The hypoxia also raises the pulmonary artery pressure (PAP), but to modest levels for which the RV can easily compensate, particularly if it builds up slowly. Loss of pulmonary vascu lar bed from emphysema will also raise PAP. The ECG often shows right ventricular hypertrop hy. During an COR PULMONALE 203 exacerbation, extra hypoxia will produce further rises in PAP with which the RV usually cop es, helped by the raised JVP providing a larger pre-load to increase RV \201 lling. Exces sive diuresis can lead to a true fall in right-sided output due to inadequate \201 lling of the RV. Clinical features \200 \200 \200 The underlying disease causing the hypoxia, e.g. COPD/bronchiectasis Easily visible veins a nd a raised JVP Cyanosis and a suffused conjunctiva (polycythaemia and vessel dilatation fr om the raised CO2) Peripheral vasodilatation with a full \200\230bounding \200\231 pulse A nkle swelling and pitting oedema Right ventricular hypertrophy (sternal heave uncommon, mas ked by hyperin \202 ated lung between heart and chest wall; more often seen with the highe r pressures of IPAH) Tricuspid incompetence (not usually severe). \200 \200 Investigations \200 \200 \200 \200 CXR \200\224enlarged pulmonary arteries/underlying lung disease FBC \200\224may have associ ated polycythaemia Oximetry \200\224cor pulmonale is unlikely if awake SaO2 over 92% Blood gasses \200\224cor pulmonale progressively more likely as PaO2 drops below 8 kPa (equivalen t SaO2 8 91%), and PaCO2 rises above 6 kPa ECG \200\224may indicate right axis deviation, p pulmonale (right atrial hyper- trophy), and right bundle branch block Echo \200\224dilated or hypertrophied RV, tricuspid regurgitation, estimate of PAP, and exclude other diagnoses such as a patent ASD Overnight oximetry \200\224to reveal unexpected degrees of hypoxia, e .g. from OSA or diaphragm paralysis. Management Minimal ankle oedema needs no treatment. \200\230Trimming \200\231 the ankles t o normal is unnecessary and may reduce RV output by reducing \201 lling. If the oedema is more substantial then the following may help: \200 \200 \200 Treat underlying condition to raise PaO2 and lower PaCO2 Raise PaO2 through added oxygen, p rovide long-term oxygen at home In hypoventilation syndromes, home overnight NIV likely to be the correct management Promote a limited diuresis with judicious use of diuretics Always elevate legs when sitting. \200 In general, \200\230cor pulmonale \200\231 is over-treated. It is usually a relatively har mless by-product of hypoxia, rather than a problem in its own right. Treating the blood gas disturbance, and making it easier for the patient to get his shoes on, are the main therap eutic aims. The long-term oxygen trials showed that improving the PaO2 was useful, not that lowering the pulmonary artery pressure was important. Further information Stewart AG et al. Hormonal, renal, and autonomic nerve factors involved in the excretion of sodium and water during dynamic salt and water loading in hypoxaemic c hronic obstructive pulmonary disease. Thorax 1995; 50: 838 \200\22345 This page intentionally left blank 205 Chapter 24 Cystic \201 brosis General principles 206 CF pulmonary sepsis: etiology 208 CF pulmonary sepsis antibiotics: 1 210 CF pulmonary sepsis antibiotics: 2 212 IV antibiotic administration 214 Management of an exacerbation 216 Other pulmonary interventions 218 Other pulmonary disease 220 Non-pulmo nary disease 222 Other issues 224 Seeing the patient with CF in clinic 226 206 CHAPTER 24 Cystic \201 brosis General principles De \201 nition and pathophysiology \200 Multisystem disease due to mutations in the gene encoding for the cystic \201 brosis tran smembrane conductance regulator (CFTR), a complex chloride channel CFTR is essential for re gulating salt and water movement across membranes Faulty regulation causes viscous secretio ns In the lungs, these secretions result in colonization with pathogenic bacteria, causing a massive in \202 ammatory response, including elastase release. This contributes to lung damage and subsequent development of irreversible bronchiectasis In the pancreas, the exocr ine ducts become blocked by secretions, leading to pancreatic enzyme insuf \201 ciency, pa ncreatic destruction, and diabetes mellitus. \200 Genetics \200 \200 \200 Autosomal recessive Gene found on the long arm of chromosome 7 Carrier frequency of this ge ne in Caucasians 1 in 25. 1 in 2500 UK live births have cystic \201 brosis CF is rare in Afro-Caribbeans, but is seen in patients of Asian origin in the UK and USA Heterozygote adv antage through resistance to E. coli diarrhea and cholera has probably led to persistence o f CFTR mutations, despite the lethal homozygous form More than 1500 different mutations in the CFTR gene are recognized to cause clinical disease The most common mutation is ZF508, w hich accounts for around 67% of CF alleles in the UK and northern Europe. This is a deletio n of 3 nucleotides resulting in the omission of a single amino acid, phenylalanine, at the 508 residue 13 other mutations have a frequency of greater than 1%, accounting for 85% of C F alleles altogether. These can be effectively screened for. They include G542X (3.4%), G55 1D (2.4%), W1282X (2.1%), and 3905insT (2.1%) Different mutations may be associated with pa rticular clinical sub- groups. The phenotype \200\223genotype relationship is closest for p ancreatic disease Non-CFTR \200\230modi \201 er \200\231 genes (such as TNFA, mannose bin ding lectin, and A1-antitrypsin), as well as environmental factors, probably further in \202 uence the clinical picture and account for phenotypic variation. Screening In the UK, neonatal heel-prick for immunoreactive trypsin measurement is now offe red routinely as part of a new national screening program. Prenatal second trimester fetal ultrasound may identify pre- sence of echogenic bowel, which can occur in CF. These babies are then screened at birth. Those with relatives with CF are advised to have pre- conceptio n CF genotyping, as are the partners of a patient with CF. GENERAL PRINCIPLES 207 Diagnosis Patients are usually diagnosed with CF as neonates or children (genetic screening , family history, failure to thrive, meconium ileus, rectal prolapse, cough, recurrent ches t infections). Diagnosis is based on compat- ible clinical \201 ndings, with biochemical or genetic con \201 rmation. The sweat chloride test is an important laboratory test, part icularly in children. Some patients are diagnosed with CF in adult life. They usually have different alleles leading to a milder phenotype. Management The ongoing care of CF patients moves to the adult CF center around the age of 16 \200\22318 (often when the patient leave s school), although a period of transitional care may occur between ages 14 \200\22316. A m ultidisciplinary team approach is recommended, consisting of respi- ratory physician, speci alist nurse, physiotherapist, pharmacist, dietician, and psychologist, with regular additio nal input from gastroenterology and endocrine teams. This transition can be a dif \201 cult time, as the patient begins to take more responsibi lity for their care and treatment. Some may have periods of rebelling, not taking medicatio ns or performing physiotherapy, despite recognizing the need to do so. Improved treatment and nutrition of CF patients has led to an increase in median survival, to around 30 years. The predicted lifespan for a baby born with CF now is 42 years. The main management issues for the adult CF patient are: Lung disease \200 \200 Maintaining lung function Monitoring lung bacteriology, including screening for multi-resis tant and transmissible organisms Consideration of referral for heart \200\223lung or liver transplant, if and when appropriate Nutrition \200 GI \200 Endocrine \200 \200 Fertility advice Ensuring psychosocial w ell-being. Nutritional support, weight, enzyme replacement, vitamins Annual screening for biliary cirrhosis and portal hypertension Annual screening for CF-related diabetes (CFRD) Annual screening for osteoporosis \200 208 CHAPTER 24 Cystic \201 brosis CF pulmonary sepsis: etiology Chronic pulmonary sepsis and its complications cause 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 estab- lished by a young age (around 5 years). \200 Patients commonly expectorate variable volumes of purulent sputum, even when well When orga nism levels are high, patients may feel generally unwell or more tired, or have anorexia, w eight 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 FEV1 levels are a reliable marker of infection and tend to decrease by \211 10 % 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 organ isms should be considered In practice: the FEV1 is the best marker of disease progression a nd can be used to assess overall decline, as well as to determine an exacerba- tion and res ponse 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. Goals o f management should be initially to prevent infection, then to eradicate it, and \201 nal ly to control the infection. Material for culture should be collected; most com- monly sput um, but BAL if necessary. Polymicrobial infection is common. \200 Typical progression of organism colonization with time is: Staphylococcus aureus Haemophilu s in \202 uenzae Pseudomonas aeruginosa worsens lung function and CXR appearance. Most pat ients with CF are chronically infected with Pseudomonas by their early teens. Non-mucoid sp ecies colonize initially and these may be asymptomatic or intermittent. These can be eradic ated. Mucoid species then follow and permanent eradication is rare. Decreasing the Pseudomo nas load produces clinical bene \201 t. \200 \200 Other organisms \200 Stenotrophomonas maltophilia Gram-negative bacteria, often with multiple antibiotic resista nce Burkholderia cepacia complex There are at least 10 different strains, or genomovars, of Burkholderia cepacia. Some are associated with a worse clinical outcome and some are not. These organisms are resistant to many antibiotics. It is crucial that Burkholderia cepacia colonized patients are separated from non-colonized patients, as the organism is highly tra nsmissible. This means separate clinics, separate spirometers, and side rooms on a differen t ward are necessary. \200\230Cepacia syndrome \200\231 is the severe worsening of pulmona ry infection with septicaemia, CF PULMONARY SEPSIS: etiology 209 which can be rapidly fatal. This is caused by one strain, genomovar III, or Burkholderia ce nocepacia. CF patients infected with this strain are usually not accepted for transplant, a s studies have shown they do less well. MRSA NTM \200 Respiratory infections u age 100 P.aeruginosa 80 e g a t n e c r e P 60 S.aureus 40 H.influenza MRSA 20 S.maltophilia B.cepacia 0 0 to 1 45 + 25 to 34 35 to 44 2 to 5 6 to 10 11 to 17 18 to 24 Age (years) Fig. 24.1 Prevalence of selected respiratory pathogens in patients with CF over time. (From Goss Thorax 2007; 62: 360 \200\2237.) Reproduced with the permission of the American Socie ty for Microbiology. Further information Goss CH. Exacerbations in cystic \201 brosis. Thorax 2007; 62: 360 \200\2237 210 CHAPTER 24 Cystic \201 brosis CF pulmonary sepsis antibiotics: 1 Antibiotic courses in patients with CF need to be longer and at higher doses than in non-CF patients. The choice of antibiotics is based on clinica l response more than in vitro resistance patterns, but recent sputum culture results will a lso guide therapy. If Pseudomonas has previously been isolated, it may need to be covered i n the current antibiotic regime. \200 In practice, be guided by the last sputum culture r esult \200 It is usually appropriate to give the patient the same regime they had during their last exacerbation, provided there was a good clinical response Microbiology advice sh ould be sought if necessary. Staphylococcus aureus A signi \201 cant pathogen causing exacerbations. Prevention and era dication are important, even if the patient is asymp- tomatic. In adults, a minimum of 2 we eks of treatment should be given when Staphylococcus aureus is cultured, with \202 ucloxa cillin, erythromycin if penicillin-resistant, tetracycline, sodium fusidate, rifampicin, or clindamycin. There is no published evidence that long-term treatment in adults has any add itional bene \201 t. Haemophilus in \202 uenzae When isolated (usually in young children) should be treated wit h amoxicillin, co-amoxiclav, second-generation cepha- losporin, tetracycline, or chloramphe nicol (toxicity risk), even if the patient is asymptomatic. Pseudomonas aeruginosa \200 Oral antibiotics The Pseudomonas colonized patient who develops a mild exacerbation should receive 2 weeks of an oral quinolone (such as cipro \202 oxacin), as well as their usual n ebulized colistin. There are problems with resistance, so therefore should not be used more frequently than every 3 months. IV antibiotics Should be used when oral and nebulized trea tments have failed, or patient is unwell. An aminoglycoside plus a B-lactam are given, whic h have a synergistic effect when used in combination. Treatment should be for a minimum of 10 days. Once or twice a day aminoglycoside dosing is used in many centers (5 \200\2237 mg/ kg), rather than tds, providing high ef \201 cacy and fewer toxic effects (Nicolau DP et a l. Antimicrob Agents Chemother 1995; 39: 650 \200\2235). Drug levels should be checked befo re and 1 h after the third dose, and adjusted if necessary. Bacterial toxicity is achieved by the high peak and safety is ensured by low trough. Renal function should also be checked during the IV course. Local policies may vary on frequency of checking. Some centers, espe cially in northern Europe, recommend that patients with chronic Pseudomonas colonization sh ould receive 2 weeks of IV anti- biotic therapy every 3 months routinely. This policy is no t widely adopted in the UK, although, as the threshold for starting treatment is low, the n umber of antibiotic courses is similar using both regimes. \200 Aerosol anti-pseudomonal antibiotics Once the patient is chronically Pseudomonas colonized, twice daily nebulized colistin is used long-term (1 \200\2232 mega units bd in 3 \200\2234 mL saline after physiotherapy) to try and minimize Pseudomonas levels. If colistin causes wheezing, it can either be given in 6 mL saline or reconstituted with 3 \200\2234 mL water for injection CF PULMONARY SEPSIS ANTIBIOTICS: 1 211 or salbutamol added. The nebulizer used should have a one-way valve in the exhaust tubing a nd this tubing should be vented to the outside. If colistin is not tolerated or is ineffect ive, aminoglycosides designed for IV injection can be tried (e.g. gentamicin 40 or 80 mg bd , made up with saline to 4 ml). Neither gentamicin or tobramycin are licensed for this use. A new preservative-free form of tobramycin (TOBI) has been developed and licensed for nebu lization; it has been found in studies to improve pulmonary function and increase weight ga in. Although it is expensive, it is becoming established in long-term management of CF pati ents in the UK. Administer all via nebulizer with exhaust tubing vented to outside as above . First isolate of non-mucoid Pseudomonas should be treated aggres- sively with 4 \200\2236 weeks of oral cipro \202 oxacin 750 mg bd and concurrent 6 weeks of nebulized colistin 1 mega unit bd. 80% of newly infected patients have Pseudomonas eradicated by this regime. If this is not successful, they should have IV therapy with 2 drugs and nebulized colistin. Satisfactory aminoglycoside levels \200 \200 od regime: trough <1 mg/L and repeat in the \201 rst week tds regimes: \200 \200 gentamicin/tobramycin: pre 1 \200\2232 mg/L, post 9 \200\22312 mg/L amikacin: pre <10 mg/L, post 28 \200\22332 mg/L Any reports of dizziness or balance problems may suggest early ototoxicity. This must be ta ken seriously as there is a cumulative dose effect. The aminoglycoside should be stopped an d ENT referral made for middle ear testing. Gentamicin and tobramycin, 7mg/kg Recommended interval to next dose 14 13 12 11 10 9 8 7 6 5 4 3 2 L / g m n o i t a r t n e c n o c d o o B 48h 36h 24h l 6 7 8 9 10 11 12 13 14 Hours between gentamicin dose and blood sample taken Fig. 24.2 Gentamicin and tobramycin dosing algorithm. Reproduced with the per- mission of t he BMJ (Antimicrodial Agents and Chemotheropy, Mar. 1995, p 626 \200\22331). 212 CHAPTER 24 Cystic \201 brosis CF pulmonary sepsis antibiotics: 2 Burkholderia cepacia is characteristically resistant to antibiotics, including colistin and aminoglycosides. Conventional IV therapy may be effective. Should be treated with combinat ion of 2 \200\2233 IV antibiotics, such as ceftazidime and an aminoglycoside. Possible syne rgistic combinations are chloramphe- nicol and minocycline, chloramphenicol and ceftazidime , or a quinolone with a B-lactam/carbopenem. Co-trimoxazole also used. MRSA is not more pat hogenic than Staphylococcus aureus. Nebulized vancomycin can be used for persisting sputum colonization, but IV vanco- mycin or teicoplanin are required for MRSA exacerbations. Oral rifampicin, sodium fusidate, or linezolid may be bene \201 cial. Macrolides have additional anti-in \202 ammatory effects, as well as anti- microbial effec ts. They do not exhibit intrinsic anti-pseudomonal activity, but there is in vitro synergy between macrolides and anti-pseudomonal antibiotics. They also seem to improve clinical sta tus compared with placebo or other antibiotics. This is seen with erythromycin, but espe- c ially azithromycin, which decreases sputum viscoelasticity and affects the bio \201 lm for med by Pseudomonas. It is administered either once daily or three times a week, e.g. at dos e of 250 mg/day with LFT monitoring, and has been found to improve FEV1 and decrease exacer bations when used over 6 months. Larger trials are needed to assess its long-term effects. Southern KW. Azithromycin for CF. Eur Respir J 2004; 24: 834 \200\2238 Further Information CF Trust. Antibiotic Treatment for Cystic Fibrosis, 2nd edn, 2002. This page intentionally left blank 214 CHAPTER 24 Cystic \201 brosis IV antibiotic administration \200 If patients are unwell or if they are commencing a new antibiotic, they should be admitted to hospital. Otherwise the majority of IV antibiotic courses can be administered at home, a fter an initial assessment and with home support from nursing staff. Many patients are rela tively well during courses of IV antibiotics and are able to continue attending work or col lege, although it can take them considerable extra time to administer the antibiotics Cours es of IV antibiotics are often administered prophylactically before surgery Most antibiotic regimes involve two weeks of IV antibiotics. This may require the siting of an intravenous cannula with a microbiological \201 lter (to make it last longer), or preferably a long- line Many patients have an indwelling port-a-cath that can be accessed when required Review patients after 1 week of treatment to ensure there is adequate clinical progress. If there is no improvement, review microbiological sensitivities and change treatment as appropriat e. Port-a-caths \200 Inserted in patients with dif \201 cult IV access, or those needing frequent courses of IV antibiotics Usually accessed/needled by a trained nurse, patient, or family member. Should be accessed only with a Huber point needle of the appropriate length; do not use standard needles, which may damage the port Should be \202 ushed with 5 \200\22310 mL of 100 u/mL heparin monthly and with 5 mL of 10 U/mL heparin at the end of each IV dose Avoid taking bl ood from port-a-cath as this increases the risk of blockage and infection. Other complicati ons include venous obstruction, tip dislocation, and leakage If port-a-cath blocks: inject 20 \200\22350 mL heparinized saline; gently alternating between irrigation and aspiration m ay clear small occlusions. Urokinase 25 000 units in 3 mL 0.9% saline instilled into port m ay help a blockage Infected or fractured lines need removal by surgeons. Antibiotic desensitization Antibiotic sensitivity is a major problem in patients with CF as repeated antibiotic courses are associated with the development of allergic reactions, esp ecially to B-lactams. Rashes are common, but anaphylaxis can occur. Document any drug react ions, provide an adrenaline pre- \201 lled syringe, and give \201 rst doses of a new ant i- biotic in hospital. Desensitization regimes can be helpful and are used for speci \201 c antibiotics that have previously caused an allergic reaction. Such regimes need to be giv en at the start of the antibiotic course each time it is used, and during the course if dos es are missed for more than one day. Give a dilute antibiotic dose over 20 min, followed by slightly stronger concentration, and repeat for 7 concentration strengths until full antib iotic strength is given. Takes 3 \200\2234 h. Stop infusion if any side-effects are noted. Local policy may advise another desensatization regime. This page intentionally left blank 216 CHAPTER 24 Cystic \201 brosis Management of an exacerbation Diagnose an exacerbation on 2 \200\2234 of the following: \200 \200 \200 \200 \200 \200 \200 \200 Increase in productive cough or dyspnoea Change in appearance or volume of sputum New signs on auscultation New CXR signs Decreased appetite Fall in respiratory function Fever 10% fa ll from baseline FEV1. Most patients with CF will know when they need antibiotics for an exacerbation. Investigations \200 \200 \200 \200 \200 \200 FEV1 Oxygen saturation Blood gasses CXR \200\224exclude pneumothorax CRP \200\224relatively non-speci \201 c, but can be a useful monitoring tool Repeat sputum M, C & S, AFBs. Consi der Aspergillus precipitins. Treatment with appropriate antibiotics, O2, physiotherapy, nutrition, NIV, consider ITU/res uscitation status if necessary \200\224liaise with CF consultant. This page intentionally left blank 218 CHAPTER 24 Cystic \201 brosis Other pulmonary interventions Physiotherapy Dedicated CF physiotherapists aim to teach effe ctive airway clearance. This improves secretion clearance, decreases air \202 ow obstructi on, and improves ventilation. Patients should do this themselves twice daily on a long-term basis. Several techniques are used: active cycle of breathing control (tidal volume breath ing, then deep inspiration, and passive expiration, followed by forced expiration to mobili ze secretions prior to coughing/huf \201 ng), autogenic drainage, with percussion if patie nts are not clearing their chest well, \202 utter devices, and positive expiratory pressu re mask. More intensive physiotherapy is administered during exac- erbations, by family and /or physiotherapist. Physiotherapists also have important role in assessment of functional ability with exercise testing and evaluating treatment and encouraging aerobic exercise. Re combinant DNase (dornase alfa or pulmozyme), a nebulized muco- lytic that cleaves DNA from dead neutrophils, decreasing sputum viscosity and aiding its clearance. It is recommended i n patients with an FVC >40% predicted, to improve pulmonary function. It is used once daily 2500 U via a speci \201 c nebulizer. It is only continued in patients who gain objec- tiv e bene \201 t, with improved lung function; for example, 10% improvement in spirometry and shuttle walk test. It is expensive and only effective in 30 \200\22340%. Hypertonic saline Use of regular inhaled hypertonic saline has been found to increase mucociliary transporta tion and hence decrease exacerbations and improve lung function. It is re-emerging as a the rapeutic aid to expectoration. Respiratory support Respiratory failure and cor pulmonale ca n occur with later stage disease. Home oxygen may be required. Nocturnal non- invasive vent ilation may be necessary as a bridge to transplant if the patient has chronic respiratory f ailure. If support is needed for acute dete- rioration related to infection with a major re versible component, this may be non-invasive initially, but the patient may need intubation and ventila- tion. Such decisions should be made with the patient, their family, and their CF consultant. These decisions can be dif \201 cult and factors, such as being on the tra nsplant list, may be relevant. Steroids Short oral courses seem to improve lung function, b ut side- effects, such as growth impairment, osteoporosis, diabetes, and cataracts, are sig ni \201 cant. They are used in ABPA, severe unresponsive exacerbations, and occasionally i n terminal care to improve the sense of well-being in a patient. Immunization Annual in \202 uenza, as well as pneumococcal vaccination. Transplant The role of transplantation in patients with CF is well estab- lished. Patients should be considered for transplant when t heir life expect- ancy is less than 2 years and their quality of life is severely impaired, despite optimal medical therapy. OTHER PULMONARY INTERVENTIONS 219 FEV1 \211 30% predicted or FEV1 >30% with rapid progressive deteriora- tion, e.g. increasi ng number of admissions, rapid fall in FEV1, massive haemoptysis Hypoxia (PaO2 <7.3 kPa) an d hypercapnia (PaCO2 >6.7 kPa) are associ- ated with <50% survival at 2 years without trans plantation, and so are useful guidelines, but patients should be referred for assessment on the basis of FEV1 criteria even in the absence of severe hypoxia/hypercapnia Young female patients with rapid deterioration have a poor prognosis and should be considered for early referral. Some patients do not want a transplant and full psychosocial assessments are necessary. Whi lst on the transplant waiting list, the patient should have optimal nutrition and physical care. Average waits are around 1 year and some patients will inevitably die on the waiting list. Bilateral lung trans- plant is usually the procedure of choice. Living-donor lobar tr ansplantation is also performed, particularly in children and small adults. Following trans - plantation, the main immediate problems are infection and acute rejection. Later, 40% of patients go on to develop bronchiolitis obliterans (see p 328). One-year survival following transplant is around 58%. 220 CHAPTER 24 Cystic \201 brosis Other pulmonary disease Pneumothorax The risk of spontaneous pneumothorax increases with ag e. It occurs in around 20% of male CF patients and slightly fewer females. It is associated with a poor prognosis. It should be managed according to the standard pneumothorax guideli nes (p 381), with initial aspiration if patient is not breathless and chest tube if this fa ils. The lung may take some time to rein \202 ate, and require prolonged drainage and suct ion. Continue physiotherapy during this. Persistent air leak may require surgical input, id eally with a limited procedure, such as local abrasion. Pleurodesis should be avoided if po ssible in those for whom future lung transplant is an option, as this can lead to increased bleeding when the pleura is dissected, but this is not an absolute contraindication. Liais e with the transplant center, as the transplant surgeon may want to perform the pleurodesis . Allergic bronchopulmonary aspergillosis (see p 466) Dif \201 cult to diagnose in CF as n early 50% of CF patients have Aspergillus hypersen- sitivity with positive skin prick tests and 25% have positive precipitins. The incidence is around 10%. Screened for annually and advised to avoid compost heaps and hay/stables. ABPA is indicated by: \200 Asthma-like sy mptoms with new CXR changes \200 Raised IgE >500 IU/L or IgE RAST \200 Eosinophilia >50 0/mm3 or \200 Hyphae in sputum. Treatment should be with oral steroids for 2 weeks and, if there is a clinical improvement, these should be continued at decreasing doses for 2 \200\2233 months. Intensive physiother apy is also an important part of the treat- ment regime. There is some trial evidence that antifungal agents, such as itraconazole 200 mg bd for 4 months, should be used in addition and may have a steroid-sparing role. Itraconazole can cause liver dysfunction, so monitor L FTs. Non-tuberculous mycobacteria (see p 518) Signi \201 cance is unclear and treatment ma y not produce a clinical bene \201 t. Should be screened for annually. If culture positive , repeat twice and consider 12 \200\22318-month course of antibiotics. CF \200\230asthma \200\231 Some CF patients have coexisting asthma and some have asthma-like symptoms of prol onged exhalation, wheeze, and crackles due to underlying lung in \202 ammation. This is di f \201 cult to diagnose, as these symp- toms and a variable PEFR are found in most CF pati ents, due to bronchial hyperreactivity. Occurs in 2 \200\22337% of patients. Bronchial hype rreactivity is found in at least 40% of patients with CF. There may be bronchodilator respo nsiveness, also bronchoconstriction after exercise or nebulized hypertonic saline. Treat wi th the standard asthma stepwise treatment: short-acting bronchodilator, inhaled corticoster oid, long-acting B2 agonist, theophyllines (which may aid mucociliary clearance), leukotrie ne receptor antagonist (limited evidence in CF, but may decrease eosinophilic in \202 am- mation), oral steroids. OTHER PULMONARY DISEASE 221 Haemoptysis Small volume haemoptysis is common, especially with concurrent infection and ad vanced disease. Check clotting and platelets; consider group and save. Stop NSAIDs, give IV antibiotics, vitamin K 10 mg od, and tranexamic acid 15 \200\22325 mg/kg/day in 4 divided doses. Massive haemoptysis (see p 43) >500 mL blood. Usually re \202 ects bron- chial artery blee ding and can be fatal. Needs in-patient support and monitoring. Cross-match blood. Sit upri ght and give ice-cold drink to cause pulmonary vasoconstriction. Nebulized adrenaline (5 \200\22310 mL of 1 in 10 000). Bolus dose of octreotide 50 g over 15 min, then octreotide infusion 400 g in 20 mL 5% dextrose at 2.5 \200\2235 mL per h. May require bron- chial a rtery embolization, bronchial artery ligation, or surgical resection. 222 CHAPTER 24 Cystic \201 brosis Non-pulmonary disease Nutritional management The maintenance of good nutrition corre- lates with survival. Nutrition is more problematic as respiratory disease progresses (raised bas al metabolic rate, increased work of breathing, ongoing infection, and in \202 ammation). Dietician input is crucial. High calorie, high protein diets are encouraged. Patients may n eed dietary sup- plements or, if necessary, supplemental overnight feeding via nasogastric tube or gastrostomy. Perform weight and body mass index measurements at the annual review. Aim for BMI >20. \200 Pancreatic enzyme supplementation to avoid high fecal fat/energy loss. The smallest dose of pancreatin, containing lipase, required to control steatorrhoea should be used. Typical pr eparations are Creon (contains lipase, protease, and amylase) 10 000, 25 000, or 40 000, taken pre-meals. Typically patients take 10 \200\22320 tablets per day. The dietician can e ducate patients to adjust the dosage according to the fat and protein content of each meal. Constant re-education is often required to optimize enzyme supplementation. High strength pancreatic enzyme preparations have been found to be associated with the development of col onic strictures, or \201 brosing colonopathy; hence maximum levels of lipase of 10 000 un its/kg/day have been recommended Vitamins Fat-soluble vitamins are not absorbed well in pat ients with CF and these need replacement. Vitamins A, D, and E should be started when pancr eatic insuf \201 ciency is diagnosed and vitamin K if there is evidence of liver disease, with prolonged prothrombin time. Vitamins should be taken at meal times with pancreatin. Vi tamin levels should be checked at annual review Salt tablets in hot weather, due to excessi ve losses in sweat. Gastrointestinal disease \200 Distal intestinal obstructive syndrome (DIOS)/abdominal pain (meconium ileus equivalent). B loating, abdominal pain, possible pal- pable caecal mass, and complete or incomplete intest inal obstruction. Abdominal X-ray shows empty colon and ileal distension with air- \202 ui d levels. Occurs secondary to dehydration, or rapidly increased doses of pancreatic enzymes . Rarely needs surgery. Medical treatment with senna and oral acetylcysteine 200 mg tds and gastrogra \201 n 50 \200\223100 mL tds for 5 days is usually adequate. If not, perform gastrogra \201 n enema to determine site of obstruction. This can be therapeutic. Oral i ntes- tinal lavage with Kleen Prep solution and up to 10 L of \202 uid over 1 \200\2232 days can also be given. The treatment is considered to have worked when \202 uid is pass ed from the rectum and symptoms have resolved. If not resolving, may need further imaging t o rule out intussusception Re \202 ux More common in patients with CF than the general pop ulation. Symptoms may occur during physiotherapy, which require changes to positioning/tipp ing. May require treatment with a proton pump inhibitor to prevent development of Barrett \200\231s esophagus Pancreatitis Can occur in those patients who are pancreas-suf \201 cie nt. Seen in up to 15% adults with CF. May present as severe acute attack or chronic recurre nt abdominal pain. Not usually as unwell as NON-PULMONARY DISEASE 223 non-CF patients with pancreatitis. Raised amylase and abnormal USS/ CT. Treat with bowel re st, protein pump inhibitor, IV rehydration. Liver and biliary disease \200 Liver screening \200\224cirrhosis, portal hypertension Reduced bile production and deranged bile acid composition leads to biliary obstruction, portal tract in \202 ammation, and ev entual \201 brosis and focal biliary cirrhosis. Cirrhosis affects 2 \200\22325% of CF pat ients. Annual screening liver USS is performed, as blood tests can be unhelpful (although A LP most sensitive). Biopsy unhelpful as patchy disease. Established cirrhosis can lead to v ariceal bleeds, so annual screening endoscopies are performed in those with cirrhosis. Cirr hosis may need treatment with ursodeoxycholic acid, porto- systemic shunts, and sclerothera py. Liver transplant may be necessary. Metabolic disease \200 CF-related diabetes (CFRD) is becoming increasingly common as the median age of survival wi th CF increases. Pancreatic damage in CF (due to \201 brosis) causes decreased insulin se cretion. Approximately 50% of 30-year-olds will have CFRD. Presents insidiously and non-spe ci \201 cally, with weight loss or fall in lung function, and not with ketoacidosis. Scree ning glucose tolerance test or random/fasting glucose should be performed annually and more frequently in those on overnight enteral feeds or those with clinical symptoms suggestive of diabetes. Once dia- betes is diagnosed, patients should not be managed on a hypoglycaemi c diet. Lower doses of insulin are usually required than in IDDM. There is no indication fo r oral hypoglycaemics. Microvascular complications can occur and annual screening for these should be performed Osteoporosis Several studies have con \201 rmed an increased incidenc e of low bone mass in CF and increased fracture risk, particularly ribs. Risk factors inclu de malabsorption of vitamin D and calcium, low body mass index, decreased physical activity , delayed puberty, steroid use, diabetes. Treatment is with calcium and vitamin D supplemen ts to maintain vitamin D levels, weight-bearing exercises, hormones for delayed puberty (et hinylestradiol or testosterone), bisphosphonates. Other organ systems \200 Arthropathy and CF vasculitis Acute or subacute arthritis occurs in around 5% of patients w ith CF. It often responds to NSAIDs. Sometimes arthritis is associated with skin lesions, s uch as purpura or erythema nodosum. Up to 40% may be ANCA positive. Purpuric vasculitis is associated with more severe lung disease Nasal polyps and sinusitis Nasal polyps occur in 3 0% and can cause nasal obstruction. Treatment with topical or systemic steroids and deconge stants is usually not helpful and polypectomy may be required, often more than once. Asympt omatic sinusitis is common and can cause mucosal swelling. Consider sinus CT if problematic Stress incontinence occurs in both men and women, caused by coughing. It has been recogniz ed as an increasing problem. Pelvic \202 oor exercises can be taught by physiotherapists. 224 CHAPTER 24 Cystic \201 brosis Other issues Fertility Women with CF are usually subfertile. When planning a pregnancy, their physical state shoul d be optimized with antibiotics and nutrition. The outcome of a pregnancy is improved by op timizing and maintaining pul- monary function and weight gain during the pregnancy. Close m onitoring throughout is required. Pregnancy does not affect survival when compared with the entire adult female CF population, but impaired pulmonary func- tion with FEV1<60% predict ed is likely to be the main predictor of worse maternal and fetal outcome. Breast-feeding i s possible, but intensi \201 es the nutritional strain put on the mother. Most CF antibiot ics are safe to use in pregnancy, but avoid cipro \202 oxacin, chloramphenicol, metronidaz ole, and IV colistin. Care with aminoglycoside levels. Men are 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 i s normal and hence one option is surgical sperm retrieval for intracytoplasmic sperm inject ion (ICSI) into an egg, performed by fertility clinics. Genetic counseling and screening sh ould be offered to patients with CF and their partners. Psychosocial support Trained psycho logists offer personal and family support regarding education, employment, \201 nancial b ene \201 ts, burden of treatment, and adapting to progressive disease. Pre-transplant psyc holog- ical assessment is carried out, as well as terminal care and bereavement counseling. Also treat depression, anxiety, and emotional dif \201 culties, with referral to psychiat ric services if necessary. Social worker involvement to help with bene \201 t entitlements , travel insurance, disabled car badge. Care of the dying CF patient When all acknowledge t hat there are no further treatment options, the focus of care should adjust to being pal- l iative, with an emphasis on symptom relief, at home or in hospital. Future developments Gen e therapy. Replacing CFTR function to prevent progressive airways disease. Work is focusing on \201 nding a suitable vector for delivery, such as nebulizer and airway epithelial im plantation. Progress so far has been disappointing, but work is ongoing. Further information CF Trust.Standards for the clinical care of children and adults with cy stic \201 brosis in the UK 2001. www.cff.org (USA) www.cftrust.org.uk, www.cystic \201 brosis.co.uk (both UK) CF mutation database: www.genet.sickkids.on.ca This page intentionally left blank 226 CHAPTER 24 Cystic \201 brosis