5   Why does Lauren need her pancreatic enzyme increased?

6   What sort of dietary advice would be given to Lauren to optimize her nutrition?

7   Why is chest physiotherapy important to improve lung function for Lauren?

8   Why has inhaled ciprofloxacin been prescribed and how does it work?

ANSWERS

1 What is CF?

A CF is a condition with a complex multisystem involvement of the GI and respiratory systems. It is a common heterogeneous disorder with more than 1500 mutations and clinical phenotypes on chromosome 7 (Montgomery and Howestine 2009). The gene is autosomal recessive, so both parents have to be carriers for the child to inherit the disease. Where both parents are carriers of the faulty gene there is an increased incidence of one in four children being born having CF. Approximately 1 in 25 people in the UK are carriers of the CF gene.

Treatment of CF involves managing the respiratory and GI symptoms caused by the CF transmembrane conductance regulator (CFTR) mutation. Treatments are limited as there are many mutations of chromosome 7 and experimental treatments to reopen the CFTR channel have limited application to a few sufferers (Ledford 2012). The main thrust of research is the development of gene therapy. Where there is chronic respiratory dysfunction some patients are offered lung/heart transplants. CF is a mutation of the CFTR channel which mediates diffusion of chloride through epithelial cell membranes. The CFTR controls the chloride channel that allows the free movement of salt (chloride and sodium) in and out of the cells through diffusion. All cells acquire the molecules and ions they need from their surrounding extracellular fluid and there is an unceasing traffic of molecules and ions in and out of the cell through the plasma membrane. Molecules and ions move spontaneously down their concentration gradient (i.e. from a region of higher to a region of lower concentration) by diffusion (the movement of particles from an area of higher concentration to an area of lower concentration). Water can pass through the cell membrane but ions and charged molecules (e.g. salts dissolved in water) need a facilitated diffusion. The transmembrane proteins create a water-filled pore through which ions and some small hydrophilic molecules can pass by facilitated diffusion in and out of the cell. The channels can be opened (or closed) according to the needs of the cell. The CFTR provides a chloride channel to facilitate the transport of chloride across the cell membrane. The activity of the CFTR may activate water permeability in healthy individuals but not in CF. In CF the mutation of the CFTR affects diffusion of molecules and ions across the membrane. There is decreased chloride (Cl^–) secretion due to the CFTR mutation. However, there is increased sodium (Na⁺) absorption, possibly due to the loss of the inhibitory influence of the CFTR (Goodman and Percy 2005).

2 What are the clinical manifestations of CF?

A The clinical manifestations of CF are as follows.

•   Pancreatic enzyme deficiency due to blockage of the pancreatic duct. In approximately 85% of cases the pancreatic exocrine ducts become blocked and cause intestinal malabsorption due to pancreatic insufficiency. The thick viscid secretions in CF affect the digestive tract. Digestive problems may present in infancy as a GI blockage and as a meconium ileus. Infants are unable to pass the first stool that contains meconium. This obstruction means that the pancreatic enzymes are blocked from entering the duodenum, limiting digestion of proteins and fats. Older children may present with failure to thrive due to pancreatic insufficiency, with symptoms of restricted growth in the presence of a voracious appetite and a protuberant belly with decreased subcutaneous tissue on the extremities. Lack of digestive enzymes in the intestinal lumen also causes symptoms including frequent, loose, oily and malodorous stools caused by steatorrhea (fat in stool due to lack of active pancreatic lipases). A faecal elastase evaluation (Turner and McDermott 2006) is a simple and non-invasive test that allows clinicians to estimate pancreatic exocrine function. Elastase is a pancreatic enzyme which helps to break down connective tissue. It is present in the serum, urine and faeces. Pancreatic elastase does not undergo any significant degradation during intestinal transit and, therefore, acts as a useful marker of pancreatic activity.

•   Progressive chronic obstructive lung disease. Infants with CF often present with respiratory problems. Viral illnesses can progress to bacterial pneumonia as the respiratory cilia cannot clear the thick mucus. Air becomes trapped in the airways leading to bronchospasm, hyperinflation, collapse or closure of alveoli (atelectasis) and secondary infections. Chronic infection and inflammation can lead to a persistent dilation of the bronchi (bronchiectasis). Respiratory problems can present as persistent dry and non-productive coughing or recurrent respiratory infections. Auscultation can demonstrate expiratory wheezing and fine crackles due to bronchospasm. Patients are often infected with Staphylococcus aureus and Pseudomonas aeruginosa, but also by a number of other organisms, some of which are resistant to many antibiotics. The use of antibiotics is to reduce or prevent a pseudomonas-associated deterioration of respiratory function.

3 What tests can aid diagnosis of CS?

A A sweat test (pilocapine iontophoresis) involves stimulating the production and collection of sweat and measuring the electrolytes, and can be used to identify CF. The quantitative analysis requires a minimum 50mg of sweat. A measurement of sodium chloride of <70mmol/kg in a 100mg sample is indicative of CF. However, in the UK the test for CF is included in the heel-prick test to sample blood, carried out on all children. CF is increasingly being diagnosed through infant screening. The blood test is to detect immunoreactive trypsinogen (IRT) concentrations which are high in newborns with CF. If the IRT reading is high, a chromosomal mutation analysis can be performed on the same or a repeat sample. In addition, there is now a carrier test identified from saliva and an antenatal blood test offered to all mothers who are at high risk as a carrier of CF. However, some infants and older children (and even adults) may not be diagnosed as a newborn through blood tests but later following an unexplained respiratory illness or malnutrition due to pancreatic insufficiency.

4 What are the indicators that have led to the changes in Lauren’s dietary and enzyme management?

A When plotted on a percentile chart Lauren’s height and weight are below the first percentile which suggests she is underweight. As children with CF become adults there is a risk of malnutrition that is strongly linked to the severity of lung disease and body weight. Apart from the general malnutrition associated with more severe disease, many aspects of nutrition that affect bone status, including fat soluble vitamins (A, D, E and K), minerals (calcium and iron in particular) and protein intake, can lead to osteoporosis.

5 Why does Lauren need her pancreatic enzyme increased?

A Lauren, as with the majority of patients suffering from CF, is ‘pancreatic insufficient’. Unless this is treated with pancreatic enzyme supplements, digestion and absorption of food will be severely impaired. Inadequate absorption of nutrients will lead to unpleasant digestive symptoms such as:

•   constipation;

•   foul-smelling, greasy stools;

•   malnutrition;

•   poor growth;

•   weight loss;

•   specific deficiencies of the fat soluble vitamins and essential fatty acids (Littlewood et al. 2006).

Patients who are well nourished have a better outcome because malnutrition leads to impaired respiratory muscle function, decreased exercise tolerance and immunological impairment resulting in increased susceptibility to infections.

Dietetic management is an integral part of CF care to ensure normal weight gain, growth, body composition, pubertal development and vitamin, mineral and essential fatty acid status. Dietary treatment for CF is achieved by ensuring sufficient pancreatic enzyme through pancreatic enzyme replacement therapy (PERT) which administers the pancreatic enzymes protease, lipase and amylase. The pancreas has both an endocrine and exocrine function that is integral to digestion. The endocrine role is in the production of insulin and glucagon that control carbohydrate metabolism. The exocrine function involves the synthesis and secretion of pancreatic juices into the duodenum via the pancreatic duct. CF can affect both the exocrine and endocrine functions of the pancreas, but most individuals have symptoms associated with the exocrine function, leading to malnutrition due to pancreatic insufficiency.

The pancreatic juices contain:

•   sodium bicarbonate, which neutralizes the acidic material from the stomach;

•   pancreatic proteases (trypsin and chymotrypsin) that aid digestion by breaking down some proteins (but not all) to amino acids;

•   pancreatic lipase, to aid fat digestion by breaking fats down to monoglycerides;

•   fatty acids and pancreatic amylase to change starch to maltose.

As Lauren has pancreatic insufficiency she receives PERT. There are various pancreatic enzyme preparations available. All pancreatic insufficient individuals are given enteric-coated, acid-resistant microspheres (small beads in a capsule) pancreatic enzyme preparations (e.g. creon). This is to ensure the enzyme is not destroyed by hydrochloride within the stomach and aids digestion in the duodenum. The capsule therefore should be swallowed whole where possible, but if the capsule is broken open the microsphere beads should be swallowed and not chewed.

There are many factors that affect the efficacy of pancreatic enzymes, including:

•   the amount of fat intake;

•   the timing of enzyme intake with fatty foods;

•   the acidity in the gut;

•   GI transit time;

•   growth and development.

A The energy requirements of patients with CF vary widely and generally increase with age and disease severity. Lauren, as a 16-year-old adolescent, is growing and requires more enzymes and more calories. Unfortunately, many patients with CF do not manage to eat enough to meet their increased energy requirements. The reasons for this are multifactorial and include chronic poor appetite, infection-related anorexia, gastro-oesophageal reflux, abdominal pain, vomiting and depression (Duff et al. 2003). It is recommended that a detailed dietary assessment and food frequency questionnaire should be performed for all patients every two years, or more often if there are growth problems, in order to identify the factors that may contribute to a reduced energy intake (CF Trust 2009). A review by a dietician experienced in the management of CF will tailor dietary advice to meet to Lauren’s needs. There are a number of ways of increasing the energy intake that could be advised, including:

•   encouraging frequent meals;

•   encouraging high calorie snacks such as crisps and chocolate;

•   not restricting dietary fat as this nutrient is essential to achieve a good calorie intake;

•   increasing the calorie content of food by frying and roasting;

•   increasing the sugar content of diet (drinks, cakes, etc.);

•   choosing meat rich in protein;

•   choosing dairy foods such as milk, cheese and eggs as good sources of calcium.

Enzymes should be given with all foods and drinks containing fat. The timing and dose of enzyme administration will be gradually increased until the symptoms of fat malnutrition are controlled (Lowdon et al. 1998).

7 Why is chest physiotherapy important to improve lung function for Lauren?

A Chest physiotherapy is an integral part of the management of CF. Lauren has physiotherapy which she manages herself. There are a wide variety of airway clearance techniques that involve breathing techniques and postural drainage and percussion. The aim is to reduce airway obstruction by improving the clearance of the viscid secretions to maintain optimal respiratory function and exercise tolerance. In addition to chest physiotherapy, antibiotics and inhaled medicines that help to open the airways and thin the mucus (mucolytics) are also used to help clear mucus from the lungs.

In normal lung tissue, mucus is secreted from two distinct areas. The epithelium contains mucus-secreting goblet cells and the connective tissue layer beneath the mucosal epithelium serous mucous glands also produces mucus. Continual mucus production is a normal process to keep the airways moist and to trap dust and debris that may enter the lungs. The microscopic hairs (cilia) that line the epithelium aid expectoration of mucus by moving it up to the throat, allowing it to be cleared by coughing.

8 Why has inhaled ciprofloxacin been prescribed and how does it work?

A Lauren has a new P. aeruginosa infection which is a gram-negative bacterium. Patients with P. aeruginosa infection have a two- to threefold increased risk of death over an eight-year period (Kosorok et al. 2001). Successful eradication can be achieved in approximately 80% of cases of new infection by various combinations of oral, inhaled and IV antibiotics. There is no consensus on the best combinations, dosage or length of treatment courses. (Li et al. 2009). However, the CF Trust report in 2009 recommended inhaled antibiotics to control infection in patients with P. aeruginosa, preserve lung function and decrease the need for additional treatments.

Lauren is treated with ciprofloxacin as an inhaled aerosol. Ciprofloxacin is an antibiotic that belongs to the fluroquinolone class of medications. The fluoroquinolones are a family of synthetic broad-spectrum antibiotics, which eradicate bacteria by interfering with DNA replication. Aerosol antibiotics achieve high local concentrations in the airways, reduce systemic toxicity and have been used successfully for chronic suppressive treatment for established P. aeruginosa infections (CF Trust 2009). Antibiotics can be categorized by the pharmacodynamic parameters that best predict efficacy. Fluoroquinolones appear to display a ‘concentration-dependent’ pattern (Geller 2009), that is, the ratio of maximum drug concentration to the minimum inhibitory concentrations (MICs). It is difficult to know how effective the drug is as the therapeutic effect of an inhaled antibiotic depends on the amount of drug deposited in the airways, how well the drug distribution matches the location of the bacteria, and whether the local concentration of antibiotic achieved is adequate to kill the microbes (Geller 2009). Studies have found that, due to a post-antibiotic effect of fluoroquinolones concentrations on P. aeruginosa, less frequent doses are required and the medicine may therefore be administered daily or twice daily.