Fig. 11.2.2 Loculated pneumothorax in a patient who had previous pneumothoraces. A JONES & K WEBB 240 Monitor blood sugars to exclude the onset of diabetes. If the blood sugars become uncontrol led in an established diabetic put the patient onto an insulin pump. Monitor overnight oxyg en saturations and carbon dioxide levels with a transcutaneous oxygen and carbon dioxide mo nitor. Have a low threshold for establishing patient on nasal ventilation. Inability to saf ely oxygenate overnight with a marginally elevated (rather than high) carbon diox- ide leve l. Infective exacerbations can be prevented or reduced in severity with maximized care. Cystic Fibrosis Foundation. Patient Registry (2005). Annual Report. Bethseda, Maryland. Ellaf \201 M, Vinsonneau C,Coste J et al. One year outcome after severe pulmonary exacerba tions in adults with cystic \201 brosis. Am J Respir Crit Care Med 2005; 171: 158 \200 \223164. Goss CH, Burns J. Exacerbations in cystic \201 brosis. 1: Epidemiology and pathogenesis. Thorax 2007; 62: 360 \200\223367. Mahadeva R, Webb AK,Westerbeek et al. Management in pediatric and adult cystic \201 brosi s centers improves clinical outcome BMJ 1998; 316: 1771 \200\2231775. Marshall BC. Pulmonary exacerbations in cystic \201 brosis: its time to be explicit! Am J Respir Crit Care Med 2004; 169: 781 \200\223782. Pitt TL, Sparrow M, Warner M, et al. Survey of resis tance of Pseudomonas aeruginosa from U K patients with cystic \201 brosis to six commonly prescribed antimicrobial agents. Thora x 2003; 58: 794 \200\223796. Further reading Antibiotic treatment for cystic \201 brosis: Report of the UK Cystic Fibr osis Trust Antibiotic Group (2nd edn) (2002). London: UK Cystic \201 brosis Trust. Thornton J, Dodd ME, Webb AK, et al. Long term clinical outcome of home and hospital intrav enous antibiotic treatment in adults with cystic \201 brosis. Thorax 2004; 59: 242 \200 \223246. Ashleigh R, Webb AK. Radiological Intervention for haemoptysis in cystic \201 brosis. Roy Soc Med 2007; 100(suppl 47): 38 \200\22345. This page intentionally left blank A JONES & K WEBB 242 11.3 Chronic disease management Overview Cystic \201 brosis (CF) is a multi-system condition. The majority of the morbidi ty and premature mortality relate to the effects of the chronic suppurative lung disease an d exuberant host in \202 ammatory response, and malab- sorption due to exocrine pancreatic insuf \201 ciency. Management of CF lung disease Provision for patient review and advice 1 Regular outpatient review is essential. Routine visits should be at least every 3 months or more frequently de pending on clinical condition. Ideally, the CF MDT should meet both before and after the cl inic to discuss the patients attending that day to plan their long-term management. 2 Patie nts should have 24-hour access to specialist CF center care for emergency appointments and telephone advice. Specialist center care The management of adults with CF requires a MDT at a specialist CF c enter. The specialist team should comprise physicians, nurses, physiotherapists, dieticians , social workers, psychologists, pharmacists, and administrative support staff. 3 Annual assessments should be performed for all patients, including various assessments of CF lung dis- ease (see later in this chapter). Monitoring of CF lung disease Spirometry should be measured at each clinic visit and during inpatient admissions unless there is a clear contra- indication, such as a current pneumot horax. Microbiological culture of respiratory secretions is mandatory at each patient visit and during inpatient admissions. \200 \200 Survival There have been signi \201 cant improvements in quality of life and survival for patients with CF over the past few decades. Lung function and nutritional status are predic tors of patients \200\231 survival. The predicted median age of survival for infants recent ly born with CF in the UK is over 50 years old. Sputum samples are more sensitive than cough swabs. Use of induced sputum can be considered for those patients who experience dif \201 cultly providing sputum samples despite input from a physiotherapist experi- enced in CF care. The samples should be processed by a diagn ostic labora- tory with expertise in CF microbiology. Use of selective culture media for CF pathogens is mandatory. Culture for environmental mycobacteria should be performed at leas t once annually. Pathology of CF lung disease Pulmonary disease is almost universal in individuals with CF. The defective CFTR genes causes abnormalities in sodium and chloride permeability in the ai rway epithelium leading to a decrease in the airway surface liquid and impairment of mucoci liary clearance. A combination of air \202 ow obstruc- tive, endobronchial sepsis and an e xcessive host in \202 amma- tory response leads to progressive lung damage. With persisten t infection the airways become plugged by thick, mucopurulent material containing bacteria, neutrophils and mucus, the bronchial epithelium become ulcerated, abscesses form and bronc hiectasis develops. The distribution of changes is usually most marked in the upper lobes. The severe in \202 ammatory changes lead to parenchymal destruction and cyst formation wit hin the lung. Hyper- trophy of the pulmonary vasculature and new vessel formation is seen a nd bronchopulmonary shunting occurs in association with bronchiectasis. Postal kits can be used to send samples to the laboratory between clinic visits when more f requent surveillance cul- tures may be required, such as screening for early Pseudomonas ae ruginosa infection. CXR should be performed at least annually, or more fre- quently if indi cated by clinical symptoms/signs or signi \201 cant fall in spirometry. Oximetry can be me asured at rest and during exercise. Arterial blood gas, or preferably arterialised capillar y blood sample, analysis should be measured at least annually or more frequently if indicat ed by clinical symptoms/signs or signi \201 cant fall in spirometry. Transcutaneous oxygen and carbon dioxide monitoring (TOSCA) can be used to evaluate requirements for over- night oxygen and non-invasive ventilation for patients with moderate-severe respiratory disease at risk of onset of cor pulmonale and/or chronic type II respiratory failure CT scanning ca n provide further information of CF lung disease in selected cases, for example, patients w ho have infection with environmental mycobacteria. At present there is insuf \201 cient ev idence to recommend the use of chest CT-scans on regular intervals to monitor progression o f lung disease. Exercise testing can provide further assessment of pulmo- nary status and s hould be considered for patients as part of their annual review assessment. Physical activi ty questionnaires and breathlessness scores should be recorded as part of the annual assess ment. Physiological features of CF lung disease The early physiological features of CF pulmonary disease are small airway narrowing, air trapping and progressive hyperin \202 ation. In th e larger airways damage to the airway wall leads to central airway instability. Later in th e disease there is a reduction in lung volume due to the consequence of progressive \201 brosis. The FEV1 and FVC are reproducible measures of pulmo- nary function for patients wit h moderate to severe disease. The FEV1 and FVC are used to monitor the progression of CF lu ng disease and provide an indictor for patients \200\231 survival. Data from specialist CF centers has shown a progressive reduction in the annual rate of lung function decline with each succesive birth cohort of patients over the past few decades. CHAPTER 11.3 Chronic disease management 243 Transthoracic echocardiography can provide a non-invasive estimation of pulmonary artery pr essure for patients with severe disease at risk of pulmonary hypertension. There are report s of cardiomyopathy in a small number of patients. Other new techniques, for example measur ement of the lung clearance index, are currently research tools and not yet used in routine clinical practice. Some patients succumb to a necrotising pneumonic illness associated with pyrexia and septic aemia known as the \200\230cepacia syndrome \200\231 (Fig. 11.2.1). It is probable that ce rtain species within the complex, such as B. cenocepacia, are more virulent than others. Th ere is also a worse outcome following lung transplanta- tion for patients infected with B. cenocepacia; patients infected with this pathogen are therefore often excluded from lung tr ansplantation programs. Microbiology of CF lung disease The traditional spectrum of pathogens associated with CF lu ng disease is surprisingly small, although emerging pathogens such as Stenotrophomonas malt ophilia, Achromobacter xylosoxidans, Ralstonia species, and Pandorea apista are being more frequently encountered. Environmental mycobacteria Environmental mycobacteria are occasionally isolated from sputum samples of patients with CF. The diagnosis of active infection and decision to treat the o rganism in such cases is often dif \201 cult. Consistently smear or culture positive cases , or features on a CT-scan suggest- ing active infection, may help the clinicians \200\231 decision. The fast growing environmental mycobacterial species, M. chelonae and M. abscessu s, are more likely to cause clinically signi \201 cant infection and are particularly dif \201 cult to treat. Some lung transplant centers consider active infection with M. chelona e or M. abscessus as a contra-indication to trans- plantation. Staphylococcus aureus and Haemophilus in \202 uenzae The most common pathogens in early ch ildhood are Staphylococcus aureus and Haemophilus in \202 uenzae. Meticillin-resistant Staphylococcus aureus (MRSA) There is no evidence that pulmonary infec tion with MRSA confers any further disadvantage than with meticillin- sensitive strains of S. aureus for patients with CF. However, infection does limit antibiotic treatment options, may cause problems if infection spreads to other sites, for example if the patient undergo es a surgical procedure, and leads to infection control problems. The majority of MRSA infe ctions are due to hospital- acquired strains, although whilst the proportion of infec- tion s due to community acquired MRSA strains are low in the UK, they are increasing in prevalen ce in North American CF Centers. Fungi Although Candida and Aspergillus species are frequently isolated from sputum of CF pa tients, in most patients this is not clinically signi \201 cant and does not require treat ment. Respiratory viruses Respiratory viruses are responsible for some of the acute exacerbations of pulmonary disease in CF. Respiratory viral infections, such as adenoviruses, RSV and In \202 uenza A and B, can on occasions lead to dramatic falls in lung function, that may ta ke months to recover or can be irreversible. Pseudomonas aeruginosa The major pathogen in late childhood and adulthood is Pseudomonas ae ruginosa, with approximately 80% of adults with CF having chronic infection. Early infectio n can be eradicated or suppressed by aggres- sive antibiotic treatment. Left untreated, the organism will adapt to the environment of the CF lung by producing a mucoid exopolysacchar ide in a bio \201 lm mode of growth. Once this phenotypic change occurs then eradication b ecomes impossible. Chronic Pseudomonas aeruginosa infection is associated with an increase in treatment requirements, deterioration in lung function and reduction in life expectancy for patients with CF. A combination of proactive screening, infection control and aggressiv e eradication treatment, however, are begin- ning to reduce the age dependent prevalence of infection. Treatment There are a number of treatment options available for CF pulmonary disease. The m anagement should be tailored to each individual patient, aiming to control infection, prese rve lung function, prevent associated complications, and control symptoms whilst minimizing the treatment burden. Nebulisers and compressors Nebuliser therapy is widely used in treatment of CF lung disease . It is vital that patients practice cleaning and maintenance of the equipment. In addition to the traditional nebuliser-compressor sys- tems, new nebulisers are now available that u se novel adaptive aerosol delivery, that can reduce treatment time and burden. Burkholderia cepacia complex Patients with CF are particularly predisposed to infection wit h a group of organisms known as the Burkholderia cepa- cia complex. Approximately 5 \200 \22310% of adults patients are infected by these organisms. Certain strains of these specie s are highly transmissible between people with CF. Cross-infection epidemics, with evidence of patient- to \200\223patient transmission, have necessitated the implemen- tation of dra conian infection control measures both within and outside hospitals to control spread. Infe ction is associated with an increase in morbidity and mortality above that of any other CF pathogen. Prevention of infection 1. Cross-infection control There is clear evidence that some CF res piratory patho- gens such as strains of P. aeruginosa and organisms of the B. cepacia compl ex pose cross-infection risks to others with CF. All CF Centers should have their own local cross-infection policies for their center, developed by the CF MDT and hospital infection control team, and guided by Cystic A JONES & K WEBB 244 (c) B. cepacia complex Although there is no published evidence to support or guide eradicat ion treatment for early infection with organ- isms of the B. cepacia complex, treatment in attempt to eradicate the organism should be considered given the dif- \201 cult clinical problems associated with infection by this group of pathogens. Possible treatment options m ay include nebulised treat- ment with an antibiotic with good activity against organ- isms of the B. cepacia complex such as meropenem (NB: unlicensed indication) combined with two o ral antibi- otics with activity against the organism, such as cotrimoxa- zole, or rifampici m, or chloramphenicol, or cipro \202 oxacin or minocycline, or a prolonged course of intra venous antibiotics. Fibrosis Trust recommendations. The policy should consi- der issues of surveillance, hygien e and patient segregation isolation. Good hygiene should be practiced in all outpatient cli nics and inpatient facilities to minimize the risk of transmission of pathogens between pat ients Mixing of patients should be discouraged both within and outside the hospital environ ment. Inpatients should be housed in single en-suite rooms. Patients infected with organism s of the B. cepacia complex should be treated on separate wards from other patients with CF . Outpatient clinics should be organized according to patients \200\231 microbiological sta tus and patients should be prevented from mixing at the clinic visit. Ongoing microbiologic al surveillance, including genotyping of P. aeruginosa and B. cepacia complex strains, is e ssential. 3. Vaccination \200 In \202 uenza vaccination \200\223 all adults with CF should be offered an annual in \202 uenza vaccination. Pneumococcal vaccination \200\223 pneumococcal vaccination is also recommended for patients with CF Pseudomonal vaccination \200\223 a recent large multicen tre phase III clinical trial has shown disappointing results with use of a vaccine to preve nt P. aeruginosa infection in CF, and at present, there is no clinically effective anti-pse udomonal vaccination available. 2. Eradication therapies for CF pathogens (a) Early P. aeruginosa infection Early P. aerugi nosa infection should be treated aggressively to eradicate the organism and prevent progres sion to chronic infection. It is important to actively screen respiratory secretions at reg ular intervals to detect early P. aeruginosa infection to allow prompt intervention to erad icate the infection. For patients free of chronic P. aeruginosa infection, sputum should be sent for microbiological culture every month. Samples can be collected at outpatient clini c visits or patients given postal specimen kits to send specimens directly to the microbiol ogy laboratory. The most frequently used regimen used in the UK is neb- ulised colisitin an d oral cipro \202 oxacin for 3 months. An alternative nebulised antibiotic for use is tobr amycin solu- tion for inhalation (TOBI). This may be used either as \201 rst line-therapy or second line if a patient is failing to clear early infection with colisitin. A course o f IV antibiotics can be used for any patient una- ble to tolerate nebulised therapy. Antibiotic therapy for chronic infection Intermittent IV antibiotic therapy Some CF centers have adopted an approach of using regu- lar two week courses of IV antibiotics, every thre e months. The merits of this strategy in comparison with using IV antibiotics courses only for infective exacerbations are unproven, but some individual patients may bene \201 t fro m this approach. A combination of an anti-Pseudomonal B-lactam with an aminoglycoside shoul d be the \201 rst-line IV antibiotic ther- apy for patients with chronic P. aeruginosa in fection. In vitro data and clinical experience suggests a combination of three different an tibiotics is most effective for infections with organisms of the B. cepacia complex. (b) MRSA Attempts should be made to eradicate MRSA pulmonary infection in patients with CF. Success is reported with regimens using nebulised vanco- mycin combined with a course of o ral antibiotics. Nebulised vancomycin is acidic and dif \201 cult to tolerate. It is there fore recommended that it be given as a short 5-day course at a dose 200mgs QDS under close medical super- vision as an inpatient. A fully supervised test dose and pre-treatment with a bronchodilator is mandatory. Nebulised vancomycin can be combined with a more pro- longed course of two oral antibiotics such as rifampicin and fusidic acid; liver function tests m ust be monitored during this treatment. Alternative oral antibiotics include clindamycin, t rimethoprim or tetracycline if either patient allergy or intolerance, or microbial resistan ce, preclude use of rifampicin and fusidic acid. Linezolid can be considered as a second-li ne oral antibiotic, although prolonged courses should be avoided because of potential side- effects. If \201 rst attempts at eradication are unsuccessful, then up to two further cou rses of eradication treatment should be given. Nebulised antibiotics Nebulised antibiotics are an essential component of the long-term tre atment of patients with CF and chronic P. aeruginosa infection. Nebulised antibiotics can c ause bronchospasm. They should be administered either preceded by or mixed with a bronchodi lator to prevent chest tightness. The two most commonly used nebulised antibiotics in the U K are colisitin and tobramycin solution for inhalation (TOBI). Large multicentre clinical s tudies have demonstrated improvements in pulmonary function and reduction in hospitalisatio ns with use of TOBI in a cycle of 4 weeks on/4 weeks off treatment regimen for patients wit h chronic P. aeruginosa infection and FEV1 between 25 \200\22375% predicted. Although clini cal trial evidence is less robust for the use of nebulised colisitin, there is substantial clinical experience with the use of inhalation or this antibiotic at European CF centers th e over many years of that has proved to be a safe and effective therapy for patients with c hronic P. aeruginosa infection. CHAPTER 11.3 Chronic disease management 245 glucose control, and cataract formation, will usually out- weigh the potential bene \201 t s. Oral antibiotics Anti-staphylococcal therapy Although there is some limited evidence of ben e \201 t from the use of chronic oral anti-Staphylococcal antibiotics in early childhood, there is no evidence that such treatment should be continued in later childhood and adultho od. Other drug treatments Inhaled bronchodilators Inhaled and nebulised bronchodilators can giv e sympto- matic relief, and improve airway clearance. Macrolide antibiotics Long-term treatment with an oral macrolide antibiotic has become an i mportant part of the treatment regimen for most patients with CF. Studies have demonstrated improvements in lung function, decreased need for hospitalization and IV antibiotics asso- ciated with the use of regular oral macrolide therapy for patients with CF. The most commo nly used macrolide in clinical trials has been azithromycin, although the optimal dose and fre- quency still remains unclear. The mechanism of action, whether it is antibacterial, an ti- in \202 ammatory, or another property of the drug remains unclear. Theophylline Oral theophyllines can improve sputum clearance through bronchodilation and ef fects on sputum viscosity. Recombinant human deoxyribonuclease (DNase) (dornase alpha) Nebulised recombinant human deo xyribonuclease reduces the viscoelasticity of CF sputum by degradation of extra- cellular D NA within CF mucus. It can improve lung function and reduce exacerbations. There is good ev idence for bene \201 t in patients with moder- ate and severe lung disease and some eviden ce of bene \201 t in mild asymptomatic patients. Hypertonic saline There is evidence of reduced respiratory exacerbations, improvement in pu lmonary function and increased muco- ciliary clearance with use of 7% hypertonic saline in patients with CF. Side effects are cough and bronchospasm. Patients should be pre-treated w ith a bronchodilator and an initial test dose should be administered under close supervisio n by an experienced physiotherapist. Anti-viral drugs Treatment with oseltamivir, a viral neuraminidase inhibitor, should be com menced immediately if within 48 hours of start of symptoms of suspected in \202 uenza infe ction. Oseltamivir can also be given as post-exposure prophylaxis for patients in close con tact with someone suffering from an in \202 uenza illness. Anti-in \202 ammatory therapy As the excessive airway in \202 ammatory response in CF pla ys a major role in the pathogenesis of CF lung disease, anti- in \202 ammatory therapies h ave been explored as part of the treatment strategies for CF lung disease. However, the mos t effective anti-in \202 ammatory agent for CF lung disease is an oral macrolide, as outli ned in the previous section. N-acetylcysteine There is no evidence that use of oral or nebulsied N-acetylcysteine is ben e \201 cial in patients with CF. Sodium chromoglycate There is no evidence that use of inhaled sodium chromo- glycate is ben e \201 cial in patients with CF. NSAIDs There are a small number of North American CF Centers that advocate use of NSAIDS as chronic anti-in \202 ammatory therapy for CF lung disease. Ibuprofen has a narrow therape utic window, and is asso- ciated with potential side effects, in particular gastro- intesti nal bleeding and renal problems. Measurement of serum levels is necessary, but this testing is not widely available. However, outside of a minority of North America CF Centers there is little enthusiasm for use of NSAIDS in CF lung disease. Other therapies Exercise Regular cardiovascular exercise improves lung function, exercise c apacity and well-being and should be actively encouraged as part of the regular therapy for adults with CF. Exercise programs should be tailored to the individual patient to take int o account patient preference, severity of lung disease, associated comorbidities (such as l ow bone mineral density and diabetes mellitus), and general level of \201 tness. Use of s upplemental oxygen may be necessary to maintain exercise capacity. Inhaled corticosteroids Although widely prescribed, the role of inhaled steroids in the man agement of CF lung disease is unresolved. Inhaled steroids can help the bronchial hyper-rea ctivity that accompanies CF. Some small studies have suggested clinical bene \201 ts form inhaled steroids in CF lung disease, however, a recent multi-center UK study showed no adve rse effects from withdrawal of inhaled corticosteroids in adults with CF. Airway clearance Each patient should be taught airway clearance techniques as part of their self-care package by a physiotherapist experienced in CF care. Various techniques are avai lable, including active cycle of breathing technique, autogenic drainage, high frequency ch est wall compression, high frequency oscillation, oscilla- tory positive expiratory pressur e, positive expiratory pres- sure, postural drainage and percussion. Studies have not demon strated any technique to be superior to another. The airway clearance technique regimens us ed by a patient should be tailored to the individual patient with advice from an experience d physiotherapist. Oral corticosteroids There is some evidence that oral corticosteroids may slow the rate of progression of CF lung disease. However, for the majority of patients the possible side eff ects of treat- ment, such as reduction in bone mineral density, abnormal A JONES & K WEBB 246 Non-invasive ventilatory support Non-invasive ventilatory support was traditionally used in CF lung disease as a bridge for hypercapnic patients to lung transplantation. However, it can improve symptoms, exercise capacity and respiratory function and should be considered a t a much earlier stage for all patients with daytime hypercapnia. Flying and holidays Patients deemed to be at respiratory risk from the lower partial pressu re of inspired oxygen in \202 ight, should be advised to use supplemental oxygen during t he \202 ight. An in- \202 ight oxygen assessment test using FiO2 15% should be arranged for patients with moderate or severe lung disease who are planning an aircraft \202 ight. The in \202 ight risk should be assessed by a clinician experi- enced in CF taking into c onsideration the result of the 15% normobaric oxygen challenge together with the patient \200\231s FEV1 and recent clinical status. Patients should be given course of emergency ora l antibi- otics to start immediately if they develop an infective exac- erbation whilst on holiday and instructions to seek medical attention. They should be provided with a letter d etailing their current medial condition and medication, and a treat- ment protocol if they present to a medical center with little experience of CF care. Supplemental oxygen The oxygen requirements of patients with CF should be assessed on a reg ular basis. For many patients with CF, supplemental oxygen will be required to relieve brea thlessness and keep the patient ambulatory. Smoking cessation Smoking history should be explored for all patients. Smokers should be co unseled and smoking cessation treatment implemented accordingly. Gastro-intestinal re \202 ux The contribution of gastro-intestinal re \202 ux should be c on- sidered in patients whose respiratory symptoms are not responding to conventional treat ment for CF lung disease. Lung transplantation Bilateral lung transplantation can further improve the sur- vival and quality of life for patients with end-stage CF lung disease. Indications for referral inclu de FEV1 below 30% predicted, a rapid decline in FEV1, increased need for oxygen therapy and /or non-invasive ventilation, pulmonary hypertension, poor quality of life and increasingly frequent exacerbations despite optimal medical treatment. A chronic shortage of donor orga ns means that there is usually a considerable waiting time for patients with CF between lis ting and receiving a lung transplant, and 30 \200\22340% of patients still die whilst await ing transplantation. Haemoptysis Chronic haemoptysis can be a frequent complication in adult patients with CF, o ften in association with infective exacerbations. Investigations should include a coagulati on screen and a platelet count. Vitamin K supplementation (phytomenadione 10mg OD) should b e given to patients with chronic haemoptysis. Tranexamic acid (500 \200\2231000mgs QDS) can be helpful in lim- iting haemoptysis. Consideration should be given to discontinuing DNase until the haemoptysis abates. A large haemoptysis (>300ml fresh blood) is a medical emerge ncy (see Chapter 11.2). Respiratory complications Antibiotic allergy Antibiotic allergies are more common in adults with CF. Antibiotic desensitization should be considered under hospital supervision when a llergies limit treatment options. Allergic bronchopulmonary aspergillosis (ABPA) Patients with CF are at increased risk for d evelopment of ABPA. The underlying clinical features of CF lung disease often makes ABPA di f \201 cult to diagnose in this group of patients. Features suggesting ABPA include asthma -like symptoms, new CXR changes, raised eosinophil count, raised total and aspergillus spec i \201 c IgE, positive aspergillus precipitins, or positive skin test to aspergillus. Trea tment options include oral corticosteriods and/or an anti-fungal agent with activity agains t Aspergilllus species, of which the most commonly used is itraconazole. Itraconazole level s should be measured and liver function tests checked. Intravenous access/totally implantable IV access devices Totally implantable IV access devi ces can be a useful aid for patients with dif \201 cult venous access or those requiring f re- quent courses of IV antibiotics. The use of these devices requires expert care to preve nt complications such as infection that invariable necessitates removal of the line, or occ lusion. Other complications include line displacement, leakage and venous occlusion. Nutrition The nutritional status of a patient with CF in \202 uences their lung function a nd susceptibility to infective exacerbations. For patients with undernutrition, enteral fee ding can improve and stabilize lung function and reduce exacerba- tions. Cystic \201 brosis related diabetes mellitus (CFRD) Poor glycaemic control affects sputum viscosity and exac- erbates CF lung disease. There can be an accelerated decline in lung f unction even for the year or so prior to the advent of clinical CFRD. An unexplained declin e in lung function should trigger close testing for dysregulation of glucose control. Treatment adherence The CF MDT should monitor adherence with treatment regimens and provide encouragement to the individual patients with their treatment. The CF MDT should continuou sly assess the patients \200\231 care package, trying to minimize the treatment burden whil st controlling symptoms and preventing disease progression. CHAPTER 11.3 Chronic disease management 247 Varicella-zoster pneumonia In cases of chickenpox, patients with CF are at risk of developi ng varicella pneumonia. Treatment with acyclovir should be commenced immediately. Support group Cystic Fibrosis Trust, 11 London Road, Bromley, Kent BR1 1BY. Tel 020 8464 72 11, Fax 020 8313 0472, e-mail enquir- ies@cftrust.co.uk, website www.cftrust.co.uk Further reading Antibiotic treatment for cystic \201 brosis. Cystic Fibrosis Trust, 2002. Methicillin-resistant Staphylococcus arteus (MRSA). Cystic Fibrosis Trust, 2008. Clinic guidelines for the physiotherapy management of cystic \201 brosis. Cystic Fibrosis Trust, 2002. Pseudomonas aeruginosa infection in people with cystic \201 brosis: sug- gestions for pre vention and infection control. Cystic Fibrosis Trust, 2004. Fig. 11.3.2 Mucoid Pseudomonas aeruginosa. Standards of clinical care of children and adults with cystic \201 brosis in the UK. Cystic Fibrosis Trust, 2001. The Burkholderia cepacia complex: suggestions for prevention and infection control. Cystic Fibrosis Trust, 2004. Fig. 11.3.1 Typical CXR features of advanced CF lung disease and the presence of a totally implantable IV access device. H FIRTH & J HURST 248 11.4 Cystic \201 brosis genetics ZF508 as the other allele typically causes the much milder phenotype of CBAVD without respi ratory symptoms. Criteria for the diagnosis of CF (after Rosenstein and Cutting 1998) CF is the most common life-limiting autosomal recessive (AR) disorder in the white populati on. Three clinical phenotypes are associated with mutations in the CF transmembrane conduct ance regulator gene (CFTR) on 7q31 \200\22332. 1 Classical CF. Obstructive lung disease, br onchiectasis, exocrine pancreatic insuf \201 ciency, elevation of sweat chlo ride concentr ation (>60mM), and infertility in males due to congenital bilateral absence of the vas defe rens (CBAVD). Diagnosis requires at least one criterion from each group Group 1 \200 One or more characteristic phenotypic features (see below), e.g. chronic sinopulmonary dise ase, gastrointes- tinal and nutritional. Abnormalities, salt loss syndromes, and male uroge nital abnormalities, e.g. CBAVD. Sibling with CF. Positive neonatal IRT (immunoreactive try psinogen test). 2 Non-classical CF. Chronic pulmonary disease 9 pan- creatic exocrine disease elevated s weat chloride (>60 mM) CBAVD. \200 3 CBAVD. The incidence of CF in Caucasians of European extraction is 1/2000 \200\2231/4000 newborns (1/2500 in the UK). CF is rare in native Africans and Asians. The mutation spectru m and frequency are highly dependent on ethnic background. See Table 11.4.1 for the diagnos tic criteria for CF. More than 1000 mutations in CFTR have been identi \201 ed (see Table 11.4.2), of which the most common by far is delta F508 (ZF508). ZF508 encodes a three-nucle otide deletion resulting in a CFTR protein lacking phenylalanine (F) at postion 508 in the protein. This causes misfolding of the newly synthesized mutant CFTR so that it does not in tegrate into the cell membrane, but remains in the cyto- plasm where it is degraded by the ubiquitin \200\223proteosome pathway. ZF508 accounts for 70% of CF alleles, but the exact proportion varies depending on ethnic origin. The next most common mutations are G542X, G55 1D, delta1507, W1282X, and N1303K, each accounting for only 1 \200\2232.5% of known CF alle les. W1282X is common in the Ashkenazi Jewish population. Standard commercial kits for DNA diagnosis usually identify 29 mutations. In the English population this accounts for 87% of CF alleles. Thus, using a standard screen, 76% of English patients with CF will have two identi \201 able CFTR mutations, 22% will have a single identi \201 able CF mutation, an d 2% of patients with CF will have no identi \201 able mutation. Specialist labs may offer rare mutation screens. Polythymidine (Poly-T) tracts in intron 8 affect the splicing ef \201 ciency of a CFTR allele. The most ef \201 cient polymor- phism is 9T, 7T has reduced ef \201 ciency, and 5T has signi \201 - cantly reduced ef \201 ciency. R117H in cis with 5T, with ZF508 as the other allele, usually results in non-classical CF (pan- creatic suf \201 cient), whereas R117H in cis with 9T with Group 2 \200 Sweat chloride >60mM on 2 occasions ( \211 75mg of sweat is critical to reliability). Some laboratories assay sweat osmolality which is increased in CF (normal range is 62 \200\22319 6mOsm/kg) Identi \201 cation of 2 CF mutations Abnormal nasal potential difference (measur e of CFTR- mediated ion transportation) \200 Phenotypic features consistent with diagnosis of CF (after Rosenstein and Zeitlin 1998) \200 Chronic sinopulmonary disease. Persistent colonization with typical CF pathogen (Staphyloco ccus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia), chronic cough and sputum pro- duction, persistent CXR abnormalities (bronchiectasis, atelectasis, in \201 ltrates, hyperin \202 ation), airway obstruction (wheezing and air trapping), nas al polyps, X-ray or CT abnormalities of paranasal sinuses, clubbing Gastrointestinal and nu tritional abnormalities. Meconium ileus (10 \200\22320%), rectal prolapse (20%), distal int estinal obstruction, pancreatic insuf \201 ciency, recurrent pancrea- titis, focal biliary cirrhosis or multilobular cirrhosis, failure to thrive (protein \200\223calorie malnutriti on), hypopro- teinaemia and oedema, complications secondary to lack of fat-soluble vitamins Salt loss syndromes. Acute salt depletion, chronic metabolic acidosis Male urogenital abno rmalities resulting in obstructive azoospermia. CBAVD. Table 11.4.1 Functional classi \201 cation of CFTR alleles (after McKone et al. 2003) Alle le Class G542X, R553X, W1282X, R11162X, 621 \200\2231G l T, 1717 \200\2231G l A, 1078ZT, 36 59ZC ZF508, Z1507, N1303K, S549N G551D, R560T Functional effect of mutation I Defective protein production II Defective protein processing III Defective protein regulation IV* Defective protein conductance R117H, R334W, G85E, R347P 3849 +10 kbC l T,2789+5G l A, A455E 711+1G l T, 2184DA, 1898+1G l A V* Reduced amounts of functioning CFTR protein Unknown Compared with class II (including ZF508 homozygotes). classes IV and V have a signi \201 c antly lower mortality rate and milder clinical phenotype. See http://www.genet.sickkids.on. ca/cftr for the Cystic Fibrosis Analysis Consortium CF mutation database. CHAPTER 11.4 Cystic \201 brosis genetics 249 Clinical approach History: key points \200 \200 unidentified allele(s) and enable prenatal diagnosis. Pre-implantation genetic diagnosis (P GD) for ZF508 homozygotes is available in some centers. Three-generation family tree. Genotype of affected individual if known. Predictive testing This may be applicable in younger siblings of a child recently diagnosed with CF, in view of the bene \201 ts of treatment with prophylactic antibiotics and pancr eatic and vitamin supplements. Examination: key points Usually not relevant if affected individual is under the care of CF pediatrician/physician or you are seeing another family member. Other family members When an individual is diagnosed with CF, and mutation analysis is perf ormed, it is routine practice to offer carrier testing to both parents. Cascade screening o f the extended family for the mutation identi \201 ed in their relative can then be offere d. Where an individual is shown to be a CF carrier, population-based screening (see Table 1 1.4.2) can be offered to his/her partner to determine the risk to their offspring. Carrier testing of children is usually deferred until 16 years when they are of an age to be involv ed in decision-making and old enough to understand the implications of the result. Investigation DNA sample for mutation analysis of CFTR. Genetic advice Inheritance and recurrence risk \200 Autosomal recessive (AR) and so the recurrence risk to parents of an affected child=1/4. Th e following recur- rence risks are based on pedigree analysis and assuming no consanguinity , no family history of CF in a partner, and a CF carrier rate of 1/23 (see below for carrie r rates in different ethnic groups). This risk estimate can be sub- stantially modi \201 e d by CF mutation analysis in the relative and his/her partner (see below). Risk to offsprin g of healthy sib of an affected child is 2/3 \2271/23 \2271/4=1/138. Risk to offspring of a unt/uncle or half-sib of an affected child is 1/2 \2271/23 \2271/4=1/184. Risk to offspring of an affected individual is 1 \2271/23 \2271/2=1/46. Table 11.4.2 Carrier rates and mutation detection rates in different ethnic populations Population Carrier frequency Mutation detection rate with panel appropriate to ethnic group (%) Ashkenazi Jewish 1 in 23 97 Northern European 1 in 23 90