Diagnosis
In the absence of a neonatal screening programme, most children with CF will present in the first two years of life, usually with one of the following problems• Prolonged neonatal jaundice
• Meconium ileus at birth
• Failure to thrive
• Loose abnormal stools
• Recurrent or persistent chesty cough
Less common presentations include
• Rectal prolapse
• Heat stroke
• Hyponatraemic hypochloraemic metabolic alkalosis (pseudo-barterr syndrome)
• Bulging fontanelle (vitamin A deficiency)
10% of patients with CF have mutations which result in some residual CFTR function, and consequently they have a milder phenotype. These patients may present later in childhood or in adult life with less obvious symptoms and signs. These include
• Nasal polyps
• Abnormal bowel habit
• Persistent productive cough
• Recurrent pancreatitis
• Male infertility
Newborn screening
Newborn screening was established in Wales in 1997, and universally established across the UK in 2007. There is good evidence that newborn screening improves outcomes in children with CF, particularly in terms of growth and nutrition.
Screening detects most infants with CF using a combination of IRT and gene mutation testing. The screening programme in Wales differs from the programme adopted later in England. In Wales, all children with one identified mutation are screened with a sweat test. In England, children with one mutation and a low IRT at 21-28 days are not screened with a sweat test and are given a screen negative label. As a consequence, in Wales, more children with 2 mild mutations will be detected, and children who are CF carriers will be positively identified.
Downloads
• CF screening in Wales: A comprehensive guideline
• The screening programme algorithms for Wales and for England.
Department of Health leaflets for parents:
• The screening programme
• Advice for carriers
• Advice for those suspected of having CF
Management of newly diagnosed patients
Newly diagnosed patients will be introduced to physiotherapy and the need for a high calorie diet. A faecal elastase will identify whether they are pancreatic insufficient, in which case they will need treatment with pancreatic enzyme replacement. They will also need to start Flucloxacillin prophylaxis and fat soluble vitamin supplements (usually Dalavit and Vitamin E syrup).
The family will have many questions over the next few weeks and and direct access to the CF nurses should be established. The family are likely to use the internet to gather information, and they should be encouraged to use the CF Trust website as a reliable source of information.
A discharge plan should be made with follow up within the next 2 weeks. The GP should be informed and sent a discharge summary (written by the Respiratory SpR) and an information letter about usual CF management. This can be found here
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Meconium ileus
15-20% of children with CF present with neonatal intestinal obstruction due to inspissated meconium. This is associated with echogenic bowel on antenatal ultrasound. Sometimes there is evidence of intrauterine bowel perforation and meconium peritonitis.
Meconium ileus requires urgent treatment. In most children the diagnosis is made with a contrast enema which will demonstrate a microcolon and meconium inspissation in the ascending colon and terminal ileum. In many infants the obstruction can be relieved with a gastrograffin enema. In other infants surgery is required – In theatre, the obstruction may be alleviated by simple forward flushing out of the meconium via an enterostomy, or may require bowel resection which is usually combined with a Bishop-Koop ileostomy – this is a single lumen stoma, with the distal loop anastomosed to lateral wall of the proximal loop. The idea behind this configuration is that trophic volumes of bowel content will enter the distal lumen. The distal limb of the ileostomy may need to be flushed to ensure it is clear. One approach is to use diluted acetylcysteine 20% solution (30ml of made up to 100ml with normal saline; 30-50ml daily for 3 days). If an ileostomy is formed, it can usually be reversed at around 3 months of age.
Post enema or Post op management
There are other causes for neonatal microcolon and bowel obstruction at birth. The diagnosis of CF needs to be made, and this can be difficult from a practical perspective as sweat is difficult to obtain in young babies. A blood sample should be sent to clinical genetics for CF mutation screening. IRT can be useful but only if it is taken before surgery for meconium ileus.
Post-op or post enema the baby will initially be on IV fluids and will start establishing milk feeds. If CF has been confirmed or is suspected, pancreatic enzyme supplements will need to be given with milk. While the baby is on small amounts of milk, they should be given ½ scoop of Creon micro (contains 5000iu per scoop) approximately every 4 hours. If they are fed via a nasogastric tube, Pancrex sachets can be used as Creon granules will not fit down the tube. Once babies are on half milk feeds they should be given ½ a scoop of Creon micro per feed. This should be given with water, milk or fruit puree. A 3kg baby on 3-4 hourly feeds will require approximately half a scoop of Creon micro with each feed (total approximately 30-40,000 iu/day).
While on the neonatal unit, attention should be given to the chest. The family need to be introduced to chest physiotherapy which needs to start on the neonatal unit. > A cough swab should be taken and if there are any chest symptoms, the child should be started on IV antibiotics. When the child is on half milk feeds, flucloxacillin (125mg bd) and fat soluble vitamins should be started (Dalavit 0.6mls, vitamin E 0.5mls). These babies will need their neonatal vitamin K as an IM injection rather than oral vitamin K
A discharge plan needs to be made with the CF nurse specialist. This should include a discharge summary (written by the Respiratory SpR) which should be sent to the GP and the referring hospital on the day of discharge. The GP and referring paediatrician need to be aware of the discharge and any management plans, and follow-up arrangements. An information letter about CF also needs to go to the GP. This can be found here
Chest exacerbation
Children with CF may have low grade persistent pulmonary inflammation. Usually as a consequence of intercurrent viral infection, bacteria in airway secretions may increase in number and their lung disease gets worse. This usually presents with increased cough, increased sputum production, change in sputum colour, decreased appetite, decreased exercise tolerance and a drop lung function. There may be weight loss if there has been a period of prolonged symptoms. There is rarely an associated fever and examination of the chest may be unchanged. There is no international consensus as to what constitutes a chest exacerbation.
Outpatient management
If the cough is of short duration and the child is otherwise well, the exacerbation can be managed at home with oral antibiotics and increased attention to secretion clearance with increased physiotherapy . A cough swab should always be taken. These are obtained by encouraging the child to cough (by using physio or sometimes by rubbing the swab on the back of the throat and then doing a pharyngeal swab). This can be done in clinic, or can be arranged by the CF nurses either at home or through attending hospital.
Oral antibiotics should be given in the first instance for 2 weeks. Routine choices include co-amoxiclav or azithromycin. High dose flucloxacillin or co-trimoxazole are alternatives. In older children, Doxycycline is often useful. The choice of oral antibiotic will depend on what has grown on previous cough swabs so always check on Clinical Portal. If the child is known to isolate Pseudomonas aeruginosa, then they will be on nebulised Colistin and the exacerbation should be treated with 3 weeks of oral Ciprofloxacin. The CF nurses will usually chase the cough swab result. If there is a positive growth, antibiotic cover may need to be changed accordingly.
Increasing secretion clearance is essential during a chest exacerbation, and physiotherapy should be done at least twice a day. Some of our children are on adjuncts to physiotherapy including DNAse and hypertonic saline. Often we increase the frequency of these treatments when the child has increased symptoms. Be guided by the physiotherapists.
All antibiotic courses should be given for a minimum of 2 weeks, but can be extended to cover the child for a week after the cough has resolved. If the cough is getting worse after one week, or has failed to resolve after 2 weeks treatment, the patient needs to be reviewed in clinic. If they remain constitutionally well, still have increased symptoms but are slowly improving, a second 2 week course of a different oral antibiotic may be given. Make sure you let the CF nurses know you have started treatment so that they can follow up appropriately.
Inpatient management
If a chest exacerbation has failed to respond to 4 weeks oral antibiotics, or there is a general deterioration often including weight loss, the child may need a course of IV antibiotics.
At the Children’s Hospital for Wales, we manage all children who need intravenous antibiotics as inpatients, so that particular attention can be given to physiotherapy and nutrition. Home intravenous antibiotics are an option in some of the shared care clinics in the region, but we recommend at least one week inpatient care so that nutrition and physiotherapy can be optimised.
Children will need reliable intravenous access for 2 weeks. This can be achieved using either an indwelling access device such as a portcath or a temporary long line. It is the registrar’s responsibility to site the long line which can usually be done under sedation on the ward. Sometimes, children will need a bronchoscopy before commencing IV antibiotics, in which case, the registrar should prepare to site the line in theatre under general anaesthetic. Consent will need to include the long line procedure.
There is an admission sheet for children with CF admitted with a chest exacerbation. This is a place to document investigations. On the back, there is guidance on inpatient management protocols including the use of aminoglycosides. It is not a proforma and patients will need to be formally clerked in by junior staff. Admission bloods are FBC, UE creatinine, LFT, CRP, IgE, HbA1C. Unless there is a specific indication (focal signs, new oxygen requirement, pyrexia) a chest x-ray would not normally be done.
All children will have a cough swab. Cough swabs all need to be labelled as “CF patient” and need to be sent for MCS, AFB, fungal cultures. A viral upper airway sample also needs to be taken. In addition many children will have an induced sputum procedure before IV antibiotics commence either on clinical grounds or as part of the CF-SpIT trial. Please discuss with Consultant or physiotherapist.
During the admission, all children should have twice weekly weight and spirometry (age >6 years) checked on Mondays and Thursdays before the ward round. They will need twice weekly tobramycin levels on day 2, and on Tuesdays and Fridays thereafter for the duration of the admission. Children over the age of 10 years should have 24 hour spot glucose monitoring and a single overnight oxygen saturation trace at the beginning of the admission.
Other routine investigations unrelated to the chest exacerbation may also be requested such as annual review bloods, abdominal ultrasound, Dexa scan.
All investigations and results need to be documented on the admission sheet which will be reviewed on each consultant ward round.
The choice of IV antibiotics depends on which organisms have been isolated in the past, so please ask the consultant on service. Most children are treated with ceftazidime and tobramycin. There is guidance for tobramycin on the back of the admission sheet – in particular it is important to check that the child has not previously had a high tobramycin level as this will influence what dose you give. Make sure you check the child’s electrolytes before starting tobramycin.
Daily ward rounds should be used to encourage patients to be as active as possible, which may involve leaving the hospital between physiotherapy sessions and IV treatments.
Specific Infections
MSSA – Methicillin Sensitive Staph aureus
• Staph aureus is an important organism in Cystic Fibrosis and is often identified early in life. Prophylactic flucloxacillin should be given twice daily to all children with cystic fibrosis for at least the first 2 years of life. Antibiotics are always prescribed for isolates of Staph aureus.
• Flucloxacillin is the oral antibiotic of choice for children not on prophylactic flucloxacillin. For children already on prophylactic flucloxacillin, treatment of isolates should be managed with high dose oral flucloxacillin (QDS) together with a second oral antibiotic (fusidic acid, rifampicin, azithromycin, clindamycin, co-trimoxazole, doxycycline in children > 12 years)
• If infection is not eradicated on repeat culture 2 weeks later, add in a second agent if on monotherapy and continue for a further 4 weeks. If after 6 weeks treatment the infection has not cleared, consider IV antibiotics. If at any point the child becomes unwell treat with IV antibiotics. In a child less than one year of age, consider earlier treatment with IV antibiotics even if they are asymptomatic.
MRSA – Methicillin Resistant Staph aureus
• MRSA is no more virulent than MSSA but is harder to eradicate. There is some evidence that children who isolate MRSA from airway secretions do less well overall than children who are MRSA-free. This may apply even if MRSA has been eradicated successfully.
• Local guidelines on how to eradicate MRSA will vary. The CF Trust guidelines on MRSA are available here.
The following eradication protocol from the Northern Ireland Paediatric CF Centre demonstrated 90% success rate in eradication and is what we recommend here in Cardiff.
Step 1:
• Discontinue prophylactic flucloxacillin
• Collect swabs from nose, axilla, and groin
• Hygiene advice – change bed linen at start of treatment, use own towel, face cloth and tootbrush and replace all nebulization components
• Topical mucopirocin 2% to anterior nares twice daily for five days
• Chlorhexidine for baths and hairwashing
• Sodium fusidate 50 mg/kg/day for five days
• Rifampicin 20–40 mg/kg/day for five days
Respiratory samples and multi-site swabs are repeated for detection of MRSA on completion of treatment step 1. If MRSA persists then proceed to step 2
Step 2:
• Repeat Step 1 for a further five days
Respiratory samples and multi-site swabs are repeated for detection of MRSA on completion of treatment step 2. If MRSA persists then proceed to step 3
Step 3:
• Intravenous teicoplanin 10–15 mg/kg/daily 12h x three doses; then Intravenous teicoplanin 10–15 mg/kg/daily once daily for nine to 13 days
Respiratory samples and multi-site swabs are repeated for detection of MRSA on completion of treatment step 3 and again at each clinic visit for up to one year after last isolation of MRSA.
If eradication fails, the presence of MRSA in future on cough swabs or sputum cultures should be managed as follows:
• When the child is well, 2 week courses of Rifampicin and Fusidic acid should be used. Alternatives include Trimethoprim, or Tetracycline or Doxycycline in older children. 2 agents should always be used to reduce the risk of resistance developing.
• If a child with respiratory symptoms and MRSA on cough swab does not respond to oral antibiotics, they should be treated with iv teicoplanin or vancomycin.
• Vancomycin can also be nebulised at a dose of 3mg/kg made up to 4 ml in normal saline, given 3 times per day – this should only be used for a 2 week course. Prolonged use can result in vancomycin resistance (VRSA).
Screening for MRSA
• Children awaiting elective surgery (gastrostomy or a portacath) should have surface swabs to check their MRSA status. If they are MRSA positive, they should undergo the eradication protocol prior to the procedure.
• Any patient on the lung transplant list should have 2 monthly surface swabs for MRSA as well as cough swabs. The transplant team should be informed if they are MRSA positive and their advice should be sought regarding eradication protocols.
Pseudomonas aeruginosa
• Chronic infection with Pseudomonas infection is associated with declining lung function in children with CF.
• Pseudomonas has a non-mucoid form and a mucoid form. Mucoid transformation, in which an alginate biofilm forms around the bacterial colony, protects bacteria from antibacterial agents and the host immune response. This occurs with chronic infection and is thought to make eradication of Pseudomonas aeruginosa impossible.
• Early infection is usually intermittent and non-mucoid in phenotype, and every effort at this stage should be made to eradicate it. Aggressive repeated eradication treatments though childhood can delay chronic pseudomonas infection until the late teens or early adult life.
• There are several definitions for Chronic Pseudomonas infection. Chronic infection is likely if there are repeated positives isolates of mucoid phenotype Pseudomonas on microbiological testing. Specific definitions include >3 positive isolates/year or if greater than 50% of samples are positive/year (Leed’s criteria). The importance of detecting and treating new isolations of Pseudomonas is one of the major reasons for carrying out frequent airway cultures.
• 80% of isolates can be successfully eradicated using 3 weeks of oral ciprofloxacin in combination with 3 weeks of nebulised Colistin. The time to repeat isolation can be increased by treating with 3 months of ciprofloxacin together with 3 months of nebulised Colistin (time to relapse 18 months versus 9 months). We treat isolates with 3 months of ciprofloxacin together with 6 months of Colistin.
• If positive cultures persist on or off treatment, options include trying to eradicate with a one month course of TOBI or with a 2 week course of IV antibiotics. If eradication is unsuccessful, maintenance treatment should continue indefinitely with nebulised Colistin. Exacerbations thereafter should be treated with 2 weeks of ciprofloxacin in the first instance.
• Long term treatment with nebulised Colistin can be reduced from twice to once daily if patients remain well and have no positive isolates on cough swab. Exacerbations in these patients should be managed with 2 weeks of ciprofloxacin and double up of nebulised Colistin to twice daily.
• Children with chronic pseudomonas infection and symptomatic exacerbations may benefit from alternate month Colistin / Tobramycin nebulisers as background therapy.
Burkholderia cepacia complex
• Burkholderia cepacia complex (BCC) is a group of closely related bacterial species or genomovars that can cause respiratory infection in patients with CF. BCC infection can be associated with a rapid deterioration in lung function.
• BCC organisms are environmental organisms found particularly in soil and freshwater sediment.
• Most clinical problems are associated with B. cenocepacia (genomovar III). Some forms of BCC are transmissable between patients, particularly the ET12(III) epidemic strain of B. cenocepacia.
• Nearly all BCC strains show multiresistance to antibacterials.
• BCC can cause cepacia syndrome, a fulminate infection characterised by progressive radiological and clinical deterioration associated with necrotic pneumonia, pyrexia, sepsis and almost universal death. Cepacia syndrome is most frequently associated with B cenocepacia, but has been described with B. Multivorans (genomovar II) and B.cepacia (genomovar I).
• Some patients with chronic BCC remain very stable for many years. In some patients infection is transient.
• Accurate identification of BCC species is very important and can be time consuming. Samples usually need to be sent to the reference laboratory. ALWAYS take note of a gram negative rod on microbiology samples – this will need chasing up for further clarification.
• Treatment is difficult and should be guided as best as possible by sensitivity patterns. IV tobramycin, meropenem and ceftazidime may be a good first line therapy. IV tobramycin, temocillin and septrin with nebulised meropenem in older children may also be a good combination. Chloramphenicol is also effective against BCC. Prednisolone treatment in addition to antibacterials has been described in the management of cepacia syndrome.
• Maintenance therapy should include nebulised meropenem and TOBI on alternating months, and meropenem nebulisers should be introduced during the initial IV treatment course.
• Strict infection control is mandatory. Patients with BCC are admitted to South ward for inpatient stays, and are seen on the third Tuesday morning of the month for outpatient appointments.
• Children will need to be free from B cepacia on at least 3 consecutive microbiology samples for at least 12 months, and should have an induced sputum and bronchoscopy to establish that they are truly infection free before they can be reintroduced into general CF clinics.
Non-tuberculous mycobacterial infection
• NTM is a low virulence environmental organism and a potential respiratory pathogen for patients with CF.
• The prevalence in patients with CF is 13%. In pre-adolescent children the prevalence is 3-5%.
• All annaul assessment airway cultures taken from patients with CF are routinely sent for AFB and NTM culture.
• Single isolates of NTM in patients with mild disease may not represent active infection and do not necessarily require treatment. These isolates may represent colonisation or contamination. Repeated positive cultures should probably be treated, especially if associated with new chest symptoms, x-ray changes or loss of lung function.
• The ATS guidelines suggest evaluation of patients suspected of having NTM with CT scan and repeated airway cultures. We investigate single NTM isolates with elective induced sputum and bronchoscopy. Children with repeated isolates will need a CT scan.
• Infection is usually caused by M. avium complex or M. abscessus. A single isolate of M. abscessus must be taken seriously. Fast growing organisms include M. abscessus, M. cheloniae, M. fortuitum. Slow growing organisms include M. avium complex, M. xenopi, M. malmoesse and M. kasasii.
• M. Abscessus. Treatment for M. abscessus can be divided into intensive therapy and continuation therapy. Often treatment courses are long and punctuated with admissions for intensive therapy during exacerbations. Standard Intensive therapy at UHW is given for a minimum of 3 weeks and includes IV Amikacin, cefoxitin, Imipenem, and oral clarythromycin. Tigecycline and Septrin may also be used particularly if there are drug intolerances. Antiemetic therapy needs to be optimised. Continuation therapy at home should continue for at least 18 months and will usually involve nebulised Amikacin, Ciprofloxacin (age<12 years) or Moxifloxacin (age>12 years), clarithromycin, septrin (age<12 years) or minocycline (age>12 years). Nebulised Meropenem may also be used.
• M. avium complex. Treatment for MAC is with ethambutol, rifampicin and clarythromycin for a minimum of 18 months.
• Infection with NTM, particularly M abscessus, can adversely affect outcome of lung transplantation. Vigorous efforts should be made to treat and eradicate this infection if transplantation is being considered. Untreated infection with M. abscessus is a contra-indication to transplantation in most units.
• M. Abscessus is transmissible between patients and strict infection control is mandatory. Patients with BCC are admitted to South ward for inpatient stays, and are seen on the third Tuesday morning of the month for outpatient appointments. Children will need to be free from M. abscessus on at least four consecutive microbiology samples for at least 12 months, and should have an induced sputum and bronchoscopy to establish that they are truly infection free before they can be reintroduced into general CF clinics.
• See Generic ATS guidelines for the management of NTM. ECFS/CFF Guidelines for the management of NTM in patients with Cystic Fibrosis is under development. Also see CF guidance from the Brompton protocol.
Stenotrophomonas maltophilia
• S. maltophilia is a gram negative rod, which is increasingly being isolated from airway secretions in patients with CF, both in UK and US patient series. It is commonly transient and may not always be pathogenic. Its role as a pathogen has not been established and it has not been associated with a worse clinical outcome. It is however isolated in patients with lower lung function, and who experience more chest exacerbations. It may therefore be a marker of more pronounced lung disease.
• S. maltophilia should be treated and the antibiotic of choice is Co-trimoxazole. Other treatments will depend on sensitivity patterns and include minocycline or doxycycline (age >12 years), or chloramphenicaol (expensive). IV Co-trimoxazole should be included in the choice of IV antibiotics for children being treated for a chest exacerbation who have isolated stenotrophomonas in the last 12 months.
Achromobacter xylosoxidans, Ralstonia species, Pandoraea species
• The pathological significance of these Gram negative rods is unclear. Please discuss these findings with a consultant.
Allergic Bronchopulmonary Aspergillosis
• Aspergillus fumigatus is a fungus found in the secretions of up to 30% of children with CF. In most instances this does not constitute an invasive infection. 1-10% of children may develop a vigorous immune response to Aspergillus which can result in deterioration in lung function and progression of bronchiectasis.
• UK prevalence of ABPA in patients with CF in 2012 is 2%.
• ABPA is difficult to diagnose but should always be considered if there are:
• Onset of new symptoms, particularly wheeze
• New infiltrates on chest xray
• Increased cough and especially if there is production of brown sputum
• Unexplained drop in lung function
• The diagnosis is supported by
• Total IgE >500iu or a rapid increase in IgE
• Aspergillus specific IgE positive.
• Aspergillus Precipitins positive.
• Eosinophil count >0.5 *109/L
• Galactomannan positive (also positive in invasive disease where IgE is not necessarily raised)
• How many criteria are required for the diagnosis is unclear, but if the diagnosis is suspected, a trial of prednisolone should be given and the response assessed.
• If IgE is >1000iu, and specific IgE to aspergillus (previously RAST) and specific IgG (previously precipitin lines) are positive, then treatment should be considered even if the patient is asymptomatic
• Treatment is with prednisolone and itraconazole.
• Prednisolone should always be non-enteric coated in children with CF. Commence prednisolone at a dose of 1mg/kg/day (max 40mg) for 2 weeks. If there is a clinical response at 2 weeks, the dose can be reduced to 0.5mg/kg day for the next 6-8 weeks.
• Itraconazole should be started concomitantly with steroids at the beginning of treatment and continued for a three month course. (Dose 2.5mg/kg bd). Oral solution has better absorption than the capsule formulation and is preferred in children with CF. It should be given in the fasting state. Itraconazole requires an acid environment to be absorbed and should be given with orange juice or coke, especially if the patient is on ranitidine or omeprazole. Liver function tests need to be monitored while on treatment.
• Serum total IgE and CXR should be repeated at 6-8 weeks. A significant drop in total IgE suggests remission and prednisolone can be weaned further over the next 2-4 months.
• Children on systemic steroids should be warned about the increased risks of infection in particular chicken pox, and their varicella status should be checked before starting treatment.
• Any child on a daily dose of prednisolone exceeding 0.5mg/kg for more than 2 weeks should be assumed to have adrenal suppression and advised that additional steroid replacement may be necessary during illness. See medication.
• Children with severe or recurrent ABPA who have not responded to first line treatments may benefit from Voriconazole. Levels need to be checked regularly as they are often sub-therapeutic in children with CF. Nebulused amphoterecin, IV methylprednisolone and Omalizumab may be useful in difficult cases. Inhaled steroids have not been shown to be effective in treating ABPA or maintaining remission.
Haemoptysis
• Haemoptysis can occur in patients with CF as a consequence of mucosal inflammation and coughing or secondary to erosion of the bronchial arteries
• Mucosal injury from infection and coughing causes low level streaky haemoptysis and is not uncommon with respiratory exacerbations. It is not a cause for alarm and the exacerbation should be treated in the normal way.
• In moderate to severe lung disease, bronchial arteries may become tortuous and enlarged and may erode into the airways. This usually results in frank haemoptysis and is often accompanied by a sensation of bubbling in the chest so that the patient may be able to localise where the problem is coming from. The chest xray is likely to show new airspace infiltrates from accumulation of blood in the alveolar space. Frank haemoptysis may be massive and life threatening but most episodes resolve spontaneously. It occurs in 1 in 3000 children age <16years with CF per year.
Management of frank haemoptysis
• Admit to hospital.
• Site a secure IV cannula (2 if major haemoptysis) and cross-match 2 units of blood.
• Check clotting, FBC, and electrolytes.
• Give IV vitamin K.
• Start IV antibiotics for presumed chest exacerbation.
• Stop all NSAIDs
• DNAase can be continued. Limit physiotherapy to huffing manoeuvres. It is important that some physiotherapy is continued.
• If the bleeding persists or PT is deranged, FFP may be needed.
• Antifibrinolytic drugs such as tranexamic acid may be beneficial in preventing re-bleeding.
• In cases where bleeding is massive or prolonged, bronchial artery embolization should be considered. In practice all abnormal tortuous bronchial arteries are embolized. This is performed by interventional radiology colleagues here at UHW (contact is Dr Andrew Wood). The procedure can take several hours, and sometimes needs to be repeated on several occasions. There is a risk of spinal artery embolization. There is also a risk of massive bleeding during induction of anaesthesia. Bronchial artery embolization has a very high (> 90%) immediate success rate in stopping the bleeding. After bronchial artery embolization there may be pleural and oesophageal pain and dysphagia due to altered blood supply to these structures. Re-bleeding after bronchial artery embolization occurs in 40% of patients within 5 years.
• Very rarely, emergency lobectomy may be required.
Images taken before and after bronchial artery embolization
Pneumothorax
• Pneumothorax is serious and a potentially life-threatening complication of CF. It occurs in about 1% of older children with CF each year and is occurs more frequently in children with severe lung disease (FEV1 < 40%).
• Tension pneumothorax can occur without complete collapse of the lung because of the abnormal stiffness of the CF lung and although a CXR is usually sufficient to make the diagnosis, it is not definitive. Typical symptoms are sudden onset of chest pain and breathlessness but there may be less specific symptoms such as unexplained loss of lung function. There needs to be a low index of suspicion and If there is any doubt, a chest CT scan may be needed to make the diagnosis
• Recurrence is common (about 50%) on both the ipsilateral and contralateral sides.
• Pneumothorax is associated with an increased 2 year mortality at all levels of lung function. Inability to remove the drain by 5 days carries a poorer prognosis.
Management
• All children with CF who have a pneumothorax should be admitted to hospital, even if they are asymptomatic and the pneumothorax is small
• 10–30% of small pneumothoraces (< 20% of hemithorax) will resolve spontaneously.
• For larger or symptomatic pneumothoraces, a chest drain should be placed and suction applied. A 10–14F pigtail drain is usually adequate. It is essential that the lung fully re-inflates after placing the drain, so that the visceral and parietal pleura come into contact. Without this situation, the leak is less likely to heal spontaneously. Siting a second drain should be considered (often most successful if directed towards the apex of the lung from the second intercostal space in the midclavicular line).
• IV antibiotics should be started as sputum clearance will be less effective. Physiotherapy manoeuvres will need to be modified. PEP physiotherapy should be avoided. Nebuliser treatments will need to be reviewed.
• If the pneumothorax fails to resolve after 3 days, thoroscopic surgery, with partial pleurectomy or pleural abrasion should be considered. Chemical pleurodesis should be reserved for children who cannot tolerate or who refuse surgery.
• Pleurodesis does not significantly alter outcome after lung transplantation, although it does make the surgery more difficult. Previous pleurodesis is not a contraindication to lung transplantation.
Distal Intestinal Obstruction Syndrome
• DIOS affects approximately 10% of patients with CF. It presents with abdominal pain and a tender mass in the right iliac fossa. It can be acute or chronic, presenting with partial or complete bowel obstruction. Appendix mass and intussusception need to be considered in the differential diagnosis.
• DIOS is thought to be due to slow transit time and persistent steathorroea and is therefore more common in children who are non-compliant with pancreatic enzyme replacement.
• Children who have had a previous laparotomy may have adhesions contributing to the obstruction and may be refractory to conservative treatments.
• Incomplete obstruction may be managed as an outpatient. For mild symptoms lactulose 10-20mls BD or movicol 1-2 sachets/day may be sufficient. Children with a persistent or recurring right iliac fossa mass should be on long term movicol at a dose that keeps the stool soft.
• Children who present with pain or vomiting should be admitted to hospital for management. These patients should be discussed with the consultant on-service at the Children’s Hospital for Wales. If there is complete bowel obstruction with abdominal distension, bilious vomiting and distended loops of bowel on AXR, an urgent surgical opinion should be sought. Arrangements should be made for these children to be transferred to the Children’s Hospital for Wales.
• Children who are not vomiting can be managed with oral movicol 2 sachets 2-3 times / day or NG macrogols such as Klean Prep. Oral gastrograffin should be used if little progress is made. All oral treatments will need to stop if there are signs of complete obstruction.
• Children who have complete bowel obstruction, fluid levels on AXR or who are vomiting should not have oral treatments and gastrograffin administered by enema should be considered. These patients will need to be managed with active involvement from the paediatric surgeons and other causes should always be considered.
• Gastrograffin can cause fluid shifts and electrolyte disturbances so IV access should be established and electrolytes checked. We do not generally administer gastrograffin to patients in the outpatient setting.
• Ensure that pancreatic enzyme supplements are reviewed and optimised.
• Children with CF may also get conventional constipation with faecal impaction in the rectum with distended proximal loops of bowel.
Dose: Oral/NG gastrograffin
age<8 years 50ml in 200mls juice
age>8 years 100ml in 400mls juice
Encourage oral fluids. Can be repeated every 12 hours
Rectal prolapse
• Rectal prolapse is usually a problem that affects younger children with CF. It can be the presenting feature of CF and is an indication to perform a sweat test.
• There is usually a history of a red swelling at the bottom which is visible only during or after defecation. Occasionally the parent may need to push back the prolapse manually.
• The cause may be related to the passage of frequent bulky stools.
• It can usually be treated conservatively by ensuring adequate pancreatic enzyme supplementation and starting low dose laxative to prevent the child straining at stool.
• If rectal prolapse does not respond to conservative treatments than it should be investigated further to exclude other problems such as rectal polyps or mucosal inflammation. If necessary, rectal prolapse can be treated surgically with injection sclerotherapy.
• Ensure that pancreatic enzyme supplements are reviewed and optimised.
CF-related Diabetes
• CFRD is a distinct type of diabetes with features of both Type 1 and Type 2 diabetes. Progressive fibrosis and fatty infiltration of the exocrine pancreas lead to progressive disruption and destruction of islet architecture leading to loss of both insulin and glucagon secreting cells. Glucose levels can therefore be quite unpredictable as both insulin and glucagon responses may be affected. The onset is often insidious and should be suspected with unexplained weight loss or drop in lung function.
• 4% of patients < 16years and 30% of patients >16 years have CFRD. Prevalence increases with age by 5% per year from age 10.
• The diagnosis can be made using oral glucose tolerance test (OGTT) and by using continuous glucose monitoring profiles (CGMP).
• Fasting and random glucose levels and glycosylated haemoglobin (HbA1c) measurements have poor sensitivity and specificity.
• All children have an HbA1c and random serum glucose at annual review.
• Children over age 12 years also have a glucose tolerance test.
Glucose tolerance test
• 1.75g/kg glucose (maximum 75g) is taken orally. Blood glucose is measured 2 hours later.
Less than 7.8mmol/l – Normal GTT:
Monitor with annual GTT
7.8mmol/l to 11mmol/l – Glucose intolerance:
Assess clinically. Organise 6 day continuous glucose monitoring profile (CGMP). These are available in all outreach centres. The CF consultant will discuss the case with the paediatric endocrinologists and may treat if clinical parameters suggest glycaemic control needs correction. Continue to monitor with annual GTT.
Greater than 11.1mmol/l – CFRD:
Organise 6 day continuous glucose monitoring profile (CGMP). These are available in all outreach centres. Ask the family to keep a food and activity diary. The case will be discussed by the CF consultant and seen by the paediatric endocrine team for assessment and introduction of insulin therapy if necessary. The diet in patients with CFRD needs careful attention from a dietitian experienced in this condition.
The endocrine team
• Patients with CFRD and CF related glucose intolerance are seen by the endocrine team at their CF Annual assessment in Cardiff, in the first slot of the afternoon diabetic clinic. The CF consultant will also attend this appointment.
• Children with CFRD should have annual monitoring for retinal disease, blood pressure, microalbuminuria, and renal function, and these will be organised through the diabetic clinic
• The endocrine team will organise outreach diabetic follow up directly through their own shared care network as appropriate. Every patient has different needs.
• For those patients who have shared care at a hospital not covered by the Cardiff endocrine team (Nevill Hall, Royal Gwent, Hereford), the CF consultant covering that hospital will liaise directly with local diabetic services to ensure tertiary cover locally.
Other points
• Glycaemic control is worse when patients are on steroids or during an infective exacerbation and results of screening undertaken under these circumstances may not reflect the patient’s usual glycaemic control. Conversely, patients with poor glycaemic control during an exacerbation may benefit from short term insulin therapy during the illness.
• Remember to exclude CFRD in children attending for surgery, or who are starting supplemental enteral feeds or steroid therapy.
CF related liver disease
• CF-related liver disease is a rare complication of CF. 10% of children age <16 years have liver disease. 1-2% have established cirrhosis with or without portal hypertension.
• Neonatal cholestasis and prolonged jaundice affects 2–5% of infants with CF and will resolve spontaneously. These infants should receive a parenteral dose of vitamin K to protect them against haemorrhagic disease of the Newborn .
• Liver function is monitored at annual review with liver function tests, PT and liver ultrasound (see section on annual review). Transient elevation of serum transaminases is common in children with CF (about 30% of children), and may occur with or without changes in liver texture on ultrasound or an enlarged liver clinically.
• Ursodeoxycholic acid is a bile salt that can improve bile flow. It may affect the natural history of CF liver disease, although this has not been demonstrated. We start it in children who have either 2 liver abnormalities (ultrasound, transaminases, PT or palpable liver) or one abnormality in 2 consecutive years. Ursodeoxycholic acid treatment does usually lower transaminase levels.
• Gall stones are found in around 5% of children with CF but the need for surgery is very rare (prevalence 0.1%). Asymptomatic gallstones should be treated with ursodeoxycholic acid.
• Regular oral vitamin K should be given to all children with established liver disease.
• Established liver disease may present with signs of portal hypertension (hypersplenism and thrombocytopenia, oesophageal varices and ascites) even if synthetic liver function is preserved.
• There is no evidence that screening endoscopy for identification and treatment of asymptomatic oesophageal varices affects risk of bleeding in children with CF-related liver disease. However, once an episode of bleeding has occurred, a programme of injections should be arranged at a specialist paediatric liver unit.
• Liver transplantation should be considered in children with hepatocellular failure or uncontrolled portal hypertension with recurrent variceal bleeding.
Emergency management of acute GI bleeding
• Haematemesis is most often due to bleeding oesophageal or gastric varices. Melaena follows but may be delayed for up to 24h.
• Maintain circulating volume, initially with crystalloid and then with packed red blood cell transfusion.
• Give vitamin K (2–5mg slow IV) and 10–20mL/kg fresh frozen plasma
• Give IV ranitidine to reduce any acid-related bleeding.
• Pass an NG tube. This can be used to assess ongoing bleeding.
• If conscious level is diminished, consider intubation to protect the airway.
• Vasopressin may help persistent bleeding. Discuss urgently with paediatric gastroenterology team and liver specialists.
• Most episodes will settle spontaneously. If bleeding persists, urgent endoscopy and variceal sclerosis or banding may be needed.
• The high protein content of the blood meal that results from variceal bleeding may precipitate an encephalopathy. The severity can be reduced by giving lactulose or macrogols to clear the bowel more rapidly and metronidazole to decrease the numbers of ammonia-producing colonic bacteria.
• Once varices have bled, a programme of endoscopic treatments should be arranged in consultation with the paediatric gastroenterology team and liver specialists.
CF related low BMD and osteoporosis
• The relationship between low bone mineral density (BMD) and fracture risk has not been established in CF. The term CF-related low bone mineral density should be used unless there have been fragility fractures, in which case the term osteoporosis should be used.
• Dual energy X-ray absorptiometry (DEXA) scans are used to measure bone mineral density. Interpretation of DEXA scan BMD values in children, adolescents and small adults is particularly complex because of the effect of bone size on the value obtained
• The term CF-related low BMD is applied to patients with a BMD z score of -2. 30% of adults have CF-related low BMD. Measurements of bone density in most children with CF are not different from those in normal controls, except in those treated with long-term oral steroids.
Risk factors for low bone mineral density are:
• low BMI
• poor respiratory health
• delayed puberty
• CF-related diabetes
• CF-related liver disease
• corticosteroid use
• low levels of physical activity (often a result of poor lung function)
• Good nutrition and adequate vitamin D supplementation throughout childhood is the best prevention. 40% of adult bone mass is accumulated during the pubertal growth spurt, and inadequate mass cannot be made up later. Regular exercise may also be protective and should be encouraged. Exercise capacity and BMI are strong predictors of bone mineral density.
Specialist dietetic supervision of appropriate and proactive interventions with oral calorie supplements is fundamental to care. Calcium intakes of 1300–1500 mg/day have been suggested in children with CF over eight years of age.
• Vitamin D levels should be measured at annual review together with calcium, phosphate, alkaline phosphatase and PTH. We aim for total 25-hydroxyvitamin D level in the upper part of the normal range (aim for 75–150nmol/L [30- 60μg/l]).
• Vitamin K also plays a role in bone metabolism. Although there are no long-term outcome data, we recommend vitamin K supplementation for all patients on chronic steroid therapy, CF-related liver disease, and delayed puberty. See section on vitamin supplementation.
• We carry out DEXA scans in all children with CF. If they have no additional risk factors for low BMD, they have a single DEXA scan at age 15 years. There should be a lower threshold for DEXA scans in children with CF-related liver disease, low vitamin D refractory to supplementation, delayed puberty or chronic corticosteroids therapy who will need a DEXA scan every three years from age 12 years. Special attention can then be directed towards these children to ensure adequate calcium intake, adequate vitamin D and K supplementation, and possibly a programme of weight-bearing physical activity.
• Bisphosphonate treatment is recommended in adults with CF who have had fragility fractures, or who have very low DEXA scores, or have medium low scores in patients who are starting a long course of oral corticosteroids, or who are awaiting transplant. The role of bisphosphonates is children is less clear, and in most centres is currently limited to those with fragility fractures.
Bone fractures
• Rib and crush vertebral fractures are particularly relevant in people with CF because they can cause a pneumothorax or prevent effective sputum clearance.
• Patients will need hospital admission for treatment. They will need a CXR to exclude pneumothorax as the cause of pain. Adequate analgesia is vital. Nonsteroidal agents may be adequate, but nerve blocks and opiate infusions may be necessary. Subcutaneous calcitonin has been reported to give rapid pain relief in some patients with rib fractures. IV antibiotics should be started to minimize the effects of any infective exacerbations and DNAase commenced if the patient is not already using it. Approaches to physiotherapy may need to be modified -, breathing and huffing techniques, PEP mask, vibrating jackets, or IPPB may all be useful.
Delayed puberty
• Puberty is often delayed in boys and girls with CF. The average delay is around 2 years and can occur despite good health and nutrition.
• Delayed puberty has important psychological consequences fro children with chronic disease.
• Bone density increases in puberty as a result of the action of sex steroids. Delayed puberty may adversely affect bone mineralization and may increase risk of fractures later in life.
• Children with delayed puberty should be on both vitamin D and vitamin K supplements.
• If there are no signs of the onset of puberty by age 13 years in girls or 14 years in boys, consider referral to paediatric endocrinology for treatment with sex steroids Ethinyloestra-diol is used for girls, and testosterone for boys).
Electrolyte disturbance
• Excessive sodium loss in sweat with secondary hyperaldosteronism can cause lethargy, listlessness and poor weight gain. This occurs most commonly in infants and also in hot weather. It usually presents in an indolent fashion. Urinary sodium will be low (usually <10mmol/l) and urinary potassium will be high. Symptoms generally respond well to sodium replacement.
• Rapid deterioration may occur in prolonged hot weather, or on holidays abroad, with dehydration and hypovolaemia and secondary hypokalaemic hypochloraemic metabolic alkalosis. This is called Pseudo-Barterr’s syndrome. Treatment of acute hypokalaemia is with IV fluids with both sodium and potassium supplements.
• Infants born with meconium ileus who have needed an ileostomy and who have high GI losses are at particular at risk of Pseudo-Barterr’s syndrome because of excessive GI losses of sodium. These children generally require sodium supplements until their ileostomy is reversed.
• Salt intake for exotic holidays and hot weather should be managed with increased salt intake in the diet, and this is usually adequate in children > 2 years old. In younger children and those with ileostomies, salt supplementation may be necessary. For short holidays, dioralyte drinks are the easiest way to supplement salt intake. For long term therapy, and in infant formal salt supplements may be necessary.
• 1 dioralyte sachet (200ml) contains 12 mmol sodium.
• 1 Slow sodium 600mg tablet contains 10 mmol sodium.
• Hypertonic saline solutions are available from hospital pharmacy for infants.
Polyps
• Nasal polyps occur in 10% of children with CF.
• Polyps cause nasal obstruction, persistent nasal discharge or postnasal drip with constant throat clearing. They can be bilateral.
• Nasal steroids are usually effective, using drops initially if nasal obstruction is complete and changing to maintenance treatment with an aerosol spray.
• Surgery will give immediate relief of obstruction but regrowth of the polyps is common.
Stress incontinence
Regular urinary incontinence is reported by 25% of adult women with CF. Stress incontinence may also occur in adolescent girls with CF and in to a lesser extent in adolescent boys. Coughing, huffing, laughing, and physical activity may all cause incontinence and may lead to cough suppression and poor compliance with physiotherapy. Pelvic floor exercises can help control stress incontinence. This condition may not be brought up by the patients and must be asked about specifically. It is routinely asked about by the physiotherapist or CF nurse at annual assessment.
Arthritis
Joint pain related to CF affects 5–10% of older children. There are 2 types of disease.
CF-associated arthritis
• This is a recurrent large joint oligo-arthropathy affecting the ankle, knee, hip, elbow and shoulder.
• It can be associated with pulmonary exacerbations, can be exacerbated by IV antibiotic therapy, may be associated with rash and fever, and is self-limiting over the course of about 7 days.
• It is a non-erosive arthropathy without radiographic changes and may be caused by immune complexes.
• It is usually responsive to NSAIDs or a short course of prednisolone.
Hypertrophic Osteoarthropathy
• This occurs as part of the same process that causes finger clubbing.
• It usually occurs in young adults and may flare up with pulmonary exacerbations.
• It can cause swelling and tenderness at the end of long bones. It can also cause joint swelling with effusion and usually affects the wrist, knees, or ankles. It is usually symmetrical.
• It may be associated with radiographic changes, with periosteal elevation and layers of new bone formation.
• It is usually responsive to NSAIDs or a short course of prednisolone. Occasionally steroid-sparing drugs such as methotrexate or azathioprine may be needed.
Portacaths
• Portacaths may be inserted in children where IV access is needed frequently or where access has proven difficult in the past. These may inserted electively or as an emergency.
• Portacaths need to be flushed once a month. Difficulty flushing a portacath or withdrawing blood back should prompt an assessment using the portacath protocol available here
Outpatient Clinic
• Children with stable CF and a well structured home care plan for routine care should be seen in the outpatient clinic every 2 months as routine. Outpatient appointments are an opportunity to monitor symptoms, obtain cough swab/sputum cultures, monitor nutrition and lung function, and reinforce or modify current care plans. Children less than 1 year of age are seen every month as routine. Children with poorly structured care at home, or who are non-compliant with treatments may need to be seen and monitored more frequently.
• At each visit, we routinely ask about frequency and nature of cough, amount and colour of sputum, exercise tolerance, night-time symptoms, physiotherapy routine, appetite, abdominal pain, bowel habit, school attendance, medications, and whether they have required additional courses of oral antibiotics from their GP. We measure lung function, height, weight and oxygen saturations at every visit. Enquires into more general problems about adherence, or problems within the family should be made where appropriate. The patient and family are also seen by the Physiotherapist, Dietician and Specialist CF nurse, and may also be seen by the CF Psychologist where appropriate.
• Outpatient clinic is designed to segregate patients from each other as some CF respiratory pathogens are transmissible. Patients known to isolate Burkholdaria cepacia complex and M. abscessus are not seen at all in routine clinic, but instead are seen on the third Tuesday morning of each month.
• In all CF clinics each patient is housed in a consulting room for the duration of their clinic visit, and all members of the MDT circulate between patients. Patients see all the MDT in approximately 75 minutes, and the room is vacated for a minimum of 15 minutes before the next round of patients arrive. Windows need to be open and surfaces cleaned between patients. Patients and parents like this clinic design – Audit.
• A maximum of 12 patients are seen in clinic, with two annual assessments interspersed with routine clinic appointments. The clinic is run by one consultant but the SpR is welcome to attend, and GRID trainees are expected to contribute to annual assessments for full care patients.
• We sometimes recruit patients for CF-SpIT (CF-Sputum Induction Trial) in outpatients when they attend for annual assessment. The induced sputum is generally performed at 12.30 in the REACH room, once all other CF patients have left the clinic. Occasionally there may be extra non-routine attendances for consultant only assessment and these may be seen at 12.30. These patients must not be seen in the room next to the REACH room.
Annual Review
• Children under full-care in Cardiff and shared care with their local DGH all attend for annual review at the Children’s Hospital for Wales. Annual review for full care patients is on Tuesday mornings and for shared care patients, there is a Thursday morning clinic. Clinic directions
• At Annual Review, children receive an in-depth assessment of their current health and treatment strategy. There is an Annual Review proforma. Children are seen in depth by the full MDT and there is a case-discussion for each child the same afternoon. The Consultant collates all MDT contributions and prepares the annual review report. Information from the annual review is put on CF-PORT and a local database for all full-care and shared-care patients.
Annual blood tests are taken at the clinic appointment 2 months prior to annual review. These blood tests are always checked by the CF specialist nurses so that abnormal results can be picked up as soon as possible. Shared care hospitals email over the blood results for their patients having annual review in Cardiff. CF Annual Review Information Sheet. Routine blood tests are FBC and differential, PT, UE Creatinine, LFT, Vitamin ADE, calcium, phosphate, PTH, random serum glucose, HbA1C, CRP, immunoglobulins, IgE, specific IgE and precipitins to Aspergillus fumigatus.
Chest xray is taken on the day or in the two months before annual review. Where possible the chest xray should be performed when the child is well.
Standardised spirometry is performed in all children > 6 years on the day of assessment.
Liver ultrasound. Liver ultrasound may identify early changes in liver echotexture suggestive of fatty infiltration. Important measures from the ultrasound include liver echotexture, portal vein size and pattern of flow, and spleen size. Children need to be starved for a minimum of 4 hours prior to the examination to ensure that the portal vein (and gallbladder) is clearly visualised. All children have an ultrasound in preparation for their first annual review. If this is normal, then no further routine ultrasound is needed until age 5. After age 5 children have a routine liver ultrasound every 2 years. If at any point the ultrasound is abnormal, it will need to be repeated on an annual basis. Ursodeoxycholic acid is started if there are abnormalities on two of the following: liver function tests, PT or liver ultrasound, or alternatively if any abnormality lasts for two consecutive years.
Glucose tolerance test. All children should have an annual glucose tolerance test from age 12 years onwards.
DEXA scan. All children have a single DEXA scan age 15 years. Children with poor growth, the need for significant supplementary feeds, chronic refractory Vitamin D deficiency, delayed puberty or who are on long term steroids will need closer assessment with DEXA scans every three years from the age of 12 years. Particular care is needed to optimise vitamin D metabolism in these patients and consideration should be made with regard to commencing vitamin K supplementation.
Induced sputum. An assessment of the sputum microbiology obtained over the year is extremely important. Many patients receive in addition, an induced sputum procedure at annual review or at another point over the year as part of the CF-SpIT trial.
Patients with CFRD or CF related glucose intolerance will be seen in the afternoon diabetic clinic (first clinic slot) for assessment of their glycarmic control. The Cf consultant will also attend this appointment
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Physiotherapy
Chest physiotherapy in Cystic Fibrosis is an essential part of treatment. Newly diagnosed patients should be introduced to physiotherapy early in life. Physiotherapy needs to become part of the daily routine so that children become acclimatised to it, and parents begin to learn how to assess their children’s respiratory heath through hands-on experience. Chest physiotherapy should ideally be performed twice a day. Compliance with physiotherapy may be difficult particularly in toddlers and again during adolescence, and parents need to be supported through this. See CF Trust guidelines here.
Timing of Chest Physiotherapy
• Physiotherapy should be part of the daily routine. The physiotherapist will tailor the airway clearance techniques to the child’s needs. Morning physiotherapy can be useful to clear those secretions that have accumulated overnight. Evening physiotherapy is performed so that retained secretions do not become irritating overnight.
• Chest physiotherapy should be performed with the stomach as empty as possible especially in infants.
• The frequency of chest physiotherapy should be increased when the child is unwell.
Techniques
• In the newborn period, children and parents will be introduced to physiotherapy in the from of manual techniques (e.g. percussion), PEP mask and activity. The physiotherapist may teach the use of positioning and postural drainage to aid removal of secretions from individual lobes using gravity to assist percussive manoeuvres. Head down tilt is not encouraged.
• As children become older, more sophisticated techniques may be used which incorporate non-passive manoeuvres for secretion clearance and give the child some independence in their physiotherapy regimen. Active Cycle of Breathing Technique (ACBT) incorporates breathing and huffing at different lung volumes. In older children who are capable, Autogenic Drainage (AD) is a highly sophisticated approach to physiotherapy that can be extremely effective.
• Positive end expiratory pressure (PEP) may significantly improve secretion clearance in some individuals. The PEP mask, the PEP mouthpiece, oscillatory PEP (Acapella) and bubble PEP in younger children may all be very effective and can also help patients concentrate on their physiotherapy regimen.
• Exercise has an important contribution to respiratory health and patients should be encouraged to participate in regular physical activity. The physiotherapist can help with advice on appropriate training programmes.
Adjuncts to physiotherapy
DNAse and hypertonic saline are nebulised treatments that are important adjuncts to physiotherapy – they are described in more details in the medication section.
Physiotherapy in Clinic
Patients should be seen by the physiotherapist at every clinic visit. The physiotherapist will review the effectiveness of current techniques and suggest improvements or change technique where necessary. The physiotherapist can provide very useful information regarding airway secretions at the time of the visit and will help in the decision regarding antibiotic treatments and whether to start hypertonic saline or DNAse. Research shows that physiotherapists are usually best at judging treatment compliance in CF patients.
Physiotherapy for in-patients
• In-patients should be seen by a paediatric physiotherapist twice a day while in hospital. The hospital admission will be used to make a comprehensive assessment of physiotherapy techniques and will often result in some changes to optimise treatment.
• Patients on hypertonic saline will receive this twice a day (or more) while in hospital, and those on DNAse will receive this daily even if they are on alternate day treatment at home. In some patients DNase and/or hypertonic saline may be introduced for the duration of the hospital admission only. Additional approaches may be introduced as needed including IPPB or NIV.
• Parents are encouraged to do some of the routine work, especially when they are learning the techniques. Weekend physiotherapy can be provided twice a day, but if the patient is well enough, it is sometimes acceptable for parents to do the physiotherapy so that ward leave can be maximised.
Obtaining respiratory cultures
• Sampling respiratory secretions is an essential part of the care of children with cystic fibrosis. Only by identifying airway infections early can treatment be started and lung damage minimised. This means collecting samples regularly, even when patients seem otherwise well. In some older children, a good session of physiotherapy may be enough to induce some sputum. Children who are unable to expectorate should have a cough swab. Ideally this entails holding a microbiological swab in the pharynx whilst the child coughs. Some children will do this for themselves if they are shown how. If it is not possible to coordinate the cough, a deep pharyngeal swab is taken immediately after cough, induced either by physiotherapy or by pharyngeal stimulation with the swab. A simple throat swab is inadequate.
• Ideally, All children who are not spontaneously productive should have an induced sputum manoeuvre when they are unwell, particularly if no organisms have been identified on recent microbiology samples. The Induced sputum manoeuvre is currently being assessed in the CF-SpIT trial here in Cardiff. It is more accurate at identifying lower airway bacteria when compared to cough swab. The protocol for induced sputum is outlined below. [download here] ECFS2013
Protocol for induced sputum sampling
• Induced sputum should be performed after a 2 hour fast.
• Make an initial assessment of the chest.
• Attach an oxygen saturation monitor and document oxygen saturations, heart rate, respiratory rate. Perform lung function in children older than 7 years old.
• Before the procedure, obtain a cough swab.
• Administer 200mcg salbutamol via metered dose inhaler and spacer to prevent broncho-constriction.
• Use a jet nebuliser attached to wall oxygen at a flow rate of 5 l/min to deliver 8 ml of 7% sterile hypertonic saline for 15 minutes.
• Make an assessment of the chest every 5 minutes.
• After 15 minutes, apply physiotherapy techniques including manual techniques, ACBT, AD, and PEP.
• Obtain sputum either by expectoration or by suctioning through the nasopharynx or oropharynx using a sterile, mucus extractor or suction catheter size 6.
• Make a final assessment and document observations, oxygen saturations, and lung function in children over 7 years old.
• Repeat cough swab after procedure even if induced sputum sampling is unsuccessful.
Nutrition and supplemental feeding
• Good nutritional status can be achieved in the majority of children with cystic fibrosis by combining a high calorie diet with adequate pancreatic enzyme supplements.
• Poor nutrition in CF may result from the following
• Malabsorption
• Poor appetite and dietary intake
• Increased energy demands from poor health
• Energy requirements for patients with CF will vary, but a high energy and fat diet providing 120% – 150% of the estimated average requirement for energy is recommended.
• Nutritional intervention is required in children with CF who are unable to sustain weight or maintain growth.
Poor weight gain in CF
In children who are unable to sustain weight to maintain growth, there are several ways to increase total energy intake:
In children older than 2 years of age, BMI centile is also used as an indicator of growth
Oral Nutritional supplements
• Advice should concentrate on maximizing energy density of meals, and optimising pancreatic enzyme replacement. If weight gain is poor despite this, oral nutritional supplements should be considered.
• There are three main types of supplements.
• High Energy Infant formulas
• High Energy supplements
• Nutritional supplements
—– High calorie milkshakes, fortified milks and juice based drinks.
—– Nutritionally complete preparations given as oral supplements or by enteral feeding
High Energy infant formulas
SMA High Energy, Infatrini, and Similac High Energy (1kcal per ml) are high energy milk formulas suitable from birth up to around 18 months. These are not used as first line feeds but are useful when an infant has poor weight gain due to insufficient intake or high energy needs.
High Energy supplements
These include powders such as Maxijul and Polycose (glucose), Calogen (fat), and Duocal (Glucose and fat), and also energy rich liquid preparations such as ProCal (Glucose, fat and protein).The amount used will vary depending on age and should be ascertained by a dietician. They are useful to enhance energy density without increasing volume of fluid or food. Procal (>3 kcal/ml) is a high density energy liquid which may be given in small volumes, a bit like a medication rather than a supplement
Nutritional supplements
High calorie milkshakes, fortified milks and juice based drinks
• These supplements are not nutritionally complete and are used to supplement rather than replace the patient’s current intake.
• Supplements should only be given after meals or as snacks and should not replace mealtimes.
• Enzymes are required for all the milk based supplements but are not normally required for the juice based drinks.
• The suitability of supplement preparations varies for patient age and weight, and with patient preference. These patients must be seen by a dietician.
• There are a wide range of nutritional supplements available in a variety of flavours:
• Powdered milkshake style made up with milk (Scandishake, Enshake, Calshake).
• Ready to drink Juices (Paediasure Juce, Ensure Plus Juce, Fortijuice, Provide Xtra).
Nutritionally complete supplemental preparations
• Nutritionally complete supplemental preparations are generally either whole protein or elemental preparations. They can be given as daytime supplements but every effort should be made to avoid children becoming nutritionally dependant on these supplements as an alternative to regular meals.
• Nutritionally complete preparations commonly used as supplements to a normal diet include ready to drink milkshake and yoghurt style drinks (Paediasure plus, Ensure Plus, Ensure Plus Yoghurt style, Resource, Fortisip, Fresubin)
Enteral Feeding
• Children who have poor weight gain may require enteral feeding.
• Poor weight gain can be a result of poor appetite, which may be chronic or may be a consequence of an acute severe exacerbation.
• Enteral feeding is indicated if after the use of oral nutritional supplements:
• Weight for height ratio is <85%
• Weight has fallen by two centile positions
• No weight gain for 6 months
• The majority of children who receive enteral feeds will do so continuously overnight via a pump. This may be via NG tube or gastrostomy. Each child will be individually assessed for the most appropriate feed by the Dietician. Pancreatic supplements will need to be adjusted in accordance with the feed. Children on insulin therapy for CFRD will need reassessment of nighttime glucose profiles and insulin dosing if overnight feeds are introduced. The dietician will provide pumps, feed and all equipment required. Advice will be given with regard to safe feeding overnight.
• Elemental feed is completely hydrolysed formula. The main elemental feed used in CF is Emsogen. This feed is based on 83% MCT and therefore significantly reduces the pancreatic replacement enzymes required. Some children can manage this feed without enzymes. Emsogen is mainly used in children over 5 years, but can be used with caution in children 1 – 5 years old.
The table below outlines some of the commonly used nutritionally complete supplements.
Drugs used in CF patients
Many of the drugs that are used in children with CF are used outside of licensed indications. References in the BNFc may therefore not apply. Consensus documents that are used in CF care include the CF Trust guidelines. We take our drug dosing from the Brompton CF guidelines which are comprehensive and regularly updated. They are available here.
Antibiotics
Prophylactic oral antibiotics
Flucloxacillin
Children treated from birth with Flucloxacillin prophylaxis have been shown to have fewer infective exacerbations in the first 2 years of life and may have slightly improved lung function. There is no evidence for its use over aged 2, but many centres will continue flucloxacillin until age 5 and this is our current policy. Any child who repeatedly isolates Staph aureus should be started on prophylactic flucloxacillin. There is some concern that prophylactic flucloxacillin may result in earlier infection with P.aeruginosa if used for longer periods.
Azithromycin
Azithromycin has been shown to improve FEV1 at 6 months (approx 4%) and reduce exacerbation rate by 50% in older children and adults with chronic pseudomonas infection. In younger children (mean age 10), who are negative for P. Aeruginosa and who have normal lung function, no improvement in lung function is seen, but exacerbation rate is still reduced by 50% at least in the short term. There are also some effects on weight gain and a reduction in frequency of Staph aureus isolation. Azithromycin may also have anti-inflammatory effects and may also affect quorum sensing in Pseudomonas aeruginosa infection. Long term azithromycin therapy is associated with NTM macrolide resistance. All children treated with azithromycin should therefore have regular airway cultures for NTM, and azithromycin should be discontinued if NTM is isolated.
Treatment oral antibiotics
• Children with a respiratory exacerbation are usually treated with oral antibiotics even if they have mild symptoms. A cough swab should be arranged before empirical antibiotics are commenced. Treatment can then be modified later according to what has grown.
• Young children already on prophylactic flucloxacillin can be managed in the first instance with high dose flucloxacillin (QDS) until cultures are returned. Alternatively co-amoxiclav or azithromycin can be given for a two week course. Children who have previously isolated P. Auriginosa should be given ciprofloxacin for 2 weeks, and those who have previously isolated S. Maltophilia should be given Co-trimoxazole. Children > 12 years may benefit from Doxycycline as an alternative to co-amoxiclav or azithromycin.
Intravenous antibiotics
• Children receive iv antibiotics for respiratory exacerbations which have failed to clear despite oral treatment or who have isolated specific organisms where eradication therapy is indicated.
• IV antibiotics are given in Cardiff as inpatient treatment only, as part of an intensive programme with optimisation of secretion clearance and nutrition. Treatment is given for a minimum of 14 days. For children who have frequent exacerbations and do little care at home, stand alone short admissions for physiotherapy and nutritional support without IV antibiotics can help recover their lung function and widen the gap between toxic IV antibiotic treatments. ECFS2014
• Standard treatment is with IV ceftazidime TDS and IV Tobramycin OD. Children with CF clear IV aminoglycosides from the blood more quickly than other children and higher doses are therefore used.
• Aminoglycosides should be avoided in all children where there is a family history of deafness irrespective of whether or not they have CF. This is because there is a mitochondrial mutation that is rare in the genrrla [population hut enriched infamilies with deafness (m.1555A>G) – this mutation is associated with deafness after the first dose of aminoglycoside. We do not routinely screen for this mutation in children with CF if there is no family history of deafness.
• Aminoglycosides can cause cumulative nephrotoxicity and ototoxocity, and levels are carefully monitored. The half life in the middle ear is approximately three months and so we are reluctant to use IV aminoglycosides more frequently than every 3 months. Alternatives to prevent frequent use of IV aminoglycosides include alternating treatments of IV ceftazidine and tobramycin, either with IV meropenem and colomycin, or IV meropenem with nebulised TOBI bd. Background nebulised antibiotics are generally continued through IV treatments unless patients are given the same drug IV. If patients have chronic Staph aureus infection they are often given Flucloxacillin as a third agent. If they have isolated S. maltophilia recently, IV cotrimoxazole should be given as a third IV treatment.
More information on treating specific infections can be found here.
Starting IV antibiotics
see CF admission sheet
First line intravenous antibiotics on admission:
• Ceftazidime 50 mg /kg three times a day with a maximum of 3g per dose.
• Tobramycin 10 mg /kg as a single daily infusion over 30 minutes to a maximum of 660 mg.
• If the child is <1 month of age or has previously had high levels of tobramycin use a dose of 7 mg/kg/day.
• If the child is unwell, please discuss when to start tobramycin with the consultant as this may be delayed to allow for adequate hydration. If the child is well, try to have the first dose of tobramycin given at approximately 4pm on the day of admission.
• U&E, creatinine must be taken AND CHECKED before the first dose of tobramycin is given.
Tobramycin levels
• These are taken on day 2, and on every Tuesday and Friday morning of the week thereafter.
• There is usually no need to take levels at the weekend.
Interpreting Tobramycin levels
The first tobramycin level is measured 18 hours after the first dose, together with U&E, creatinine (10am)
• If 18 hour tobramycin level is <1.0mg/l then continue current dose.
• If 18 hour tobramycin level is >1.0mg/l omit the dose that evening.
Repeat tobramycin level next morning together with UE creatinine. Discuss the result with the consultant.
• If the repeat tobramycin level is still >1.0mg/l omit the dose that evening
• If the repeat tobramycin level is now <1.0mg/l restart tobramycin that evening at a dose reduced by 20%.
Only restart tobramycin when levels are <1.0mg/l
When tobramycin is restarted at a reduced dose, levels must again be taken 18 hours after the first dose.
All future courses of IV tobramycin should be commenced at the dose that has produced appropriate plasma levels.
Nebulised Colistin and Tobramycin
• Children with chronic P. aeruginosa infection should be treated with continuous nebulised antibiotics. This may work by preventing further infection or by suppressing chronic infection. Either way, the aim is to prevent further lung damage.
• Nebulised colistin is given twice daily but may be reduced to once daily if airway cultures remain negative and the patient is asymptomatic. If the patient re-isolates P. aeruginosa while on once daily colistin, they should be restarted on twice daily colistin thereafter. The dose of colistin is 1MU bd for children aged < 2 years and 2MU bd for children aged > 2 years.
• Nebulised Tobramycin is given twice daily for one month on then one month off, and is sometimes combined with Colistin on alternate months. TOBI and Bramitob are two formulations of tobramycin for nebulisation that can be given to children over the age of 6 years at a standard dose of 300mg BD.
• Patients starting nebulised antibiotic treatment will need a tolerance test dose in hospital. Please contact Jodee to arrange this.
Adjuncts to physiotherapy
• also refer to physio section
DNAse
• Recombinant human DNAse (Pulmozyme) is a mucolytic.
• DNAse is one of the NHS High Cost drugs
• Infected secretions in the CF lung are full of neutrophilic debris. Neutrophilic DNA polymerises into huge rafts and contributes to the viscosity of the mucous. DNAse is an inhaled treatment that works to cleave these DNA rafts thereby reducing the viscosity of the secretions and helping secretion clearance.
• DNAse can improve FEV1 in some patients by up to 5-8% and this benefit is sustained with ongoing therapy. It has also been shown to result in small (2–3%) but significant improvements in lung function (FEF25–75) in well 6–10 year old children over a 2 year period and to reduce the number of infective exacerbations.
• Traditionally, candidates for this therapy were patients with chronic pseudomonas infection, an FEV1 of <70% with a chronic productive cough despite optimized physiotherapy. An increase in FEV1 >10% after 4 weeks of treatment was required to continue treatment. However, any child with a persistent cough, significant changes on chest xray, or recurrent chest exacerbations should probably have a trial of DNAse even if their lung function is normal.
• It is our policy to commence all children on DNAse from the age of 6 years, and earlier in those that have persistent chest symptoms. Short term DNase is usually started in all children who are admitted to hospital for IV antibioitcs irrespective of age.
• DNase is generally given once a day and should be given at least one hour before physiotherapy so that it has time to have an effect. We recommend that children who are on DNase take it when they come home from school, so that it has time to work before evening physiotherapy. Alternatively DNAse can be taken in the morning after the physiotherapy session so that it works during the day, and contributes to effective secretion clearance in the afternoon. We do not advise that it is given before bedtime, as loosening secretions may precipitate coughing overnight.
• The dose of DNase is 2.5mg irrespective of body weight. There is some evidence that there is little loss of effect in administering DNase on alternate days compared to daily, and stable patients may be transferred to this regimen if they become asymptomatic.
• DNAse is licensed for the Pari LC Plus nebulizer, but is administered in some patients through the eflow and Ineb systems. There is no need for children to have a tolerance trial when first starting DNase.
Hypertonic saline
• Nebulised 6% (MucoClear) or 7% (Nebusal) hypertonic saline (HS) is an effective aid to secretion clearance. It works by increasing airway surface liquid in CF lungs thereby aiding mucociliary clearance. It is resorbed quickly and has a short duration effect and must therefore be given just before or during physiotherapy manoeuvres. The dose is generally 4mls and can be administered through all nebulisers.
• Hypertonic saline therapy has been shown to reduce exacerbation rate and improve lung function in 2 controlled trials and 3 open label trials in patients > 6 years of age. Improvement in lung function was moderate but showed large variation between subjects.
• Hypertonic saline has been shown to improve LCI in children > 6 years with normal lung function. The ISIS trial in children aged <6 years showed no benefit in exacerbation rate, but LCI significantly improved in the subgroup of patients who were studied.
• We recommend the use of hypertonic saline as an adjunct to physiotherapy from an early age
• Hypertonic saline can be poorly tolerated but our experience is that it can be incorporated into daily care from as early as 6 months of age. Adverse events include vomiting, increased cough, throat irritation, wheezing and a transient drop in FEV1. Salbutamol should be given prior to HS to minimise bronchospasm, and the first dose should be given in the hospital setting. HS is cheaper than DNase (£360/year v £7500) and should be used as first line to aid secretion clearance. DNAse and hypertonic saline work through different mechanisms and many children can benefit from using a combination of the two treatments.
Steroids
Inhaled steroids
Cystic Fibrosis is an inflammatory condition and steroid therapy can be beneficial.
Many patients with CF are treated with inhaled corticosteroid therapy (ICS) despite the lack of evidence. In children this is usually to treat symptomatic wheezing. The long term effects of ICS therapy on lung inflammation remains unclear and a recent Cochrane review was inconclusive with regard to whether ICS are of benefit in CF. One RCT looking at withdrawal of ICS therapy in children with CF demonstrated no change in time to exacerbation, no increased wheezing and no change in lung function.
Prednisolone
Oral prednisolone may used in children with cystic fibrosis in the following situations:
• During a viral chest exacerbation with prolonged wheezing that has been refractory to oral antibiotics.
• In the second week of a course of IV antibiotics for a significant chest exacerbation.
• As chronic therapy in some children with significant disease who demonstrate an improvement on steroid therapy. A recent Cochrane review concludes that lung function decline is reduced by prednisolone at 1mg/kg on alternate days over a 2-4 year period.
• As part of the treatment for ABPA.
• Prednisolone should always be non-enteric coated in children with CF
• Patients on long term oral steroids should be screened regularly for glucose intolerance (urine dipstick), high blood pressure, sub-capsular cataract formation, poor growth and warned of the increased risk of infection.
• It can be assumed that all children who have been on >0.5mg/kg prednisolone for >2 weeks will have adrenal suppression, and these patients may need hydrocortisone replacement during intercurrent illness and im hydrocortisone during vomiting illnesses when they are unable to take their steroids orally.
• Children on >0.5mg/kg/day prednisolone should be provided with a STEROID TREATMENT CARD
• Children on prolonged prednisolone therapy (>3months) may take longer to recover adrenal function once steroids are withdrawn and use of hydrocortisone replacement and synacthen tests to check recovery should be considered.
• Children who have not had an obvious episode of chickenpox should have their VZ titres measured, and if these are not protective should be given appropriate advice should they come into contact with chickenpox.
Pancreatic enzymes
Several formulations are available (Creon, Pancrease, Pancrex). Some high lipase forms of these enzymes were implicated in the aetiology of a colon disorder called fibrosing colonopathy. Some of these formulations have now been withdrawn from the market (creon 25,000 and creon 40,000 are available and can be used). The enzyme we routinely use in Creon 10,000. The 10,000 refers to units of lipase per capsule. The total daily dose a child is given should not routinely exceed 10,000 units of lipase per kg body weight. The capsule can be broken open and the granules taken with food, yoghurt or apple puree. Each granule is enteric coated, so they are still protected from gastric acid. However since children tend to chew them, their efficiency is reduced, and swallowing the capsules whole is desirable. For infants and young children Creon micro (granules) are available which are dispensed in 5000u scoops. We encourage this to be given in yoghurt or apple puree from birth to aid efficient swallowing.
H2 antagonists and Proton pump inhibitors
These agents are sometimes given to reduce gastric acid production. The efficiency of replacement pancreatic enzymes is maximal when the duodenal and jejenal pH is alkaline. Excessive gastric acid secretion with consequent overflow into the duodenum may inhibit the release of these enzymes thereby reducing their efficacy. Giving H2 antagonists or omeprazole will sometimes improve this situation. Omperazole may need to be given at high dose and twice daily to be effective.
• Ranitidine: 3mg/kg/dose twice daily (1 hour before meals) (1mg/kg/dose bd if < 6 months)
• Omeprazole: 0.7mg/kg/dose twice daily (max 40mg)
Vitamin supplements
see Vitamin guidelines
.
Ursodeoxycholic acid
• Ursodeoxycholic acid is a bile salt and is thought to improve bile flow and may affect the natural history of CF related liver disease.
• We use ursodeoxycholic acid for infants with neonatal cholestasis, in patients with gallstones, or if at annual review they have 2 or more of the following: heterogenous liver on ultrasound, raised transminases, abnormal clotting or a palpable liver or spleen. We also start ursodeoxycholic acid if any of these parameters are abnormal for 2 consecutive years.
• The dose of ursodeoxycholic acid is 10-15mg/kg twice daily
CF Trust Guidelines
CF Trust guidelines are available here:
• Standards for the Clinical Care of Children and Adults with cystic fibrosis in the UK. Second edition. December 2011
• Standards of Care and Good Clinical Practice for the Physiotherapy Management of cystic fibrosis. Second edition. June 2011
• Physiotherapy treatment for babies and toddlers with cystic fibrosis Factsheet – March 2013
• Laboratory Standards for Processing Microbiological Samples from People with Cystic Fibrosis. First edition. September 2010
• Antibiotic Treatment for cystic fibrosis. Third edition. May 2009
• Methicillin-resistant Staphylococcus aureus (MRSA). April 2008
• Bone Mineralisation in cystic fibrosis. February 2007
• Pseudomonas aeruginosa infection in people with cystic fibrosis. Suggestions for Prevention and Infection Control. Second Edition. November 2004
• The Burkholderia cepacia complex. Suggestions for Prevention and Infection Control. Second Edition. September 2004
• Management of cystic fibrosis-related Diabetes Mellitus. June 2004
• Nutritional Management of cystic fibrosis. April 2002
Dr Julian Forton 8/4/2014