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Cystic fibrosis 

Cystic fibrosis
Chapter:
Cystic fibrosis
Author(s):

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

DOI:
10.1093/med/9780198703860.003.0024
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date: 30 November 2021

General principles

Definition and pathophysiology

  • CF is a multi-system disease due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a complex chloride channel

  • CFTR is essential for regulating chloride permeability across epithelial tissues and, in addition, has other complex cellular roles (e.g. CFTR downregulates transepithelial sodium transport, in particular the epithelial sodium channel, and influences expression of other genes, including those involved in inflammatory responses, ion transport, and cell signalling)

  • Loss of CFTR function or quantity causes inadequate hydration of mucous secretions. In the lungs, this results in defective mucociliary clearance, mucus obstruction of the luminal space, and colonization with pathogenic bacteria. Recurrent cycles of infection and inflammation contribute to lung damage and subsequent development of bronchiectasis

  • In the pancreas, the exocrine ducts become blocked by secretions, leading to pancreatic destruction, pancreatic enzyme insufficiency, and CF-related diabetes.

Genetics

  • CF is an autosomal recessive disease, with a carrier frequency of 1 in 25 in Caucasians; 1 in 2, 500 UK live births have CF. CF is rare in Afro-Caribbeans but is seen in patients of Asian origin in the UK and USA

  • Heterozygote advantage through resistance to diarrhoeal disease may have led to persistence of CFTR mutations at relatively high population frequencies, despite the lethal homozygous form

  • >1, 800 different mutations in the CFTR gene are recognized and can be classified on the basis of the mechanism by which they cause disease (see Table 24.1)

  • The most common mutation is F508del (previously termed DeltaF508; a deletion of three nucleotides, causing the loss of a phenylalanine at residue 508), which accounts for ~70% of defective CFTR alleles in patients, with a decreasing prevalence from north-west to south-east Europe

  • Thirteen other mutations have a frequency >1% (e.g. G542X (3.4%), G551D (2.4%), W1282X (2.1%), 3905insT (2.1%)), accounting for 85% of CF alleles altogether. These can be effectively screened for

  • CF is characterized by wide variation between patients in disease severity, rate of progression, and, to an extent, organ involvement. This phenotypic variation is caused, at least in part, by (i) class of CFTR mutation (correlates highly with pancreatic status but not with severity of lung disease), (ii) polymorphism in non-CFTR ‘modifier’ genes (e.g. IFRD1, which regulates neutrophil function), and (iii) environmental factors (e.g. compliance, socio-economic status, access to care, smoke exposure, pathogen-specific factors).

Table 24.1 Classes of CFTR mutation

Class I

Defective protein synthesis, e.g. G542X

Class II

Defective protein maturation and trafficking, e.g. F508del

Class III

Impaired chloride channel opening (gating), e.g. G551D

Class IV

Defective channel ion transport (conductance), e.g. R117H

Class V

Defective splicing

Class VI

Accelerated turnover at cell surface

Screening

In the UK, neonatal heel-prick for immunoreactive trypsinogen measurement is offered routinely as part of a national screening programme. Positive samples are tested for common CFTR mutations and, if needed, a second immunoreactive trypsinogen screen, followed by sweat testing.

Diagnosis

Patients are usually diagnosed with CF as neonates or children (genetic screening, family history, failure to thrive, meconium ileus, rectal prolapse, cough, recurrent chest infections). Diagnosis is based on the presence of two disease-causing CFTR mutations, along with a positive sweat test (sweat chloride concentration >60mmol/L, usually 90–110mmol/L) and compatible clinical features. Sweat chloride levels are usually lower in CF that presents in adulthood (borderline is 40–60mmol/L; <40 is considered normal although can occur in CF).

CFTR-related disease

refers to patients with mild manifestations of CFTR dysfunction such as single organ involvement (e.g. late-onset bronchiectasis, congenital bilateral absence of the vas deferens, or idiopathic pancreatitis). These typically occur with ‘milder’ CFTR mutations (classes IV or V; see Table 24.1) that result in residual CFTR function, and patients tend to be pancreatic-sufficient. A grey area exists between CF and CFTR-related disease, and, in some cases, a firm diagnosis is not possible on initial investigation but becomes apparent during follow-up; note that CF remains a clinical diagnosis.

Management

The ongoing care of CF patients moves to the adult CF centre around the age of 16–18 (often when the patient leaves school), although a period of transitional care may occur between ages 14–16. An MDT approach is essential, comprising respiratory physician, specialist nurse, physiotherapist, pharmacist, dietician, and psychologist, with regular additional input from gastroenterology and endocrine teams.

Improved treatment of CF has led to an increase in median survival to around 40y, and >55% of UK CF patients are adults. The predicted lifespan for a baby born with CF now is at least 50y.

Further information

UK CF Trust. Cystic fibrosis http://www.cysticfibrosis.org.uk.

CF Trust consensus documents on aspects of cystic fibrosis care. Cystic fibrosis http://www.cysticfibrosis.org.uk/about-cf/publications/consensus-documents.aspx.

CF mutation database. Cystic fibrosis http://www.genet.sickkids.on.ca.

CF microbiology: overview

Chronic pulmonary sepsis and its complications account for much of the morbidity and mortality in CF. The airways of a CF patient are chronically colonized by pathogenic bacteria from an early age. Bronchiectasis is usually established by a young age (around 5y).

  • Patients commonly expectorate variable volumes of purulent sputum, even when well

  • When organism levels are high, patients may feel generally unwell or more tired, or have anorexia, weight loss, temperature >38°C

  • They may have symptoms of dyspnoea, increased volume of more purulent sputum, haemoptysis, wheeze, and chest ache

  • Examination and CXR can be unchanged from normal

  • With effective antibiotic treatment, FEV1 levels should rise to the pre-infection normal. If they do not, further antibiotics may be necessary, and other diagnoses or unusual organisms should be considered

  • In practice, the FEV1 is the most reliable marker of disease progression and can be used to assess overall decline, as well as to determine an exacerbation and response to treatment (as PEFR would be used in asthma).

Organisms

Airway colonization changes over time, with increasing age, and organisms become more resistant to antibiotics. Typical progression of organism colonization with time is Staphylococcus aureus, followed by Haemophilus influenzae, and then Pseudomonas aeruginosa (see Fig. 24.1). Goals of management should be initially to prevent infection, then to eradicate it, and finally to control the infection. Material for culture should be collected; most commonly sputum, but BAL if necessary. Polymicrobial infection is common.

Fig. 24.1 Prevalence of selected respiratory pathogens in patients with CF over time. Reproduced from Goss C., Thorax (2007) 62: 360–7 with the kind permission of BMJ

Fig. 24.1 Prevalence of selected respiratory pathogens in patients with CF over time. Reproduced from Goss C., Thorax (2007) 62: 360–7 with the kind permission of BMJ

CF antibiotics 1

Antibiotic courses in patients with CF need to be longer and at higher doses than in non-CF patients. Indications for treatment in adults include any new isolate from sputum (even if asymptomatic) or features of an exacerbation (see Cystic fibrosis pp. [link][link]). Treatment should be for 14 days with either oral or IV antibiotics. IV antibiotics are indicated for severe infection or failure to eradicate organisms with oral antibiotics. Choice of antibiotics is based on clinical response more than in vitro resistance patterns, but recent sputum culture results will also guide therapy.

  • In practice, it is usually appropriate to give the patient the same regime they had during their last exacerbation, provided there was a good clinical response, taking into account the patient’s antibiotic allergies (desensitization may be required; see Cystic fibrosis pp. [link][link])

  • Recent sputum culture results can be helpful, although note that sputum cultures lack sensitivity. Have a low threshold for including anti-pseudomonal cover if P. aeruginosa has previously been isolated (even if assumed to have been eradicated). Results of in vitro antibiotic susceptibility testing do not always correlate with clinical response to antibiotics

  • All CF centres will have written management protocols which should be followed. Seek expert advice from your local CF centre if unsure.

Pseudomonas aeruginosa

is associated with a more rapid decline in lung function. Most CF patients are chronically infected with P. aeruginosa by their early teens: non-mucoid species colonize initially, which may be asymptomatic or intermittent and can be eradicated, and mucoid species then follow and permanent eradication is rare. The aims of treatment are prompt eradication of new isolates and maintenance therapy to reduce the bacterial load in colonized patients.

  • First isolates of P. aeruginosa in patients who were previously Pseudomonas-free or who have never had P. aeruginosa should lead to prompt treatment with an eradication regimen (even if asymptomatic). Failure to treat may lead to the development of chronic airway infection. There is no clear evidence favouring a specific eradication regimen. An initial treatment protocol combining nebulized colistin 2MU bd for 3 months with oral ciprofloxacin 750mg bd (avoid in epilepsy; reduce dose in severe renal impairment; warn patient to stop if ankle pain, as risk of Achilles tendon rupture) for 3 months is widely used. Consider a 2-week course of IV anti-pseudomonal antibiotics (see Box 24.1) before starting treatment with nebulized colistin and oral ciprofloxacin in patients with a new P. aeruginosa isolate in the context of a respiratory exacerbation. Failure of eradication with oral and nebulized antibiotics should also prompt IV therapy

  • Maintenance treatment for chronic P. aeruginosa infection comprises long-term nebulized anti-pseudomonal therapy, typically either nebulized colistin 1–2MU bd or alternate months of nebulized tobramycin 300mg bd (the alternate month can either be medication-free or the patient may nebulize colistin). Alternative, recently approved maintenance anti-pseudomonals include dry powder inhaler forms of colistin and tobramycin and nebulized aztreonam

  • Treatment of exacerbations in patients with chronic P. aeruginosa infection Mild exacerbations (e.g. following a viral URTI) should be treated with a 2-week course of oral ciprofloxacin, alongside usual maintenance nebulized antibiotics. IV anti-pseudomonal antibiotics (see Box 24.1) for a minimum of 2 weeks are indicated for moderate and severe exacerbations as well as for first P. aeruginosa isolates not cleared by ciprofloxacin and colistin.

CF antibiotics 2

Staphylococcus aureus

is a significant pathogen causing exacerbations. Prevention and eradication are important, even if the patient is asymptomatic. In adults, a minimum of 2 weeks of treatment should be given when S. aureus is cultured, with flucloxacillin, or erythromycin or clindamycin if penicillin-allergic. Note that macrolide resistance is increasingly common in MRSA. If S. aureus continues to grow, despite treatment with flucloxacillin, check that the S. aureus isolate is not MRSA, and add in a second anti-staphylococcal antibiotic (e.g. sodium fusidate or rifampicin) for 2 weeks. More prolonged oral antibiotics (e.g. further 4 weeks) or a course of IV antibiotics may be required. There is some evidence to support long-term flucloxacillin prophylaxis in colonized children, but this is not widely practised in adults, reflecting a lack of evidence of benefit in this age group as well as concerns regarding the development of MRSA.

Haemophilus influenzae

should be treated with, e.g. co-amoxiclav or doxycycline, even if the patient is asymptomatic. More prolonged oral antibiotics or a course of IV antibiotics (e.g. co-amoxiclav or ceftriaxone) may be required. Resistance to amoxicillin and macrolides is common.

Burkholderia cepacia complex

comprises at least ten different subspecies (genomovars) of B. cepacia. These organisms are often resistant to many antibiotics and display inherent resistance to colistin. Some genomovars are highly transmissible, and patients colonized with B. cepacia should be segregated (including separate clinics and spirometers, and side rooms on a different ward) from non-colonized patients. Clinical consequences of infection are highly variable, ranging from asymptomatic to severe worsening of pulmonary infection with septicaemia (‘cepacia syndrome’), which can be rapidly fatal. B. cenocepacia (genomovar III) is particularly associated with cepacia syndrome and is usually considered an absolute contraindication for lung transplant due to poor outcomes. Treat exacerbations with combination antibiotic therapy, directed by in vitro sensitivities where available. Meropenem appears to be a particularly useful antibiotic, and other options often include ceftazidime, piperacillin-tazobactam, aminoglycosides, and temocillin. Mild exacerbations may respond to oral ciprofloxacin, doxycycline, or co-trimoxazole.

MRSA

has been associated with increased mortality in CF and leads to difficulties in antibiotic choice and delivery of care. Follow local guidelines for topical eradication in patients with MRSA skin carriage. 4-week long courses of oral rifampicin with sodium fusidate are useful for sputum eradication; other options include linezolid or nebulized vancomycin. IV teicoplanin or vancomycin are required for MRSA pulmonary exacerbations.

NTM

Mycobacterium avium complex (MAC) and Mycobacterium abscessus are the most frequently encountered NTM in CF (see Cystic fibrosis pp. [link][link] for diagnosis and treatment). In general, consider and treat other causes of deterioration (e.g. P. aeruginosa) prior to initiating anti-mycobacterial therapy. The clinical and radiological features of NTM may be difficult to distinguish from other infections, particularly P. aeruginosa, and both long-term antibiotics (e.g. macrolides, tobramycin) and bacterial overgrowth may inhibit NTM culture. Recent studies have suggested that the M. abscessus subspecies massiliense may be spread between patients within CF centres, although the transmission route and infection control measures required to control this organism are currently unknown. Furthermore, isolation of M. abscessus pre-transplant appears to be a risk factor for the development of post-transplant NTM disease and a poor outcome, and active M. abscessus infection is considered an absolute contraindication to transplant in many units.

Stenotrophomonas maltophilia

The clinical significance of S. maltophilia colonization in CF remains unclear. Address other causes of clinical deterioration in colonized patients prior to considering antibiotic treatment directed at S. maltophilia. S. maltophilia is inherently resistant to carbapenems, and most strains are also resistant to anti-pseudomonal drugs. Co-trimoxazole is the usual antibiotic of choice; other options include doxycycline, ticarcillin-clavulanic acid, or tigecycline.

Achromobacter xylosoxidans

The clinical significance of A. xylosoxidans infection is uncertain; consider treatment in chronically colonized patients with evidence of clinical deterioration in the absence of other causes. A. xylosoxidans is often multi-resistant, and antibiotic choice should be on the basis of susceptibility testing results; useful agents often include minocycline, meropenem, piperacillin-tazobactam, and chloramphenicol.

Further information

CF Trust consensus document on antibiotic treatment for cystic fibrosis, 3rd edn, 2009. Cystic fibrosis http://www.cysticfibrosis.org.uk/about-cf/publications/consensus-documents.aspx.

Management of exacerbations

Pulmonary exacerbations are the most common reason for hospital admission of CF patients. Patients are usually adept at recognizing a deterioration in their condition requiring treatment, and treatment is usually required if they present acutely, even if they appear fit and healthy.

Signs and symptoms of an exacerbation include:

  • Increase in productive cough or dyspnoea

  • Change in appearance or volume of sputum

  • New signs on auscultation (often absent)

  • New CXR changes (often absent)

  • Weight loss >1kg or 5% of body weight, associated with anorexia

  • Fall in FEV1 >10%

  • Fever.

Persistent, low-grade symptoms, such as cough alone, are an indication for IV antibiotics if oral antibiotics have failed to bring about an improvement. IV antibiotics should also be considered if a new positive sputum culture fails to clear with appropriate oral antibiotics.

Investigations

  • Baseline spirometry for FEV1

  • Weight

  • O2 saturation and, if <92%, blood gas

  • CXR (exclude pneumothorax)

  • Sputum (M, C, & S, including specific testing for P. aeruginosa and B. cepacia, and AFBs)

  • Bloods, including CRP (note that not all patients exhibit high inflammatory markers, even during severe exacerbations)

  • Monitor blood sugars.

Treatment

is with appropriate antibiotics (see Cystic fibrosis p. [link][link]), O2 therapy, increased physiotherapy and nutritional support, and control of hyperglycaemia. Many patients will self-administer IV antibiotics at home (see Cystic fibrosis pp. [link][link]). Indications for inpatient treatment include: too unwell for home therapy; significant weight loss; poor response to recent home IVs; poor compliance or unable to self-administer IV therapy; patient preference; other complications (e.g. significant haemoptysis or pneumothorax; see Cystic fibrosis pp. [link][link]).

If failing to improve with empirical antibiotics:

  • Review microbiology; repeat sputum M, C, & S and AFBs, and consider empirical change in antibiotics, including anti-pseudomonal cover (see Cystic fibrosis pp. [link][link])

  • Consider hospital admission if failing to improve with home-based treatment

  • Optimize airway clearance with intensive physiotherapy, and review mucolytics (see Cystic fibrosis pp. [link][link])

  • Optimize nutritional support and glycaemic control (see Cystic fibrosis pp. [link][link])

  • Assess adherence to treatment

  • Exclude ABPA (see Cystic fibrosis pp. [link][link])

  • Review and repeat CXR imaging, and consider CT chest, followed by bronchoscopic lavage targeted to area of nodularity/consolidation on imaging (?NTM or fungal infection); stopping all antibiotics (including long-term macrolides and nebulized anti-pseudomonals) may increase the yield from bronchoscopy

  • Consider empirical oral prednisolone in severely unwell patients who are failing to improve with appropriate antibiotics.

NIV may assist with airways clearance, in addition to providing ventilatory support. Consider the appropriateness of ICU admission as well as resuscitation status in severe exacerbations—liaise with CF consultant.

IV antibiotic administration

  • The majority of IV antibiotic courses can be administered at home, after an initial assessment and with home support from nursing staff. Many patients are relatively well during courses of IV antibiotics and are able to continue attending work or college, although it can take them considerable extra time to administer the antibiotics

  • Most antibiotic regimes involve 14 days of IV antibiotics. This may require the siting of an IV cannula with a microbiological filter (to make it last longer), or preferably a long line

  • Many patients have an indwelling venous access device (see following section) that can be accessed when required

  • Prior to starting IV antibiotics, clinical assessment, including spirometry, should be made. Patients should be reviewed at day 7 to ensure satisfactory clinical progress (and to consider changing antibiotics if little or no improvement) and at end of the course in outpatients to ensure clinical improvement

  • Courses of IV antibiotics are often administered prophylactically before surgery, and regular elective courses of IV antibiotics may be useful for patients who have experienced a rapid and progressive increase in the decline of their lung function or who suffer frequent exacerbations.

Implantable venous access devices (IVADs)

(e.g. Port-A-Cath®)

  • Inserted in patients with difficult IV access or those needing frequent courses of IV antibiotics

  • Usually accessed by a trained nurse, patient, or family member. Access only with a Huber point needle of the appropriate length; do not use standard needles, which may damage the IVAD

  • Flush with 5–10mL of 100U/mL heparin monthly and with 5mL of 10U/mL heparin at the end of each IV dose

  • Avoid taking blood from IVAD, if possible, as this increases the risk of blockage and infection. Other complications include venous obstruction (including SVC obstruction), thrombosis, tip dislocation, and leakage

  • If pain or swelling around IVAD site, arrange a portagram/linogram to look for occlusion or damaged catheter. If IVAD blocks: injection of 20–50mL heparinized saline, gently alternating between irrigation and aspiration, may clear small occlusions. If this fails, consider urokinase 25, 000U in 3mL 0.9% saline instilled into IVAD

  • Infected or fractured lines need surgical removal.

Antibiotic desensitization

Antibiotic sensitivity is a major problem in CF, as repeated antibiotic courses are associated with the development of allergic reactions, especially to β‎-lactams. Rashes are common, but anaphylaxis (see Cystic fibrosis pp. [link][link]) can occur. Always give first doses of a new antibiotic in hospital with resuscitation facilities at hand. Desensitization regimes can enable treatment with antibiotics that have previously caused an allergic reaction. Such regimes need to be given at the start of the antibiotic course each time it is used and during the course if doses are missed for >1 day. Depending on local policy, give a dilute antibiotic dose over 20min, followed by slightly stronger concentration, and repeat for seven concentration strengths until full antibiotic strength is given. Takes 3–4h. Stop infusion if any side effects develop.

Other pulmonary interventions

Physiotherapy

Specialized CF physiotherapists teach effective airway clearance with the aim that patients perform this themselves twice daily on a long-term basis. This improves secretion clearance, decreases airflow obstruction, and improves ventilation. Several techniques are used: active cycle of breathing control (tidal volume breathing, then deep inspiration, and passive expiration, followed by forced expiration to mobilize secretions prior to coughing/huffing), autogenic drainage, Acapella or flutter devices, high-frequency oscillatory (vest) therapy, positive expiratory pressure mask, and use of NIV for airway clearance. More intensive physiotherapy is administered during exacerbations. Physiotherapists also have key role in assessment of functional ability with exercise testing, evaluating treatments, and encouraging aerobic exercise.

Recombinant DNase

(dornase alfa) is a nebulized mucolytic that cleaves DNA from dead neutrophils, decreasing sputum viscosity and aiding its clearance. Recommended in patients with FVC >40% predicted to improve pulmonary function. Used once daily 2500U nebulized and should be taken at least 30min prior to doing airway clearance. Only continue in patients with clear benefit, e.g. 10% improvement in spirometry and shuttle walk test (SWT). It is expensive and only effective in 30–40%.

Hypertonic saline

Use of regular nebulized hypertonic (7%) saline appears to increase mucociliary clearance and improves QoL and reduces exacerbations in trials. Consider if secretions are thick, tenacious, and difficult to expectorate. It is used immediately before or during usual airway clearance regime. Bronchospasm is a relatively common side effect: patients should receive a test dose, and pre-dosing with bronchodilators is usually required.

Inhaled mannitol

has recently been approved for use in CF patients with rapidly declining lung function (defined as fall in FEV1 >2%/y) who cannot use DNase (because of ineligibility, intolerance, or inadequate response) or other osmotic drugs.

Macrolides

have anti-inflammatory and immunomodulatory effects, in addition to their antimicrobial activity, and seem to improve FEV1 and decrease exacerbations in a subset of CF patients. They do not exhibit intrinsic anti-pseudomonal activity, but there is in vitro synergy between macrolides and anti-pseudomonal antibiotics, and the macrolide azithromycin decreases sputum viscoelasticity and disrupts P. aeruginosa biofilms. Consider a 6-month trial of oral azithromycin (250mg taken three times per week if <40kg, or 500mg three times per week if >40kg) in patients who are deteriorating on conventional therapy. Checklist when considering macrolide therapy:

  • Check LFTs after 1 month; use with caution if pre-existing liver disease

  • Warn patient to stop immediately if symptoms of ototoxicity (hearing loss, disequilibrium, tinnitus), and omit macrolide whilst receiving IV aminoglycosides

  • Macrolides may prolong QT interval—check baseline corrected QT interval is <430ms (♂) or <450ms (♀) on ECG, and use with caution alongside other QT-prolonging drugs (e.g. citalopram, domperidone, moxifloxacin, antifungals, etc.)

  • Care with drug interactions, e.g. warfarin, itraconazole

  • Avoid in patients with evidence of NTM infection and screen sputum for NTM prior to starting macrolides and whilst on treatment.

Ivacaftor

is a mutation-specific, small molecule CFTR potentiator that is the first treatment to effectively target the basic CFTR defect: oral treatment resulted in significant improvements in lung function, exacerbation rate, weight gain, and QoL, and notably a halving of sweat chloride, in patients with a G551D mutation. Very high cost but recently approved for UK use in the 5% of CF patients with this mutation. It is widely believed that ivacaftor is likely to transform the prognosis for these patients, although long-term outcome data are awaited.

Respiratory support

Respiratory failure and cor pulmonale can occur with later stage disease. Home O2 may be required. Nocturnal NIV may be necessary as a ‘bridge to transplant’ in chronic respiratory failure and may also be useful in the palliation of symptoms of hypercapnia.

Steroids

Short oral courses may improve lung function, but side effects, such as growth impairment, osteoporosis, and diabetes, are significant. They are used in ABPA, severe unresponsive exacerbations, and occasionally in terminal care.

Immunization

Annual influenza as well as pneumococcal vaccination.

Lung transplantation

(see Cystic fibrosis p. [link]) has a well-established role in CF, and patients should be considered for referral when their risk of death within 2–3y is high. Predicting prognosis in CF is difficult; historically, an FEV1 ≤30% predicted was associated with a poor prognosis and used as a trigger to consider transplantation, but, in the modern treatment era, this low level of lung function is associated with a median survival of 5.3y and should not constitute the sole criterion for referral. Additional factors should be considered alongside absolute FEV1 such as evidence of rapid progressive deterioration (e.g. increasing number of admissions/exacerbations, rapid fall in FEV1), recurrent major haemoptysis not controlled by embolization, and recurrent or refractory pneumothorax; hypoxia (PaO2 <7.3kPa) and hypercapnia (PaCO2 >6.7kPa) are associated with <50% survival at 2y and remain useful guidelines for transplantation. Young female patients with rapid deterioration have a poor prognosis and should be considered for early referral.

Active M. abscessus or B. cenocepacia infection is considered an absolute contraindication to transplant in most UK centres. Whilst on the transplant waiting list, the patient should have optimal nutrition and physical care, including treatment of low bone mineral density and gastro-oesophageal reflux, and maintenance of good diabetes control and BMI >17. Average waits are around 1y in the UK, and approximately one in three CF patients die whilst on the waiting list. Following transplantation, the main immediate problems are infection and acute rejection, with bronchiolitis obliterans the predominant late complication (see Cystic fibrosis pp. [link][link]). 1y survival following transplant is ~85%.

Other pulmonary disease

Pneumothorax

is more common in patients with advanced lung disease and is associated with a poor prognosis (48% 2y mortality rate). Presentation is typically with breathlessness and chest pain and interestingly often also haemoptysis. Manage according to standard pneumothorax guidelines (see Cystic fibrosis p. [link]). Consider IV antibiotics and physiotherapy (with modification of airway clearance, as necessary). Withhold positive pressure techniques if the pneumothorax is undrained. Avoid spirometry. The collapsed lung can be stiff and take longer to reinflate and require prolonged drainage and suction. Persistent air leaks may require surgical input, ideally with a limited procedure such as local abrasion. Pleurodesis is no longer considered a contraindication to later lung transplantation. Liaise with transplant centre if surgery is required.

Haemoptysis

Small-volume haemoptysis is common, especially with concurrent infection and advanced disease. Massive haemoptysis (see Cystic fibrosis p. [link]) typically reflects bronchial artery bleeding and can be fatal. Management of haemoptysis: correct clotting (e.g. vitamin K 10mg od) and platelets; stop NSAIDs; low threshold for IV antibiotics; oral or IV tranexamic acid 1g every 6–8h (contraindications include renal failure, ischaemic arterial disease). For massive haemoptysis, anaesthetist may be required for airway management; sit patient upright, and give an ice-cold drink (reduces pulmonary pressures and vasoconstricts bronchial arteries); cross-match blood; consider nebulized adrenaline (1mL of 1:1, 000 made up to 5mL with NaCl 0.9%); consider IV terlipressin (vasopressin analogue, increases systemic arterial pressure and reduces PAP; follow local guidelines for administration, typically 2mg IV and then 1–2mg every 4–6h if continued bleeding). Physiotherapy review: airway clearance is usually stopped during active bleeding and then modified and recommenced as bleeding subsides. Many clinicians temporarily stop NIV in patients with massive haemoptysis; nebulized drugs may also provoke further bleeding (particularly hypertonic saline); we recommend weighing their benefit against risk on an individual patient basis. Bronchoscopy is rarely of value, instead perform CTPA to look for bronchial artery hypertrophy; bronchial artery embolization is the gold standard treatment of massive haemoptysis or recurrent bleeding; discuss with interventional radiology.

ABPA

(see also Cystic fibrosis pp. [link][link]) May be difficult to diagnose in CF, as hypersensitivity (with positive Aspergillus skin prick tests and precipitins) and sputum culture of Aspergillus are both common. ABPA is screened for annually and should be considered when exacerbations respond poorly to appropriate antibiotics. Guidelines define a ‘classic case’ of ABPA in CF as:

  • Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced asthma, decline in pulmonary function, increased sputum) not attributable to another cause

  • Serum total IgE concentration >1, 000IU/mL (unless receiving systemic corticosteroids, which will suppress IgE)

  • Presence of serum IgE antibody (RAST) to A. fumigatus

  • Precipitating antibodies to A. fumigatus

  • Infiltrates or mucus plugging on CXR or chest CT that have not cleared with antibiotics and physiotherapy.

Blood eosinophilia is also a common finding, and ABPA may occur with intermediate serum IgE concentrations of 500–1, 000IU/mL.

Treatment

is with oral prednisolone 0.5–1.0mg/kg (non-enteric-coated; maximum dose 60mg) for 2 weeks, and, if there is a clinical improvement, these should be continued at decreasing doses for 2–3 months. Intensive physiotherapy is also an important part of the treatment regime, and hypertonic saline may be useful. Add antifungal therapy with itraconazole for 3–6 months if there is a slow or poor response to corticosteroids, relapse of ABPA, and in corticosteroid-dependent cases. Itraconazole checklist:

  • Initial itraconazole dose is 5mg/kg/day; give od, unless dose exceeds 200mg/day, in which case it should be given bd; maximum daily dose 400mg/day

  • H2 antagonists and PPIs reduce absorption of itraconazole—take itraconazole with an acidic drink (e.g. orange juice or cola) if also taking antacids

  • Check LFTs at baseline, after 1 month, and then every 3 months if therapy continues

  • Review concomitant medications to avoid a drug-drug interaction.

In addition to ABPA, other forms of Aspergillus-related lung disease described in CF include aspergillomas (see Cystic fibrosis pp. [link][link]) and ‘Aspergillus bronchitis’ (a newly proposed entity of positive respiratory cultures for A. fumigatus and radiological infiltrates in symptomatic patients who do not fulfil the above diagnostic criteria for ABPA but respond to antifungal therapy).

CF ‘asthma’

Some CF patients have coexisting asthma, and some have asthma-like symptoms of prolonged exhalation, wheeze, and crackles due to underlying lung inflammation. This is difficult to diagnose, as these symptoms and a variable PEFR are found in many CF patients due to airway hyperresponsiveness. There may be bronchodilator responsiveness or bronchoconstriction after exercise or nebulized hypertonic saline. Treat with the standard asthma stepwise treatment: short-acting bronchodilator, inhaled corticosteroid, LABA, theophyllines (which may aid mucociliary clearance), leukotriene receptor antagonist (limited evidence in CF but may decrease eosinophilic inflammation), oral steroids.

Extrapulmonary disease

Nutritional management

The maintenance of good nutrition correlates with survival in CF, and dietician input is crucial. Nutrition is more problematic as respiratory disease progresses (raised basal metabolic rate, increased work of breathing, ongoing infection, and inflammation). High-calorie, high-protein diets are encouraged. Patients may need nutritional supplements ± supplemental overnight enteral (nasogastric (NG) or gastrostomy) tube feeding. Weigh patients at every review, and aim for BMI >19.

  • Pancreatic enzyme supplementation to avoid high faecal fat/energy loss is essential if pancreatic-insufficient (85% of patients). Use the smallest dose of pancreatin-containing lipase, required to control steatorrhoea. Typical preparations are Creon® (contains lipase, protease, and amylase) 10, 000, 25, 000, or 40, 000, taken pre-meals. Typically, patients take 10–20 tablets/day and are educated to adjust the dosage, according to the fat and protein content of each meal. High-strength pancreatic enzyme preparations have been linked to fibrosing colonopathy; maximum lipase levels of 10, 000U/kg/day are recommended

  • Fat-soluble vitamins are poorly absorbed in most patients with CF (particularly if pancreatic-insufficient) and require supplementation—a widely used combined preparation is AquaDEKs®, two capsules daily.

GI disease

  • Distal intestinal obstructive syndrome (DIOS, previously termed meconium ileus equivalent) comprises bloating, abdominal pain, possible palpable right lower quadrant mass, and complete or incomplete intestinal obstruction by viscid faecal material in terminal ileum and proximal colon. Abdominal X-ray characteristically shows ‘foamy’ gas pattern in the right flank ± dilated small bowel loops/fluid levels. Can occur spontaneously or secondary to dehydration or intercurrent infection. Treatment is medical. Mild cases may respond to high doses of regular polyethylene glycol (Movicol®). Correct hydration using IV fluids, if necessary. More severe cases may be relieved by oral Gastrografin® (50mL mixed with 200mL of water or cordial tds for up to 5 days) or Klean-Prep® (can be given orally but usually via NG, and not nocturnally as risk of aspiration). If this is unsuccessful, patients will require a Gastrografin® enema (under radiological guidance) to determine the site of obstruction and for therapeutic benefit. Treatment is complete when clear fluid is passed from the rectum and symptoms have resolved. If not resolving, consider further imaging and surgical opinion (differential diagnosis includes acute small bowel obstruction, e.g. 2° to adhesions, and intussusception)

  • Gastro-oesophageal reflux is common and may worsen lung disease. Combinations of PPIs, H2 receptor antagonists, and prokinetics (e.g. domperidone 10–20mg tds) are usually required

  • Coeliac disease appears to be more common in CF

  • Pancreatitis occurs in pancreatic-sufficient patients, presenting as acute attack or chronic recurrent abdominal pain. Treat with bowel rest, PPI, IV rehydration

  • GI and pancreatic cancer is more common in CF.

Liver and biliary disease

  • Focal biliary cirrhosis affects 5–10% of CF patients and leads to portal tract fibrosis, often with preserved hepatic architecture. Cirrhosis is frequently asymptomatic and develops insidiously in childhood. Annual screening liver USS is performed, as blood tests can be unhelpful (although ALP most sensitive). Biopsy unhelpful as patchy disease. Treatment with ursodeoxycholic acid improves biochemical indices of liver function, although its long-term benefits are unproven. Established cirrhosis can lead to portal hypertension and variceal bleeding; annual screening endoscopies are performed in patients with cirrhosis.

Metabolic disease

  • CF-related diabetes (CFRD) is becoming increasingly common (e.g. affects ~50% of patients >40y) and is associated with a higher mortality. Pancreatic damage in CF (due to fibrosis) causes decreased insulin secretion. CFRD is a distinct type of diabetes but shares certain clinical features of both type I and type II diabetes. Unlike type I diabetes, onset of CFRD is usually insidious, and patients may be asymptomatic at diagnosis or present with a decline in pulmonary function or weight; ketoacidosis is very rare in CFRD. CFRD differs from type II diabetes in that weight loss is often an early feature and reactive hypoglycaemia is not unusual. Some patients exhibit overt diabetes during an infective exacerbation but return to normal glucose tolerance later. Early identification and treatment of CFRD improves health status, even in the absence of fasting hyperglycaemia; screening oral glucose tolerance test should be performed annually. Management is with insulin (usually as basal bolus regimen), with blood glucose targets of 4–7mmol/L; there is no role for oral hypoglycaemics or a hypoglycaemic diet. Microvascular complications can occur after 5–10y of CFRD

  • Low bone mineral density and increased fracture risk is common in CF. Risk factors include malabsorption of vitamin D and calcium, low BMI, decreased physical activity, delayed puberty, steroid use, diabetes. Screen with DEXA scans from age 18y. Treatment is with calcium and vitamin D supplements to ensure vitamin D-sufficient, bisphosphonates.

Other organ systems

  • Arthropathy and CF vasculitis Acute or subacute arthritis occurs in around 5% of patients and often responds to NSAIDs. Sometimes arthritis is associated with skin lesions such as purpura or erythema nodosum

  • Chronic rhinosinusitis is often troublesome and may worsen lung disease. Consider sinus CT. Treatment with topical steroids and decongestants is often unhelpful, and surgery may be required

  • Acute kidney injury is more common in CF and associated with IV aminoglycosides, NSAIDs, dehydration, and pulmonary exacerbations

  • Electrolyte abnormalities include hyponatraemia, hypokalaemia, hypochloraemia, and metabolic alkalosis. Salt tablets are required in hot weather due to excessive losses in sweat

  • Stress incontinence is very common in women; treat with pelvic floor exercises.

Other issues

Fertility

Women

with CF may be subfertile but should always be offered contraception if of reproductive age. If planning a pregnancy, their physical state should be optimized with antibiotics and nutrition. The outcome of pregnancy is improved by optimizing and maintaining pulmonary function and weight gain during the pregnancy, and close monitoring is required. Women with CF are also at risk of developing diabetes during pregnancy. Pregnancy does not affect survival when compared with the entire adult ♀ CF population, but impaired pulmonary function with FEV1 <60% predicted and BMI <18 are likely to be the main predictors of worse maternal and foetal outcome, and some patients do experience an accelerated decline after pregnancy. PHT is considered an absolute contraindication to pregnancy. Breastfeeding is possible but intensifies the nutritional strain put on the mother. Many CF antibiotics are safe to use in pregnancy, but avoid ciprofloxacin, chloramphenicol, metronidazole, and IV colistin, and, if possible, avoid IV aminoglycosides. Ceftazidime at a reduced dose of 2g tds is a safe first-line choice for patients infected with P. aeruginosa.

Men

are usually infertile due to failure of the normal development or blockage of the vas deferens, seminal vesicle, ejaculatory duct, and body and tail of epididymis. Testicular histology is normal, and hence one option is surgical sperm retrieval for intracytoplasmic sperm injection (ICSI) into an egg, performed by fertility clinics.

Genetic counselling and screening

should be offered to patients with CF and their partners.

Psychosocial support

Trained psychologists offer personal and family support regarding education, employment, financial benefits, burden of treatment, and adapting to progressive disease. Pre-transplant psychological assessment is carried out, as well as terminal care and bereavement counselling. Consider and treat depression, anxiety, and emotional difficulties, with referral to psychiatric services, if necessary. Social worker involvement may help with benefit entitlements, travel insurance, disabled car badge.

Care of the dying CF patient

When all acknowledge that there are no further active treatment options, the focus of care should adjust to being palliative, with an emphasis on symptom relief, at home or in hospital or a hospice. The transition from active treatment to palliative care is often difficult in CF, as many end-of-life events begin as an exacerbation, and it may be difficult to predict or define when patients are entering a terminal phase. There is often an overlap between active and palliative care, e.g. some ‘active’ treatments (such as gentle physiotherapy and even NIV) may have a palliative role in symptom control, and, for this reason, most deaths occur in hospital. A particular challenge is palliative care of patients on an active transplant waiting list when unrealistic hopes about the availability of a last-minute transplant may delay discussion of end of life and compromise symptom control. Open and sensitive discussion about end-of-life care is encouraged, but approaches should be dynamic and tailored to the needs of individual patients. Effective communication amongst the CF team and ward staff is essential.

Future developments

Small molecule CFTR modulators (correctors and potentiators)

The example of ivacaftor treatment for patients with a G551D mutation has proven that small molecule-based approaches to correcting the basic CFTR defect by targeting specific mutations can provide clinical benefit in CF. Long-term clinical outcome data for ivacaftor is still awaited, however. Many other orally bioavailable compounds targeting specific CFTR mutations are in clinical trials, including VX-809 and VX-661 which target the F508del mutation. Combinations of these compounds (e.g. with ivacaftor) may prove to be particularly effective in restoring CFTR function.

Gene therapy

aims to restore CFTR function by inserting a normal copy of the CFTR gene into epithelial cells to prevent progressive airways disease. This will theoretically be of benefit to patients with any mutation class, in contrast to mutation-specific small molecule-based therapies. A major challenge has been finding a suitable vector for delivery, with recent interest in adeno-associated viruses and liposomes. A multi-dose trial of a nebulized CFTR-expressing plasmid complexed with a (non-viral) cationic lipid is currently underway, run by the UK Gene Therapy Consortium.