A seven-year-old girl with known cystic fibrosis (CF) presents with coryza and sore throat. She has also had intermittent abdominal pain before bed for the past four nights, although has been eating and drinking well. Bowels have been opened every two to three days. She has been attending school, denies any increase in cough or breathlessness and she feels well in herself, which is why her parents have come to see you, rather than attending hospital. Spirometry was performed two months previously (FEV1 of 87% and FVC of 92%). Her parents tell you that she has previously been treated for pseudomonas infection about a year ago, which was eradicated and has not been grown on cough swab since.
Her current treatment includes inhaled salbutamol, vitamins A,D, E and K, creon capsules with food, hypertonic saline nebulisers, nebulised DNase.
On examination she is afebrile and of slim build. There are no signs of respiratory distress, and her chest is clear with a mildly wet huff (a crepitation heard at the end of a short, sharp expiration). ENT examination shows mildly inflamed nasal turbinates and an erythematous throat, but no visible pus. Abdominal examination is unremarkable. The GP suspects a viral infective exacerbation, but does not feel referral to hospital is warranted at this stage.
CF is an autosomal recessive condition with a carrier frequency of approximately one in 2500, affecting around 9000 people in the UK. It is caused by an autosomal recessive defect in the cystic fibrosis transmembrane regulator gene, resulting in reduced clearance of lung secretions, progressive infection, inflammation, and declining lung function. The defective gene also causes development of viscous secretions in the pancreas, causing obstructive damage to its exocrine function and malabsorption, requiring enzyme replacement (Creon) in around 85% cases.
The microbiology of CF is complex and challenging. Staphylococcus aureus can be cultured early in infancy and continual anti-staphylococcal antibiotic prophylaxis is recommended for all children under the age of three years. With increasing age, Pseudomonas aeruginosa becomes the most common pathogen, and can often be cleared with early, aggressive antibiotic therapy, but may be isolated sporadically following eradication. Preventing pseudomonas infection from becoming chronic can have a positive effect on long-term survival. With increasing age, other gram negative organisms such as Burkholderia cepacia can chronically infect the lung – usually later in disease progression – and is associated with a high mortality rate.
In most cases, CF will be diagnosed antenatally or by newborn screening. Following positive identification, diagnosis is confirmed by genetic mutation analysis and a positive sweat test. In a study completed in East Anglia over a 30-year period, a total of 730,730 babies were screened, resulting in 296 screen positive cases of CF and 29 false negatives – including 10 false negatives with meconium ileus. In the study, 10 missed CF cases were pancreatic insufficient, but all were diagnosed before their first birthday, highlighting that some children will be missed by newborn screening. Screening for CF does however detect 95% of unsuspected CF cases presenting before three years of age.
· Children missed by screening may be diagnosed by symptoms (faltering growth, persistent respiratory or gastrointestinal symptoms) and require a sweat test and genetic analysis. Education of the child and parents should be provided by the CF multidisciplinary team within seven days.
With all colds, accompanied by a cough or other lower respiratory symptoms, an oral antibiotic that will cover infection from Staphylococcus aureus and Haemophilus influenza should be started, for example co-amoxiclav. Children are not often able to expectorate sputum, therefore a throat swab and cough swab should be sent to the local microbiology department and the results followed up, and copied to the child’s CF team. The method of obtaining a cough swab is similar to that of a throat swab, but no direct contact is made with the oropharynx – the child coughs onto the swab placed at the back of the oropharyngeal cavity. It is often possible to email the CF specialist nurse to inform them that a result is pending, and antibiotic therapy should be altered as necessary. Alternatively, for those children who are already on anti-staphylococcal antibiotics, it is suggested the dose of their prophylaxis is doubled.
While awaiting microbiology results, duration of antibiotics is 14 days in order to cover the possibility of secondary bacterial infection while the child is recovering from the viral illness. Following completion of antibiotics, repeat swabs should be sent to check growth of the organism has cleared. Persistence of symptoms or growth of an organism may mean IV antibiotics are necessary.
In this case, the child has had one isolate of pseudomonas, which has been successfully eradicated, rather than being chronically infected. However, research has found that particularly with respiratory syncytial virus (RSV), the virus can act as a coupling agent between respiratory epithelial cells and pseudomonas species, potentially increasing the likelihood of a pseudomonal infection during a viral exacerbation. In this case, we would suggest co-amoxiclav is started while awaiting microbiology results.
For children with CF and chronic pseudomonal colonisation, we would advise against prescribing antibiotics without first discussing with the CF team. While awaiting microbiology sample results, the usual procedure for a clinically well child with chronic pseudomonal carriage and suspected infected exacerbation would be a two-week course of ciprofloxacin. Occasionally this would be the suggested course of action for primary care, but often the CF team can see the child urgently to assess whether IV therapy is required.
In addition to antibiotics, it should be emphasised to parents to perform twice-daily physiotherapy to aid clearance of secretions.
We would urge primary care physicians to ensure these children and their families are protected with seasonal influenza vaccine, and may also suggest additional booster vaccines – such as Haemophilus influenza B – if antibody responses have found to be suboptimal.
Complications of cystic fibrosis
Sub-distal intestinal obstructive syndrome (DIOS)
DIOS is a common complication in CF, with a paediatric lifetime prevalence of approximately 8%, mostly affecting those with pancreatic insufficiency. Viscid muco-faeculent material accumulates in the terminal ileum or caecum, leading to partial obstruction with pain usually in the right lower quadrant, abdominal fullness and a palpable mass in the right iliac fossa. Children often report having their bowels open as usual, or sometimes diarrhoea from overflow. In this case, there was mild abdominal discomfort that was not interfering with daily activity and constipation, with bowels opening every two to three days. Constipation is considered to be part of the DIOS spectrum, and tends to be limited to the rectum, rather than resulting in palpable abdominal mass. In this case, the girl would benefit from daily or as needed Movicol, as per doses recommended in NICE guidelines.
Occasionally, abdominal pain can be associated with inadequate doses of enzyme replacement, although this is more likely to be associated with diarrhoea than with constipation. Advice regarding changing doses of enzyme replacement therapy can be discussed with the CF dietician as part of the CF team.
Sub CF-related diabetes
Cystic fibrosis related diabetes (CFRD) is a distinct clinical entity separate to type 1 and 2 diabetes. It is thought to be secondary to progressive pancreatic fibrosis causing reduced insulin production and insulin resistance secondary to chronic infection, rather than autoimmune in origin. As survival of children with CF increases, the number of children with CFRD has also increased. Studies have shown a progressive decline in pulmonary function up to four years before a diagnosis of CFRD, so early identification is vital, although it can be difficult as onset is asymptomatic. In addition, because of the role of insulin as an anabolic hormone, reduced insulin production can cause an increased catabolic state and static weight or weight loss.
Currently children in the UK are screened for CFRD from the age of 12 years, although many centres screen from 10 years of age onwards, using the oral glucose tolerance test. CFRD is diagnosed if plasma glucose is >11.1mmol/l 120 minutes after the glucose load. Diagnosis may also be confirmed with continuous glucose monitoring if the blood sugar is >7.8mmol/l. A positive diagnosis of CFRD is managed with low dose long-acting subcutaneous insulin (starting dose 0.5 units per kilogram), which can place additional burden on families already on multiple medications. It is vital that primary care provide supplies of insulin, pen needles, lancets and glucometer strips.
Children with CFRD are managed jointly between the CF team and paediatric endocrinology. These children do not present with diabetic ketoacidosis but their blood sugars maybe raised if they are unwell with intercurrent infection.
Poor nutrition in CF results from a combination of increased stool losses, anorexia and poor dietary intake and the increased energy demands of the disease. In addition, energy requirements increase during infective exacerbations but the appetite reduces, so weight gain can be slow with episodes of weight loss with concurrent infection. Usually a high calorie and high protein diet will be adequate for CF children.
However, in those with chronic infections, an improvement in weight will result in an improvement in pulmonary function. The definition of growth failure is a child under five years with <85% weight for height ratio (weight equivalent to current height centile) and a weight loss over two clinic visits (four months). For those over the age of five this is extended to six months. These children may require high energy overnight nasogastric feeds or in extreme circumstances need to be referred for gastrostomy.
Paediatric CF specialist nurses and the CF team are an extremely valuable point of contact for primary care in children with CF who have many complex medical and psychological needs, and are always happy to be approached if there are questions from primary care practitioners.
Dr Donna McShane is a paediatric cystic fibrosis consultant, and Dr Louise Selby a paediatric registrar, both based at Addenbrooke’s Hospital, Cambridge.
1. Cystic Fibrosis Trust. Standards for the clinical care of children and adults with cystic fibrosis in the UK. Second edition. Bromley; CF Trust: 2011.
2. National Institute for Health and Care Excellence. Constipation in children and young people: Diagnosis and management of idiopathic childhood constipation in primary and secondary care. London; NICE: 2010
3. Calvin J, Hogg S, McShane D et al. Thirty years of screening for cystic fibrosis in East Anglia. Arch Dis Child 2012; 97: 1043-1047.
4. Van Ewick B, Wolfs T, Aerts P et al. RSV mediates Pseudomonas aeruginosa binding to cystic fibrosis and normal epithelial cells. Pediatric respiratory 2007; 61(4): 398-403.
5. DIOS and Constipation, Royal Brompton and Harefield NHS Foundation Trust
6. The UK Cystic Fibrosis Trust Diabetes Working Group. Management of cystic fibrosis related diabetes mellitus 2004.
7. Cystic Fibrosis Trust. Nutritional management of cystic fibrosis. April 2002.
Cystic Fibrosis Trust. Antibiotic treatment for cystic fibrosis. Third edition. Bromley; CF Trust: 2009Cystic Fibrosis Trust. Laboratory standards for processing microbiological samples from people with cystic fibrosis. First edition. Bromley; CF Trust: 201