombo 2011) was acknowledged by the Guideline committee, which they agreed was largely in line with their clinical experience.

The committee discussed potential equality issues. They noted adults may be more likely to go into a local hospital if the live far from the specialist centre. However, they agreed there was no need to draft additional recommendations as they had already recommended that suspected DIOS should be managed in a specialist cystic fibrosis centre, with supervision from specialists who have expertise in recognising and treating the condition and its complications. The committee noted that the expertise of these specialists should also cover the specialty areas of colonoscopy and gastroenterology.

The Guideline committee agreed that a research recommendation was not prioritised for this topic because clinical practice is already established and there are treatments which are known (based on clinical expertise) to be useful for people who are acutely ill and for secondary prevention.

At the time of publication (October 2017), diatrizoate meglumine, diatrizoate sodium solution and osmotic polyethylene glycol and electrolyte solution did not have a UK marketing authorisation for use in people with cystic fibrosis for this indication. However, there are clinical situations in which the off-label use of a medicine may be judged by the prescriber to be in the best clinical interests of the patient. As a result, the committee agreed they could recommend the off-label use of those medicines because the clinical need cannot be met by a licensed product and there is sufficient evidence and/or experience of using the medicines to demonstrate their safety and efficacy to support this.

10.3.7.6. Key conclusions

The Guideline committee concluded that in the absence of relevant published evidence, recommendations are based on their clinical experience, expert opinion and existing guidance. They agreed treatment of DIOS should be provided in a cystic fibrosis centre. The less invasive treatments should be the first choice for treating DIOS as they are generally effective in almost all people with DIOS.

10.4.6.1. Review question 1. What is the diagnostic accuracy of tests to detect/strategies to detect early and late cystic fibrosis-related liver disease?

10.4.6.2. Target condition: portal hypertension

10.4.6.3. Review question 2. What is the diagnostic and prognostic value of different strategies to detect cystic fibrosis-related liver disease and predict progression (including progression to cirrhosis and portal hypertension without oesophageal varices)?

10.4.6.4. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

10.4.7.1. Relative value placed on the outcomes considered

The aim of this review was to assess the accuracy of different diagnostic strategies to detect cystic fibrosis-related liver disease (including cirrhosis, portal hypertension and oesophageal varices) defined by gold standard tests. Additionally, the aim was to identify whether any tests are useful in predicting the progression of cystic fibrosis-related liver disease.

As sensitivity and specificity reflect patient outcomes these were considered critical outcomes for this review. Consequences for people with cystic fibrosis following diagnosis were considered by the committee. Likelihood ratios were considered to be critical diagnostic outcomes because they provide information about a test’s usefulness in assisting the healthcare professional to make a diagnosis. AUROC diagnostic data, which inform the best thresholds for defining disease, were regarded as important but not critical to the review.

Sensitivity was used to evaluate imprecision for the detection of cystic fibrosis-related liver disease, including cirrhosis. Early accurate identification of disease might be important because there was a possibility that early use of ursodeoxycholic acid treatment might prevent liver disease progression. Specificity was used to evaluate imprecision for the detection of portal hypertension or oesophageal varices. This was because accurate identification of those without disease would avoid unnecessary referral to specialist hepatology centres and unnecessary investigation for this complication of advances cystic fibrosis-related liver disease.

Adjusted hazard ratios (adjHRs) and odds ratios (ORs) were regarded as critical prognostic outcomes for assessing the risk or probability of developing clinically significant liver disease (cirrhosis, portal hypertension, oesophageal varices) in the future based on current available information. Estimates that were not adjusted for confounders were excluded from the review.

10.4.7.2. Consideration of clinical benefits and harms

The committee agreed that their priority was early detection and treatment of liver disease in people with cystic fibrosis. Early detection may prevent further damage and, in some case, may be reversible. They agreed that irreversible liver disease would be under liver specialist management and was out with the scope of this guideline.

The committee discussed the importance of reducing the likelihood of a false negative diagnosis which could result in the withholding of potentially effective ursodeoxycholic acid treatment. The committee agreed that the impact of a false negative diagnosis would be mitigated by the slow progression of the disease and that the subsequent annual review would provide a further opportunity for identification. They noted that a false positive result might lead to unnecessary treatment and have a negative psychological impact.

It was noted that, while neonates with cystic fibrosis can demonstrate transient liver dysfunction (manifested by a temporary derangement of liver function tests), any perceived harm of starting unnecessary treatment is likely to be offset by the benefit of preventing irreversible liver damage.

The committee discussed the relative benefits and harms associated with the different diagnostic tests. Although the gold standard test for identification of liver pathology in cystic fibrosis is histological examination of biopsy samples, this is rarely performed in practice as it is invasive, may miss focal lesions and has associated risks for example with respect to general anaesthesia or infection. CT scanning and MRI scanning are also used as gold standards because of the high definition images that are obtained. But the evidence review found no evidence for CT or MRI scanning as the reference standard. The committee noted that although these investigations are not invasive, they are expensive and not routinely performed. The committee noted that there would be exposure to radiation with CT scans, which the patient may receive for other systemic investigations. Overall, the committee did not find evidence to support the use of liver biopsy, MRI and CT scans for the detection of liver disease in people with cystic fibrosis and did not make recommendations regarding their use.

The committee considered that interpretation of ultrasound images could be subjective in some respects. However, transient elastography produces an objective score that might be more reliable in detecting liver disease. The committee noted that unlike transient elastography, which uses sound waves to estimate liver stiffness, images from ultrasound provide information of the staging of disease progression occurring in the liver including portal hypertension when Doppler is used. Instead of an image, FibroScan® produces sound waves that limit the results that can be interpreted. Overall, the committee agreed there was little evidence to support the use of FibroScan® for early stage detection of liver disease and agreed that, because treatment with ursodeoxycholic acid would have already been initiated, the value of adding this test to a diagnostic regimen was diminished.

The development of new liver disease after late adolescence is very unusual. Therefore, the committee agreed that routine repeat ultrasounds may not be necessary in adults with previous normal scans. The value of annual review in adults is more to monitor the progression of liver disease rather than detect new liver disease.

Children with persistently elevated liver function tests or significant abnormalities on the ultrasound of liver and spleen need to be referred to a specialist paediatric liver unit. In children with cystic fibrosis the objective of monitoring would be to detect early evidence of liver disease, to look for evidence of disease progression and progression to chronic liver disease and its complications including portal hypertension. Clinical examination is routinely performed when people with cystic fibrosis attend for clinic appointments. Clinical examination would be unlikely to detect early disease but progression might reveal important signs such as hepatosplenomegaly. The committee, therefore, recommended that a clinical assessment for evidence of liver disease should be conducted annually for people with cystic fibrosis. The committee noted that some centres include an ultrasound scan at this clinical assessment, However, the evidence did not support specific recommendations on routine ultrasound screening. The committee agreed that decisions on the tests to be included at clinical assessment should be made at individual centres using clinical judgement.

It is currently common practice to perform blood test investigations to look for evidence of liver disease. The committee recommended that blood liver function tests should be performed in people with cystic fibrosis every year.

The committee recognised that ultrasound can detect evidence of liver disease, for example changes in liver echogenicity as well as advanced changes suggestive of portal hypertension. It can also detect the presence of gallstones which sometimes occur in cystic fibrosis. Transient elastography does not reveal these specific changes although it can detect increased liver stiffness suggestive of liver fibrosis and progressive liver disease. Ultrasound scanning is commonly used to monitor cystic fibrosis-related liver disease. The committee agreed that this may not be necessary if there was no evidence of liver disease, but that a liver ultrasound scan should be performed if the blood liver function tests were abnormal.

FibroScan® gives measurement of liver stiffness. If liver stiffness is present, the person is usually referred to a specialist liver service. The lay members on the committee pointed out that from a patient perspective, FibroScan® is very quick and easy to do and may not require further referral or referral time wait. However, the committee felt the added value of FibroScan® was unclear and it was unclear what decisions should follow an abnormal FibroScan® result.

10.4.7.3. Consideration of economic benefits and harms

The economic harms associated with an incorrect diagnosis are much smaller for early stage than late stage liver disease. If the majority of people with cystic fibrosis are incorrectly diagnosed as not having liver disease (false negatives), they are likely to be picked up at their next annual review. The question arises as to whether additional monitoring between the annual reviews is cost-effective. On the other hand, the committee noted the cost of monitoring for liver disease would be relatively insignificant when compared with the downstream costs associated with liver cirrhosis and subsequent portal hypertension that could require management with a liver transplant. However, the committee agreed such cases would be rare and concluded that more frequent assessments would not be a cost-effective use of resources.

The committee noted that if abnormal liver function blood tests are the first indication of liver disease, there are potential cost savings to the NHS if those tests can replace ultrasound scans at the annual review. This saving is particularly the case in adults who are unlikely to develop liver disease without prior suspicion. Following this, the committee agreed that a recommendation in favour of liver function blood tests as the first assessment was warranted.

However, the committee agreed that the results from an ultrasound scan could lead to a change in the management strategy when, for example, cirrhosis and portal hypertension (with Doppler) are detected. Given that an ultrasound can add additional information to an abnormal liver function blood test, a recommendation in that subgroup was considered as a cost-effective use of ultrasound scans.

10.4.7.4. Quality of evidence

Most of the evidence was derived from cohort studies. Outcomes presented within these studies were often downgraded to moderate or low for serious or very serious imprecision of sensitivity or specificity estimates. Evidence for detection of portal hypertension was largely derived from a single included case control study and was low quality at best and downgraded to very low quality for imprecision of specificity for some outcomes. The settings in cystic fibrosis or liver clinics were similar in all the studies.

The committee were concerned that the included studies were heterogeneous in terms of their population and the reference standards used. The committee noted that a small body of evidence was included overall and that the studies provided no evidence regarding early cystic fibrosis-related liver disease as specified in the review question. The studies provided evidence for cystic fibrosis-related liver disease which included those with cirrhosis. Some studies included those with clinically significant liver disease states (portal hypertension with or without oesophageal varices), although this was not always specified clearly. There was also some evidence that related to cirrhosis alone and to portal hypertension with or without oesophageal varices. However no studies with participants with early disease were retrieved. Although the point estimates for likelihood ratios for several comparisons indicated that the index test would be moderately or very useful for ruling in or ruling out disease, the 95% CIs for these point estimates were mostly wide and there was uncertainty as to whether tests would be useful at all. Two exceptions were:

• High quality evidence from 1 cohort study of children and adults found that transient elastography at a threshold of 6.3kPa was at least moderately useful to rule in cystic fibrosis-related liver disease. The definition of cystic fibrosis-related liver disease was based on practice guidelines requiring biochemical and ultrasound testing.
• A second cohort study provided high quality evidence that transient elastography at a threshold of 11.5kPa was at least moderately useful to rule in portal hypertension.

There was no evidence that examined the use of MRI or CT scanning as reference tests or evidence that examined the use of ultrasound in addition to clinical and biochemical testing in adults with no history of cystic fibrosis-related liver disease.

There were very little data available regarding tests that were useful to predict the development of clinically significant liver disease. One study provided low quality evidence of an association between increasing liver stiffness detected by transient elastography and the probability of developing cystic fibrosis-related liver disease in adulthood. A second study provided high quality evidence of an association between increasing fibrosis detected by biopsy and the later development of portal hypertension. The paucity of prognostic outcome data did not permit determination of a “best” reference standard from the evidence review. As such, liver disease was defined in accordance with each reference standard.

10.4.7.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee discussed the need for a research recommendation in this topic. They noted FibroScan® gives measurement of liver stiffness. This can be useful to select who should be referred for further specialist service. From the patient perspective, FibroScan® is very quick and easy to do and may not require further referral or referral time wait. Based on this, the committee agreed it would be important to assess the added value of performing FibroScan® in people with cystic fibrosis, as good quality evidence is lacking for this population. However, the committee agreed this area was not a priority overall for a research recommendation.

10.4.7.6. Key conclusions

The committee chose not to make a recommendation regarding performance of clinical examination at other appointments for monitoring leaving this to clinical judgement.

The committee agreed that generally it was good practice to repeat liver function tests that were abnormal to confirm their accuracy, although this would depend on the clinical context. Therefore, they did not make a recommendation about this as this is part of routine clinical practice and judgement.

The committee decided that if there is evidence of chronic progressive liver disease based on clinical assessment, liver function tests or the findings of an ultrasound scan the person should be referred to a liver specialist.

Alternatively, if investigations for liver disease (such as a clinical examination, liver function tests, ultrasound imaging or FibroScan®) are persistently normal, then the cessation of treatment with ursodeoxycholic acid should be considered. Monitoring for future liver damage should continue in line with the annual monitoring schedule.

10.5.6.1. Comparison 1. UDCA versus placebo or control

10.5.6.2. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

10.5.7.1. Relative value placed on the outcomes considered

The objective of this review was to assess the clinical and cost effectiveness of UDCA for preventing liver disease progression in people with cystic fibrosis.

The committee agreed change of hepatocellular enzyme levels, progression to liver failure and development of portal hypertension indicated by an enlarged spleen (increased by at least 15%) and development of varices or ultrasound evidence of portal hypertension were critical outcomes for consideration in decision making. Health related quality of life, liver transplantation, liver related mortality and no development of liver disease were rated as important outcomes.

10.5.7.2. Consideration of clinical benefits and harms

The committee discussed the use of UDCA for primary prevention and secondary prophylaxis.

With regards to the use of UDCA in people with cystic fibrosis without liver disease, the committee noted most of the participants in the trials had pre-existing evidence of liver disease. Therefore, there was a lack of evidence to support the use of UDCA as primary prophylaxis aimed at preventing the onset of liver disease.

The committee noted that infants with cystic fibrosis who have meconium ileus, about 10–15%, were at increased risk of developing liver disease. However, in the absence of evidence showing a benefit, they did not recommend the use of UDCA even in these infants.

The committee discussed when UDCA should be given to prevent progression of liver disease and the duration of administration. They noted the available trials were small and the duration of follow-up was no more than a year. Consequently, it was unsurprising that there was no evidence for clinical benefit with UDCA in terms of preventing development of portal hypertension, liver failure or mortality.

The evidence did not show differences in terms of normalisation of hepatobiliary enzymes (including AST, ALT and GGT), final bilirubin values at 6 months or in percentage change in hepatobiliary enzymes (including AST, ALT and GGT) at 12 months between UDCA and placebo. However, the committee noted that signs of advanced liver disease, including portal hypertension were present at baseline for most of the participants. The fact that the liver disease had already progressed to this degree before starting UDCA might have led to an underestimate the potential benefit effect of UDCA in preventing disease progression.

The committee therefore recommended that if the liver function tests were abnormal, treatment with UDCA could be considered. The optimal duration of treatment was unknown and so they recommended that clinicians should think about discontinuing it if the liver function tests returned to normal levels and there was no clinical or ultrasound scan evidence of liver disease. If, subsequently, monitoring showed a recurrence of liver function test abnormality then the clinician would again consider giving UDCA. The committee also agreed that if the abnormal liver function tests did not resolve with UDCA and remained persistently abnormal, the clinician should consider referring to a liver specialist.

The committee did not made specific recommendations on the degree of abnormality of the various liver function tests used that should be considered abnormal or on the advisability of repeating blood tests when considering UDCA. They recognised that this was a complex area that required clinical expertise and judgement. A minor elevation of AST for example might not be significant whereas elevation of the serum bilirubin would be a reason for concern.

The committee believed that UDCA was considered safe for use, although in higher dosages it might cause diarrhoea.

10.5.7.3. Consideration of economic benefits and harms

The preparations of UDCA are comparable and relatively inexpensive in the short-term at a cost of approximately £1.08 to £1.27 a day (600mg daily) for capsules and oral suspension, respectively. However, the costs of prolonged use could be significant. Without knowing the benefits of UDCA in people with cystic fibrosis without liver disease, we cannot know if UDCA is a cost-effective prophylactic. Consequently, the committee agreed not to recommend UDCA in people with cystic fibrosis without evidence of liver disease.

Following this, the committee added that portal hypertension and liver disease were reported at baseline for many participants in the studies included in the clinical evidence review. As a result, they stated that this could potentially underestimate the cost-effectiveness of UDCA to prevent the initiation of liver disease.

The committee agreed that, although UDCA is relatively inexpensive and it has a good safety profile, this does not justify the continued prescription of these drugs without evidence of effectiveness. As a result, the committee made a recommendation to reduce unnecessary treatment costs and treatment burden by stopping UDCA if the annual clinical assessments show no evidence of liver disease.

No evidence was reviewed for subsequent treatment, thus, the committee made recommendations to think about referrals to a specialist to reinforce best practice.

10.5.7.4. Quality of evidence

The quality of the evidence presented in this report ranged from low to high as assessed by GRADE.

The risk of bias was one of the reasons that lead to downgrading the quality of the evidence, in particular lack of allocation concealment.

Imprecision also lead to downgrading the quality of the evidence as the confidence interval crossed 1 or 2 clinical or default MIDs (minimal important difference).

Inconsistency was not an issue as most outcomes were reported by a single study.

The evidence was not downgraded for indirectness. However, the committee noted that some of the participants had signs of liver disease at enrolment and, therefore, evidence on preventing development of liver disease is lacking.

10.5.7.5. Other considerations

No equality issues were identified by the committee for this review question.

The committee agreed to draft a research recommendation for this topic. They noted liver disease is the third most common cause of mortality in people with cystic fibrosis. Around 10 to 30% of people with cystic fibrosis will develop CFRD (See complications review). Children with meconium ileus are at an increased risk of liver disease. Starting treatment with UDCA from diagnosis may reduce this risk. UDCA appears safe, and is well tolerated and cheap. Routine use could increase people’s overall quality of life and reduce the need for subsequent treatment for liver disease, but more research is needed into the effectiveness and safety of this treatment.

The licensed indications of ursodeoxycholic acid vary depending on the preparation. In addition, the preparations that are licensed for this indication are not licensed for all ages. For this reason, the prescriber should check individual brands for licensing and follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. The General Medical Council’s Prescribing guidance: prescribing unlicensed medicines, should be sought for further information.

10.5.7.6. Key conclusions

The Guideline committee concluded that in the absence of evidence, they would not recommend using UDCA as primary prophylaxis.

The committee agreed that the available evidence did not show that UDCA was beneficial in achieving normalisation of hepatobiliary enzymes in people with cystic fibrosis and preexisting liver disease. They noted the limitations of the evidence as most of the participants in the studies had signs of advanced liver disease at baseline. Therefore, the fact that the liver disease had already progressed to this degree before starting UDCA might have led to an underestimate the potential benefit effect of UDCA in preventing disease progression. They agreed longer studies would be needed to assess whether UDCA is effective in terms of preventing development of portal hypertension, liver failure or mortality. Moreover, the committee noted liver disease is a serious complication of cystic fibrosis and so is very important to delay its progression. Based on all this, the committee agreed UDCA could be considered if liver function tests were abnormal. They agreed to monitor for response to treatment and refer to specialist advice if abnormal results are persistent.

Review question 1. What criteria should be used to determine the need for insulin therapy to achieve optimal patient outcomes?

No studies were identified for this question.

Review question 2. What thresholds of glucose dysregulation are associated with more rapid progression of lung disease?

No studies were identified for this question.

10.6.7.1. Relative value placed on the outcomes considered

The aim of this review was to define what criteria should be used to determine the need for insulin therapy to achieve optimal patient outcomes.

The committee chose change in lung function (FEV₁), forced vital capacity (FVC), lung clearance index (LCI), pulmonary exacerbations and body mass index (BMI) (z-scores for children) as critical outcomes for decision making. Adverse events and patient acceptability or satisfaction were rated as important outcomes.

10.6.7.2. Consideration of clinical benefits and harms

The committee recognised that diabetes is a very common complication in people with cystic fibrosis and it is important to identify it without delay. They highlighted early treatment with insulin is very important as it may improve lung function and weight. However, they recognised the lack of evidence in relation to these matters and were aware of a lack of consensus in clinical practice.

The committee emphasised that glucose may fluctuate in people with cystic fibrosis. The tests used to diagnose diabetes in the general population may not be suitable for the detection of CFRD. For this reason, they agreed that single point tests, when used alone, are not useful for the identification of CFRD. This is supported by a previous Health Technology Assessment (HTA 2012) and the American Diabetes Association (ADA 2010).

The committee discussed the use of the oral glucose tolerance test (OGTT) at length. They noted this test is commonly used to monitor for CFRD in current practice and is the test of choice for many professionals. The use of this test is also recommended by the American Diabetes Association [consensus recommendation] (ADA 2010) and the European Cystic Fibrosis Foundation (Alan 2014). However, they also noted the OGTT may not be an ideal test given that, as mentioned above, glucose dysregulation in CFRD is a dynamic and variable process. Based on this, they agreed OGTT may not be completely reliable and, if used and found abnormal, it should be backed up with dynamic testing. This will ensure that glucose regulation is assessed over several days. The committee discussed the important fact that hyperglycaemia associated with glucose dysregulation in CFRD can have a negative effect on clinical outcomes even before the usual diagnostic criteria for diabetes are met.

The committee discussed the potential benefit of continuous glucose monitoring (CGM). CGM would detect glucose dysregulation more reliably as it monitors the blood sugar level continuously for several days rather than relying on a single or few glucose measurements. This test is increasingly used in clinical practice for the detection of the onset of diabetes in people with cystic fibrosis. However, they acknowledged there is currently no evidence to require the routine use of this test. In addition, some drawbacks were also noted. CGM is more difficult to perform and to interpret compared to the OGTT and it has to be administered by trained staff, making it difficult to generalise its use to all cystic fibrosis clinics.

The committee agreed monitoring for CFRD should be done annually and should start from the age of 10, as recommended by the American Diabetes Association (ADA 2010) and the US Cystic Fibrosis Foundation (Moran 2010). This recommendation is consistent with current practice. Apart from the process of annual monitoring, investigation should be undertaken in a number of specific contexts. If people with cystic fibrosis have symptoms or signs of diabetes such as polydipsia and polyuria they should be appropriately investigated as recommended in existing NICE diabetes guidelines for children, young people and adults. In addition, the committee recommended consideration be given to investigating those with cystic fibrosis who, despite optimising their pulmonary management, have unexplained weight loss or an unexplained deterioration in lung function as measured by pulmonary spirometry, increased frequency of pulmonary exacerbations or lethargy and malaise. They also recommended monitoring for people taking long-term systemic corticosteroids or enteral tube feeding, in whom glucose dysregulation may occur. Monitoring should be done using CGM or serial glucose monitoring.

With regards to monitoring diabetes during pregnancy, the committee referred to the current NICE guidelines on Diabetes in Pregnancy (NG3 2015). They do not specifically address monitoring of CFRD in pregnancy. The committee noted that insulin therapy is often needed in pregnant women with cystic fibrosis as the threshold for commencing insulin is lower than in those without cystic fibrosis. They recommended that either CGM or an OGTT should be performed at the end of the first and second trimesters of pregnancy. This timing is consistent with recommendations from the US Cystic Fibrosis Foundation (Moran 2010).

10.6.7.3. Consideration of economic benefits and harms

The committee stated that people with cystic fibrosis require their own clinic space when attending for an OGTT to reduce their risk of cross-infection. This incurs a larger cost (£50) than OGTTs undertaken in a shared clinic space (NICE NG3 2015, 2-sample OGTT: £22.06). The committee added that in cases with an abnormal OGTT result, further dynamic tests such as serial blood sugar monitoring or CGM would be performed after a few days to obtain a complete picture of glucose levels.

Given that single-point tests can result in more false positives and negatives than two, or three point tests, the committee agreed that their recommendations should favour dynamic testing. This would reduce the number of people with cystic fibrosis that incur the downstream costs from an incorrect diagnosis. They ordered their recommendation on the type of test to that effect. However, when OGTT is performed, the committee agreed normal results have a higher specificity and sensitivity than abnormal results. Therefore, abnormal results should be followed by CGM or serial blood glucose monitoring to outweigh the potential costs of an incorrect diagnosis.

Unlike CGM in confirmed diabetes, the duration of CGM to monitor for its onset would be up to 5 to 7 days. For this reason, the committee stated that CGM systems would be shared across the clinic when used to monitor for the onset of CFRD. This would reduce the cost per person from approximately £3,500 per year (NICE NG17 2015) to £20 per year, including attendances and delays to receive and return the system. Following this, the committee questioned if CGM was the most expensive investigation. The cost of OGTT could overtake the cost of CGM if several visits were required, more so in children who require extra staff time to fit a cannula for their OGTT.

However, the committee noted that the majority of clinics do not have access to CGM systems or the expertise on how to use and interpret them appropriately in this population. The committee noted that each centre would require several CGM systems to ensure enough people were monitored by the centre each week. As a result, recommending CGM would lead a change in current practice and would incur upfront training costs and capital costs to implement.

Overall, the committee agreed they could not change current practice from the OGTT to CGM because there was not enough evidence to support the large injection of resources. As a result, the committee made a recommendation in favour of dynamic testing to allow centres to decide which strategy is cost-effective for them to provide. The committee also prioritised a research recommendation to identify the best strategy to diagnose CFRD in people with cystic fibrosis in order to mitigate current uncertainty in this area.

The committee outlined the populations at high risk of CFRD in their recommendations that may require more frequent monitoring. Those populations were prioritised as their condition could escalate much quicker between the annual reviews, leading to more intense and costly management.

10.6.7.4. Quality of evidence

Not applicable, as no evidence was found for this review.

10.6.7.5. Other considerations

The committee discussed potential equality issues. They noted cystic fibrosis related diabetes is common in females. However, they agreed care is the same for both genders so there was no need to draft additional recommendations.

Given the lack of evidence, and the uncertainty in relation to what is the best strategy to detect the onset of diabetes in people with cystic fibrosis, the committee agreed a research recommendation was useful. They highlighted it would be important to look at OGTT and CGM. Better testing would also provide guidance on when treatment with insulin should be initiated in people with cystic fibrosis.

10.6.7.6. Key conclusions

The guideline committee concluded that early detection of CFRD is very important. They noted OGTT is often used in clinical practice. However, they agreed it is an unreliable test and, if used, it should be backed up with dynamic testing over several days. They suggested CGM could be used instead as it monitors the blood sugar level continuously. Children should be monitored for the onset of CFRD from the age of 10 years. Monitoring should be done as part of the annual assessment and if there are symptoms suggestive of diabetes.

10.7.6.1. Evidence in children and young people

Very low quality evidence from 1 longitudinal study with 18 prepubertal and pubertal girls and young females with CF (age range 7.6 to 17.9 years) suggested that:

• a baseline z-score of −0.40 in lumbar spine BMD (measured by DXA scan) was associated with an overall change in BMD at the spine of −0.07 at 2.13 years follow-up
• a baseline z-score of −0.29 in whole body BMD (measured by DXA scan) was associated with an overall change in whole body BMD of −0.17 at 2.13 years follow-up.

Very low quality evidence from 1 prospective longitudinal study with 20 children and young people with CF (9 males, 11 females; age not reported) suggested that:

• a baseline z-score of −1.0 BMD at the lumbar spine (measured by DXA scan) was not significantly associated with a decrease in BMD at the lumbar spine at 17 months follow-up in boys and young males
• a baseline z-score of −1.5 BMD at the lumbar spine (measured by DXA scan) was significantly associated with a decrease in BMD at the lumbar spine at 17 months follow-up in girls and young females
• a baseline z-score of −0.8 BMD at the femoral neck (measured by DXA scan) was not significantly associated with a decrease in BMD at the femoral neck at 17 months follow-up in boys and young males
• a baseline z-score of −2.0 BMD at the femoral neck (measured by DXA scan) was not significantly associated with a decrease in BMD at the femoral neck at 17 months follow-up in girls and young females
• a baseline z-score of −0.3 in whole body BMD (measured by DXA scan) was significantly associated with a decrease in whole body BMD at 17 months follow-up in boys and young males
• a baseline z-score of −1.3 in whole body BMD (measured by DXA scan) was significantly associated with a decrease in whole body BMD at 17 months follow-up in girls and young females.

10.7.6.2. Evidence in young people and young adults

Very low quality evidence from 1 longitudinal study with 55 young people and young adults with CF (age range 15 to 24 years) suggested that:

• baseline lumbar spine BMD (measured by CQT or DXA) was not significantly associated with a decrease in lumbar spine BMD at 1 year follow-up
• baseline femoral neck BMD (measured by DXA) was significantly associated with a decrease in femoral neck BMD at 1 year follow-up
• baseline total hip BMD (measured by DXA) was significantly associated with a decrease in total hip BMD at 1 year follow-up.

10.7.6.3. Evidence in adults

Moderate quality evidence from 1 longitudinal study with 63 adults with CF (age range 18 to 57 years) suggested that low and very posterior-anterior spine BMD (defined as z-score ≤ −1 and z-score ≤ −2 and measured by DXA scan) were not significantly associated with greater loss of posterior-anterior spine bone mineral density at 2 years follow-up.

Low quality evidence from 1 longitudinal study with 40 adults with CF (age range 18 to 52 years) suggested that:

• a baseline z-score of −0.9 BMD at the left hip (measured by DXA scan) was significantly associated with a decrease in BMD at the left hip at 1 year follow-up
• a baseline z-score of −1.0 BMD at the right hip (measured by DXA scan) was significantly associated with a decrease in BMD at the right hip at 1 year follow-up
• a baseline z-score of −1.1 BMD at the lumbar spine (measured by DXA scan) was not significantly associated with a decrease in BMD at the lumbar spine at 1 year follow-up
• the change in total bone mineral density (measured by DXA scan) from baseline was negligible at 1 year follow-up.

Very low quality evidence from 1 prospective longitudinal study with 21 adults with CF (6 males, 15 females; age not reported) suggested that:

• a baseline z-score of −2.5 BMD at the lumbar spine (measured by DXA scan) was not significantly associated with a decrease in BMD at the lumbar spine at 17 months follow-up in male adults
• a baseline z-score of −1.9 BMD at the lumbar spine (measured by DXA scan) was not significantly associated with a decrease in BMD at the lumbar spine at 17 months follow-up in adult females
• a baseline z-score of −2.5 BMD at the femoral neck (measured by DXA scan) was not significantly associated with a decrease in BMD at the femoral neck at 17 months follow-up in male adults
• a baseline z-score of −2.2 BMD at the femoral neck (measured by DXA scan) was not significantly associated with a decrease in BMD at the femoral neck at 17 months follow-up in adult females
• a baseline z-score of −2.0 in whole body BMD (measured by DXA scan) was not significantly associated with a decrease in whole body BMD at 17 months follow-up in male adults
• a baseline z-score of −1.3 in whole body BMD (measured by DXA scan) was not significantly associated with a decrease in whole body BMD at 17 months follow-up in adult females.

Very low quality evidence from 1 longitudinal study with 59 adults with CF (age ≥ 25 years) suggested that:

• baseline lumbar spine BMD (measured by CQT or DXA) was not significantly associated with a decrease in lumbar spine BMD at 1 year follow-up
• baseline femoral neck BMD (measured by DXA) was significantly associated with a decrease in femoral neck BMD at 1 year follow-up
• baseline total hip BMD (measured by DXA) was significantly associated with a decrease in total hip BMD at 1 year follow-up.

Very low quality from 1 longitudinal study with 49 adults with CF (mean age 25.2 years) suggested that:

• a baseline t-score/z-score of −0.80 in lumbar spine BMD (measured by DXA scan) was associated with an overall rate of bone loss at lumbar spine was −0.73% at 4.3 years follow-up
• a baseline t-score/z-score of −0.57 in proximal femur BMD (measured by DXA scan) was associated with an overall rate of bone loss at proximal femur was −1.93% at 4.3 years follow-up
• a baseline t-score/z-score of −0.71 in whole body BMD (measured by DXA scan) was associated with an overall rate whole body loss was −0.40% at 4.3 years follow-up.

10.7.6.4. Economic evidence statement

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

10.7.7.1. Relative value placed on the outcomes considered

The objective of this review was to determine the most effective strategy to monitor for the identification of reduced mineral density in people with cystic fibrosis.

The committee chose change in bone mineral density as a critical outcome for decision making. Number of fractures and quality of life were rated as important outcomes.

10.7.7.2. Consideration of clinical benefits and harms

The committee acknowledged that most specialist cystic fibrosis centres currently follow the European CF bone mineralisation guidelines (Sermet-Gaudelus 2011). These guidelines recommend that a first bone density scan should be done around age 8 to 10 years and repeated every 1 - 5 years depending on severity (according to BMD t- or z-scores) and risk factors.

The committee discussed the usefulness of conducing regular monitoring for bone mineral density in children as these tests are difficult to interpret in this population. Likewise, the committee discussed whether routine DXA scans should be offered to all adults. They noted that it is unlikely that people over 18 years can build bone mass as this is mostly done during teenage years, therefore, there is limited intervention.

Careful liaison with a bone specialist should occur before commencing children or adults on bisphosphonate therapy. This should include the optimal dose of treatment, duration and monitoring of long-term effects. People should be counselled about the side-effects of bisphosphates before commencing therapy. Careful consideration should also be given to the use of bisphosphates in women of child-bearing age. Vitamin D deficiency and ensuring an optimal calcium intake need to be addressed prior to commencing bisphosphonates. It is important to minimise risk factors for low BMD for example improving nutritional status and encouraging weight bearing exercise.

Even though it was not specifically addressed in the evidence, the committee agreed it is recognised that certain groups across all age groups may benefit from monitoring as they are at a higher risk of reduced bone mineral density. These groups may include people who present with under-nutrition, those using corticosteroids (either frequently of long-term use), those with a history of low impact fracture, those who present exacerbations that require intravenous antibiotics on regular basis, those with poor lung function (low FEV₁), post-menopausal women and following transplants.

The committee noted the available evidence did not provide any clarity in relation to which body sites should be scanned. Therefore, they agreed that a z-score of −2.0 standard deviations at any body site would be considered abnormal and they recommended to seek expert advice.

The committee agreed z-scores should be used in children, whereas z-scores or t-scores can be used in adults. Although, t-scores are more useful in post-menopausal women and men over 50 years.

10.7.7.3. Consideration of economic benefits and harms

Once presented with the clinical evidence and an outline of the resources scans entail, the committee questioned the value of monitoring for reduced BMD in current clinical practice. They stated that the absence of evidence does not mean current clinical practice should be recommended when the opportunity cost of those resources is high.

The committee noted that scans are useful to compare someone’s BMD to the general population as the results can infer if they are at a higher risk of fracture. These results can potentially reduce the number of undiagnosed fractures and downstream costs they entail. Despite this, the committee agreed that management is rarely changed based on the results obtained from a scan as people with cystic fibrosis should always be encouraged to optimise calcium and vitamin D and participate in exercise. Moreover, clinicians are reluctant to prescribe bisphosphonates to maintain BMD in young adults due to their negative effects on fertility, iterating that a low BMD finding from a scan is unlikely to initiate such treatment. For these reasons alone, it was evident to the committee that the use of scans in current clinical practice was not a cost-effective use of resources.

The committee added that DXA scans can overestimate reductions in BMD. If people with reduced BMD are aware of their higher risk of fracture they may stop exercising, resulting in a counterproductive effect. Furthermore, even though the cost of one DXA scan is not substantial, performing a DXA scan every 3 years in everyone with cystic fibrosis under current practice has a substantial resource and cost use when the total is considered.

An alternative to a DXA scan is a pQCT scan. However, the committee advised that the use of pQCT scans to monitor for BMD remains a research area as their interpretation is not fully understood by clinicians in clinical practice. It was noted that pQCT scans can emit radiation and are more expensive to perform than DXA scans due to the extra time and equipment they require.

Overall, the committee agreed that monitoring for reduced BMD would not be considered cost-effective in all cases. They subsequently identified populations deemed to be at a higher risk of reduced BMD who could benefit from a DXA scan.

In those populations, the committee agreed scans could be repeated on an annual basis if the BMD SDS score is less than −2.00. However, the committee did not state the frequency of bone scans in their recommendations as the frequency should be individualised to the person with cystic fibrosis, according to clinical expertise. This would inform if treatment to prevent reduced BMD should to be escalated or stopped or if specialist advice should be sought regarding bisphosphonate treatment.

The committee considered performing a DXA scan after the transition from paediatric to adult services for a baseline BMD measure and then as necessary. However, the committee noted that weight can change BMD quite markedly, this questions the value of a baseline scan that could soon be outdated. As a result, a recommendation was only prioritised to monitor BMD in high risk populations. The committee advised that this would lead to a large change in current practice and result in cost savings, but would not compromise on health benefit as current practice was not a cost-effective use of resources.

10.7.7.4. Quality of evidence

Prospective and retrospective observational studies were included in the review. The quality of the evidence, as assessed per individual studies using a critical appraisal tool for the evaluation of the quality of prognosis studies in systematic reviews (Hayden et al. 2006), was very low. The main sources of bias in the studies were:

• poorly reported sample selection, with unclear inclusion and exclusion criteria,
• the study sample did not fully represent the population of interest with regard to key characteristics, and
• important potential confounders were not appropriately accounted for.

Due to all these limitations, the committee considered that the usefulness of the data reported in the studies is very limited.

10.7.7.5. Other considerations

Due to the scarcity and low quality of the evidence, the recommendations were mainly based on committee members’ clinical experience and consensus on good clinical practice.

The committee acknowledge there is a lack of longitudinal studies to evaluate the impact of low BMD on fractures and quality of life. However, it is known that people with cystic fibrosis are at an increased risk of developing osteopenia and osteoporosis (See section on Complications). They were also aware of cross-sectional evidence showing a correlation between low BMD, decreased lung function and poor nutritional status. However, they noted that although the main concern is the risk of fractures, the incidence of fractures in this population is not particularly high.

As discussed previously, the committee agreed the absence of evidence showing a benefit in conducting regular scans, and the fact that people receive treatment anyway, justifies the change in practice. Moreover, conducting routine exams can create anxiety. However, they agreed that people with cystic fibrosis and their carers may feel concerned about a change in practice. They suggested it is important to talk to the families and discuss their concerns.

No equality issues were identified by the committee for this review question.

The committee noted that evidence regarding the impact of low BMD in fractures was mostly conducted in post-menopausal women. They agreed it would be helpful if a study could be conducted looking at people with cystic fibrosis and highlighted the importance in assessing fractures and quality of life. However, it was agreed that this was not a priority research recommendation for the guideline as a whole.

10.7.7.6. Key conclusions

The committee concluded that there is no need to perform routine bone density scans to all children and adults with cystic fibrosis. DXA scans should only be considered in children and adults who are at risk of low bone mineral density. This is because there is little value in routine monitoring as children and young people get treated to help accrue bone mass in spite of the results of the test.

10.8.6.1. Aerobic exercise programmes

10.8.6.2. Strength resistance training/anaerobic training

10.8.6.3. High intensity interval training

10.8.6.4. Inspiratory muscle training

10.8.6.5. Combined programmes

10.8.6.6. Habitual physical activity

10.8.6.7. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

10.8.7.1. Relative value placed on the outcomes considered

The aim of this review was to determine the effectiveness of different exercise programmes in improving health outcomes for people with cystic fibrosis.

The committee chose lung function (FEV₁), quality of life and time to next exacerbation as critical outcomes for decision making. Forced vital capacity (FVC), maximum volume of oxygen (VO₂), body composition, preference for training programme and adverse events were rated as important.

10.8.7.2. Consideration of clinical benefits and harms

The committee reviewed the evidence on the effectiveness of aerobic exercise programmes compared to no exercise programme. The evidence was of moderate to very low quality. The evidence showed that these programmes were mostly effective in relation to FVC % predicted and VO₂ max, results were mixed in relation to FEV₁ % predicted or the evidence showed no benefits in relation to BMI. No evidence was found in relation to the other outcomes including adverse events. The committee concluded that the evidence showed some benefit of aerobic exercise programmes and there was no evidence of harm.

The committee reviewed the evidence on programmes of strength resistance or anaerobic training compared to no exercise programme. The evidence was of low to very low quality. The evidence showed that these programmes were mostly effective in relation to FEV₁ % predicted, VO₂ max and body composition. Results were mixed in relation to FVC% predicted, the evidence showed no benefits in relation to quality of life. No evidence was found in relation to the other outcomes of interest including adverse events. The committee concluded that the evidence showed some benefit of strength resistance or anaerobic exercise programmes and there was no evidence of harm.

The committee reviewed the evidence on programmes of combined aerobic and anaerobic training compared to no exercise programme. The evidence was of moderate to very low quality and showed no benefits of training in relation to FEV₁% predicted, FVC% predicted, VO₂ max, BMI or quality of life. This kind of training did not lead to an increase in adverse events.

Overall, the committee noted that the evidence showed some benefits for lung function and no harm of aerobic, strength resistance or anaerobic training. In addition to these benefits for lung function, the committee agreed that people with cystic fibrosis would also gain the same kind of fitness benefits from exercise that would be gained by the general population. Therefore, the committee decided to recommend to advise people with cystic fibrosis of the benefits of regular exercise in relation to lung function in addition to the expected fitness benefits.

The committee reviewed the evidence on the effectiveness of a strength resistance or anaerobic training programme compared to an aerobic training programme. The evidence was of very low quality and showed no differences in relation to FEV₁ % predicted and VO₂ max. No evidence was found in relation to the other outcomes. Therefore, the committee decided not to recommend one type of exercise over another. Rather, they decided to recommend to offer all people with cystic fibrosis individualised exercise programmes which take into account the capability and preferences of the person. The committee noted that taking someone’s preferences into account is key to increase the likelihood of adherence to a training programme.

The committee reviewed the evidence on high intensity interval training compared to a standard exercise programme. The evidence was of very low quality and was based on a population of inpatients with FEV₁ <40% predicted. The evidence showed no benefits in relation to FEV₁% predicted, VC% predicted, VO₂ max or BMI. No evidence was found in relation to the other outcomes including adverse events.

The committee reviewed the evidence on inspiratory muscle training (IMT) at 80% of maximal effort compared to usual care. The evidence was of low quality and showed no benefits in relation to FEV₁% predicted and FVC% predicted. No evidence was found in relation to the other outcomes including adverse events.

The committee reviewed the evidence on a programme of combined IMT, resistance and aerobic training compared to no exercise programme. The evidence was of low to very low quality. The evidence showed no benefits in relation to FEV₁, FVC, weight or quality of life. This kind of training did not lead to an increase in adverse events.

Given that the evidence on the 3 aforementioned training programmes did not show benefits or harm, and was of low to very low quality, the committee chose not to make a recommendation specific to these kinds of training.

The committee agreed that they could not draw a clear conclusion from the evidence on whether supervised programmes were more effective than unsupervised programmes. Therefore, they decided not to make a recommendation on this. They recommended, however, to regularly monitor exercise programmes at clinic visits so that they can be adapted as necessary. They noted that regular exercise testing is an important part of monitoring.

The committee noted that there was no evidence on what intensity or frequency of exercise would be the most effective. Therefore, they decided not to make a recommendation specific to this.

10.8.7.3. Consideration of economic benefits and harms

People with cystic fibrosis are encouraged to participate in activity and exercise that is available to the general population, leading to no additional resource or cost use. However, the committee noted that there may be individuals who would benefit from more specialised advice.

According to the committee, exercise programmes for individuals with cystic fibrosis should be developed along with support of physiotherapy teams that specialise in cystic fibrosis who can provide regular monitoring and support. This enables exercise to complement existing airway clearance techniques and treatment regimens in order to maximise and support adherence. In turn, this will improve treatment effects which the committee believed would subsequently outweigh the cost of developing and maintaining those programmes.

From the clinical review, there was no strong evidence supervised programmes were more effective than unsupervised programmes or no programme. In light of this, the committee agreed that not all people with cystic fibrosis require supervised programmes. However, there may be times when supervision is important such as to help teach technique. In those cases, such as strength and resistance training, supervision is key to ensure the exercise is performed correctly to minimise injuries and maximise benefits. The committee stated that such initial costs would be negligible compared to the potential downstream costs from injuries and inactivity.

Given that not every person would benefit from supervised programmes, the committee agreed that physiotherapists must consider the opportunity cost of their time to supervise individuals. For those reasons, the committee agreed not to recommend supervised programmes as the level of supervision would be individualised.

The committee stated that patient preference is paramount to the success and sustainability of a programme. Therefore, despite higher costs, a programme could be considered cost-effective if it provides them with greater benefits than a cheaper programme. However, the committee noted that freely available activities would be trialled first. Following this, the committee did not want to specify the type or duration of exercise as this should be tailored to someone’s preferences and capabilities.

The committee agreed that offering all people with cystic fibrosis individualised exercise programmes would not lead to a change in clinical practice as physiotherapists and dietitians regularly review participation in exercise at each review. Therefore, recommendations to offer exercise programmes were prioritised to enforce the importance of exercise. Moreover, the committee advised the cost to create an individualised programme would be negligible compared to the benefits sustained exercise can provide.

Following this, the committee highlighted the importance of maintaining an exercise programme, even during inpatient care, to prevent any additional deteriorations in their health that could lead to additional costs, such as longer hospital stays. As a result, the committee prioritised a recommendation to offer inpatients the opportunity to exercise. The committee agreed that inpatients usually have poorer health than outpatients and, in their experience, are more at risk of adverse events. Therefore, supervised exercise would be more appropriate for some inpatients in order to prevent the downstream costs from unsupervised exercise that is potentially unsafe or ineffective.

The committee agreed that an assessment upon hospital admission by a physiotherapist, and any subsequent supervision, would not deviate from current clinical practice. However, the committee were concerned that not all hospitals have sufficient exercise facilities for people with cystic fibrosis or space to store exercise equipment. Their solution was not to build a “second” gym, but to provide a schedule that promotes cross-infection control measures for people with cystic fibrosis to access the facilities. Achieving those schedules may incur additional cleaning and equipment, and reduce the time facilities are available for patient use. For these reasons, hospitals should consider if their strategies to prevent cross-infection using existing exercise facilities outweighs the cost to provide additional space and equipment devoted to people with cystic fibrosis.

Overall, the committee advised that their recommendations were within the remit of specialist cystic fibrosis physiotherapy teams. However, they noted that staffing levels and exercise facilities during episodes of inpatient care need to be prioritised to allow exercise programmes to be continued.

10.8.7.4. Quality of evidence

The quality of the evidence presented in this review ranged from very low to moderate as assessed by GRADE.

For the domain risk of bias, the studies were assigned the same risk of bias as in the Cochrane reviews and were not individually reviewed. The main biases that led to downgrading the quality of the evidence were randomisation, allocation concealment, attrition, and reporting bias. It is important to note that it was not possible to blind participants to the exercise intervention in RCTs thus increasing the risk of performance bias.

In studies on unsupervised programmes it was not possible to independently assess if the participants actually performed the exercise programmes as prescribed.

Another factor which led to downgrading the quality of the evidence was the imprecision, as confidence intervals crossed 1 or 2 MIDs. The committee noted that many trials were underpowered to detect a clinically important difference.

No serious issues were found regarding inconsistency (heterogeneity), as most outcomes were reported by a single study. Where heterogeneity was identified, and sensitivity or subgroup analysis did not explain the source of inconsistency, the results were explained to the committee.

No serious issues were found regarding indirectness of the population or the interventions.

10.8.7.5. Other considerations

The committee noted the NHS service specifications for cystic fibrosis do not cover exercise in detail, although they mention that inpatients should have access to facilities for exercise.

No equality issues were identified by the committee for this review question.

The committee felt a research recommendation was not needed as there is enough available evidence to show that regular exercise is beneficial for people with cystic fibrosis.

10.8.7.6. Key conclusions

The committee concluded that regular exercise is especially beneficial for people with cystic fibrosis due to the benefits to lung function and other health benefits. Exercise programmes should be individualised to take into account personal circumstances and preferences given there is no evidence that a specific programme may be better than another. There is no evidence to indicate whether a supervised exercise programme may be better than an unsupervised programme, however, the programme should be regularly monitored and adapted if necessary. Inpatient stays should be used as opportunities to promote regular exercise. Appropriate supervision should be offered, if necessary, depending on individual circumstances. Moreover, access to appropriate exercise facilities should be guaranteed in the inpatient setting while taking into account local infection control guidelines.

10.9.6.1. Psychological disorders

10.9.6.2. Non adherence to treatment

One study reported on the usefulness of self-report and clinician-report as measures of adherence in a population of 78 adults with cystic fibrosis on nebulizer therapy:

• there was an overestimation of adherence by the participants. No measures of reliability were reported;
• there was an overestimation of adherence by the clinicians. The intra-class correlation agreement ranged between 0.28 and 0.54.

No measures of validity were reported. It is important to note that extreme inaccuracy was observed for individual participants by clinicians and self-report adherence. This overall quality of this study was moderate.

One study reported on the usefulness of self-report and pharmacy refill history as measures of adherence in a population of 12 children, young people and adults with cystic fibrosis receiving Ivacaftor:

• there was an overestimation of adherence by the participants. There was no statistically significant correlation between overall electronic-monitoring adherence and self-report (intra-class correlation coefficient was 0.14);
• there was an overestimation of adherence by the pharmacy records. There was also no statistically significant correlation between overall electronic-monitoring adherence and pharmacy refill history (intra-class correlation coefficient was 0.26).
• No measures of validity were reported. It is important to note that individuals demonstrated wide variability in regards to the different measures of adherence. The overall quality of this study was low, mainly because it was underpowered.

One study reported on the usefulness of self-report (using the CFQ-R tool) as a measure of adherence to treatment in a population of 250 young people and adults with cystic fibrosis:

• there was a statistically significant correlation between pharmacy script collection and self-report adherence to aerosol to open air (r=0.34);
• there was a statistically significant correlation between pharmacy script collection and self-report adherence to aerosol to thin mucus (r=0.51);
• there was a statistically significant correlation between pharmacy script collection and self-report adherence to inhalers (r=0.51);
• there was a statistically significant correlation between pharmacy script collection and self-report adherence to PERT (r=0.45);
• there was a statistically significant correlation between pharmacy script collection and self-report adherence to oral nutritional supplements (r=0.51);
• there was a statistically significant correlation between pharmacy script collection and self-report adherence to oral antibiotics (r=0.51).
• there was a statistically significant correlation between pharmacy script collection and self-report adherence to nebulised antibiotics (r=0.55).

The overall quality of this study could not be assessed, as the information was extracted from a conference abstract. Full publication not available.

10.9.6.3. Economic evidence statements

No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.

10.9.7.1. Relative value placed on the outcomes considered

The aim of this review was to determine which assessment strategies are effective at identifying psychological, behavioural and adherence problems in children, young people and adults with cystic fibrosis.

Sensitivity and specificity of the tools were prioritised as critical outcomes for decision making. Positive likelihood ratio, negative likelihood ratio, AUROC, and reliability or validity were rated as important outcomes.

10.9.7.2. Consideration of clinical benefits and harms

The committee agreed the limited available evidence was not helpful in guiding them to make recommendations.

The committee discussed the issue of adherence at length. They noted adherence is an overarching issue in this guideline and should not fall under the category of psychological or behavioural disorder or problem. To reflect this, results for adherence were presented separately in this review.

The results from this review showed that there is poor correlation between what participants or professionals report, and what is actually taken. Likewise, there was poor correlation between what it is collected and what it is actually taken. According to the committee, these results are consistent with clinical practice. The committee noted that adherence is extremely difficult to measure in both clinical practice and research, unless a particular objective measuring tool is employed (for example electronic monitoring or pharmacy records), which is rare in routine clinical practice. The evidence used 2 different methods for electronic monitoring as reference standards to measure adherence: the I-neb was used in one study and the Medication Event Monitoring System (MEMS) was used in another study; however the committee noted that the I-neb is by far the commonest in the UK. The committee stressed that adherence problems are common in people with chronic conditions, and those with a number of concurrent treatments, and are not specific to cystic fibrosis. They agreed that the overarching principles from the NICE guidance on Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence [CG76] is applicable to people with cystic fibrosis. Therefore, the committee decided not to make a recommendation specific to measuring adherence in cystic fibrosis care. The committee felt no specific recommendations could be made regarding assessment tools as no evidence was found. They highlighted there are no available tools specific to people with cystic fibrosis. They noted that, although assessment tools are helpful to assess the severity of the psychological or behavioural disorder, in practice psychologists are able to intervene without a formal diagnosis. Therefore, although a case findingtool for psychological problems in cystic fibrosis would help, all people and families should be seen regularly by a psychologist..

The committee noted that routine psychological support is important to improve outcomes in a chronic and life-threatening illness. Early psychological support can improve adherence to long-term medications in adolescence, which is a major determinant of life expectancy. Following this discussion, the committee agreed a psychologist with expertise in cystic fibrosis should be an integral member of the multi-disciplinary team. They agreed people with cystic fibrosis should be seen by the psychologist as part of the annual review. However, all members in the multidisciplinary team should be aware of how to identify psychological and behavioural problems.

The committee agreed that people with cystic fibrosis should have a specialist clinical psychologist review as part of the annual review to identify psychological and behavioural problems and offer advice. Moreover, the specialist clinical psychologist should assess and advise people with cystic fibrosis, and their families and carers, at cystic fibrosis clinical visits, inpatient admissions and for further outpatient consultations (such as community visits, school or social care meetings) or telephone calls when required.

The clinical psychologist should assess the needs of family members or carers (as appropriate) in relation to the impact of cystic fibrosis to support their psychological wellbeing and to facilitate onward referral. The committee noted that if psychological needs were more of an individual nature rather than related to cystic fibrosis, the clinical psychologist would refer the person to the GP who would then provide onward referral to a mental health practitioner, who would be part of the local mental health team. The clinical psychologist should also consider (in discussion with the family) Tier 2 referral or onward referral to local psychological wellbeing services for further support (for example with the school counsellor or CAMHS). The annual review should be individualised depending on the circumstances of the person. But as a general guidance it should cover aspects such as general mental health and quality of life, behavioural problems impacting on health outcomes, adherence to treatment, school attendance, friendship and social life. The annual review should also include assessment of any emerging indicators of psychosocial problems such as poor school attendance, family break up, anxious thoughts, low mood, missing treatments, financial or home management difficulties, safeguarding concerns, employment support needs or criminality. If a severe mental health condition is identified as part of the annual assessments such as psychosis, high level of risk of self-harm or need for psychiatric care, the person should be referred to a mental health practitioner, who would be part of the local mental health team. This would normally involve a “stepping up” of care into specialist mental health services. This is already consistent with current practice. Detailed guidance on identification and management for specific mental health conditions can be found at other NICE guidelines (For example, the following guidelines on common mental health problems: Identification and pathways to care [CG123], Depression in children and young people [CG28], Depression in adults [CG90], Depression in adults with a chronic physical health problem: recognition and management [CG91], Generalised anxiety disorder and panic disorder in adults [CG113], Eating disorders in over 8s: management [CG9]; the following guidelines on social and emotional wellbeing: Social and emotional wellbeing: early years [PH40], Social and emotional wellbeing in primary education [PH12], Social and emotional wellbeing in secondary education [PH20]).

10.9.7.3. Consideration of economic benefits and harms

There will be a cost attached to the administration and interpretation of questionnaires such as the PI-ED. But the committee agreed that cost of the assessment would be negligible and outweighed if the assessment can improve identification and subsequent management. However, the committee stated that psychological and behavioural assessment tools are not validated for people with cystic fibrosis, who have a multi-system disorder and a lifetime of complex treatment schedules. Following this, the committee noted that the cost-effectiveness of a treatment can depend on adherence and provided examples when regimens become cost-ineffective, such as unused treatments which are followed with additional supplies, or treatments prescribed at higher doses, when the former was considered to be too low. To reduce those occurrences, the committee agreed that the overarching principles from the NICE guidance on Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence [CG76] should be followed.

The committee stated that the number of people with cystic fibrosis with psychological and behavioural problems is growing. One reason for this is the limited time psychologists have to take preventative measures. To reduce the high risk of missing emerging problems, the committee agreed psychologists should be available to see people with cystic fibrosis, and their family members or carers, at outpatient clinic visits and during inpatient admissions. The committee also agreed that the frequency of visits to the psychologist should be based on individual needs as it would be cost-ineffective to monitor each individual using the same schedule when the opportunity cost of the psychologist’s time is high.

Overall, the committee agreed that monitoring in addition to the annual review would promote a cost-effective use of resource as changes to a management strategy can occur sooner to reduce the negative effects psychological and behavioural problems entail. The committee also agreed that their recommendations would reinforce best practice and reduce geographical variation.

10.9.7.4. Quality of evidence

The studies included in the review aimed to establish the reliability and validity of assessment tools. The following were considered as the main criteria for assessing the quality of each study, as reported by Jerosch-Herold (2005).

• Sample size
• Sampling methodology
• Blinding of raters
• Statistical analysis

Main risk of bias in the included studies was little information given on whether observer or tester were appropriately trained or certified.

One study was only available as conference abstract and the quality could not be assessed.

In one study extreme inaccuracy was observed for individual participants by clinicians and self-report adherence. In another study, individuals demonstrated wide variability in regards to the different measures of adherence.

10.9.7.5. Other considerations

The committee discussed whether the cystic fibrosis psychologist should be available to meet people with cystic fibrosis and their families or carers at every cystic fibrosis clinic if necessary. They highlighted it is not happening in current practice. This is particularly the case in adult clinics because the number of psychologists have remained the same. This is despite the number of adult people with cystic fibrosis increasing. While this may lead to a resource impact, it was noted that early identification and intervention can help prevent more serious issues in the future.

The committee stated that when a psychologist is introduced at diagnosis stage as a natural member of the team (for example a nurse) people with cystic fibrosis and their carers are more likely to be accepting of this role.

The committee suggested some strategies effective at identifying the presence of psychological or behavioural problems.

• Informal but frequent assessments by the psychologist and multidisciplinary team members by regularly asking questions about emotional wellbeing as well as physical health.
• The team clinical psychologist can support the rest of the team in this by holding psychological wellbeing in mind, and supporting staff if they would like to think through the responses they get from patients (or family members), or provide training to staff on delivery of basic emotional support.
• Ensure team clinical psychologist presence at patient case discussions of outpatients, inpatients, complex case meetings and annual review reports.
• Annual assessment by clinical psychologist using face to face professional assessment and standardised measures of psychological wellbeing and mental health functioning.
• Providing information to people with cystic fibrosis, and their family or carer, regarding psychology services and support available including easy access to services, including self-referral.
• Increased access to clinical psychology and review of vulnerable groups and people at particularly complicated stages of cystic fibrosis. For example, newly diagnosed, mental health problems in parents or carers, substance misuse, pre- and post-transition, end stage illness, pregnancy and assisted conception, secondary diagnosis and referral for transplant.
• Provide support for people with cystic fibrosis and training for staff around sensitive issues that may be difficult to discuss. In particular, anxieties relating to transplant decisions and people’s wishes for end-of-life care.

The committee discussed potential equality issues. They noted psychological problems may be more likely in people from lower socio-economic groups. However, they agreed care is available to all people so there was no need to draft additional recommendations.

The committee agreed there was a lack of evidence to determine the best objective measures of adherence. Difficulties with full adherence to all components of the cystic fibrosis daily treatment regimen were well documented and directly resulted in poor health outcomes. Studies indicated that reports of rates of adherence varied and so subjective measures were unreliable. The committee noted that the reference standards for measuring adherence are electronic monitoring or pharmacy records, and noted that the I-neb is the most commonly used method of electronic monitoring in the UK. There needed to be further research to understand the occasions when people with cystic fibrosis do and don’t follow prescribed recommendations, and which types of treatment are more likely to be taken than others. This would help adapt prescribed treatments to support increased likelihood of compliance. This would lead to better health outcomes. The area was not prioritised for a research recommendation but the committee wanted it noted.

The committee agreed a research recommendation around psychological assessment. As noted previously, there are no validated tools to assess psychological and behavioural problems in people with cystic fibrosis. The committee thought it would be useful to validate generic measures, for example for depression and anxiety. They noted that people with a long term physical health condition are more likely to present with psychological and mental health difficulties than people without. NHSE recommendations state that prevention of psychological problems is the most cost-effective service provision. This means that all people with cystic fibrosis must be routinely and regularly assessed for their physical health status and their mental health status. People with cystic fibrosis would benefit, therefore, in having a routine screen which would indicate those who require further psychological intervention. This would allow early intervention by a team psychologist to support maintenance of good quality of life, prevention of the development of mental health disorders and improvement in health outcomes as a result of improved wellbeing.

10.9.7.6. Key conclusions

The committee concluded that the cystic fibrosis psychologist should be an integral member of the multidisciplinary team and should be available to people with cystic fibrosis and their families or carers. A psychological and behavioural assessment should be part of the annual review. People should be referred to a mental health practitioner, who would be part of the local mental health team, if a severe mental health condition is identified.