world have extensive screening programs. Infants with CF have a raised immunoreactive tryps in (IRT) in the blood in the \201 rst week of life. This is not speci \201 c for CF alth ough sensitive. A second IRT test is carried out at 4 weeks and this is more speci \201 c. If this is positive a sweat test is performed. Some screening programs also include geneti c analysis. When screening is carried out it is essential that sweat tests and counseling s ervices are available promptly. Diagnostic criteria These were summarized by the Cystic Fibrosis Foundation Consensus Confe rence: Clinical features or CF history in a sibling or The screening test Positive sweat test or Positive nasal potential PLUS or 2 disease-causing mutations in CFTR Sweat test The sweat test is the gold standard for the diagnosis of CF. The test must be pe rformed by accredited laboratories with skill and care especially in collecting the sweat. Sweating is stimulated by iontophoresis of pilocarpine, usu- ally into the skin of the fore arm (Fig. 11.1.1). The sweat is collected on a \201 lter paper or by Macroduct test tubin g. Classical cystic \201 brosis The diagnosis is usually made soon after birth due to the de velopment of meconium ileus or recurrent chest infec- tions with, or without, malabsorption and failure to thrive. A positive sweat test and two disease-causing mutations of the CF g ene are commonly present. Atypical cystic \201 brosis There are some atypical cases diagnosed later in life where t he diagnosis is dif \201 cult. Clinicians must be aware of these atypical presentations. T hese are patients who usually present late, in adolescence or even adult life, with allergi c bronchopulmonary aspergillosis, pancreatitis, sinusitis, nasal polyps, heat exhaustion or infertility. They may have mild pulmonary disease and be pancreatic suf \201 cient with o ne or no recognized gene mutations. History The frequency of presenting features of 20,096 patients in the Cystic Fibrosis Foun dation Registry in the USA is as follows: respiratory system 51%; failure to thrive 43%; ab normal stools 35%; meconium ileus and small bowel obstruction 19%; family history 17%; elec trolyte imbalance 5%; rectal prolapse 3%; nasal polyps and sinus disease 2%; and biliary di sease 1% Fig. 11.1.1 A sweat test. Localized sweating is stimulated by iontophoresis of pilocarpine into the skin and then collected on \201 lter paper, gauze or in Macroduct tubing. Clinical features Features consistent with a diagnosis are acute or recurrent chest infecti ons often associated with Staphylococcus aureus, Haemophilus in \202 uenzae and/or Pseudom onas aeru- ginosa, together with malabsorption due to pancreatic insuf \201 ciency. Older patients may develop diabetes mellitus, osteoporosis, pancreatitis, liver disease, and gall stones. Other features include \201 nger clubbing (which is almost universal), male infer tility due to mal-development of the vas deferens, salt depletion in hot climates and chron ic metabolic alkalosis. The test is reliable after two weeks of age and CF patients have a chloride >60mmol/l and s odium >70mmol/l. Some normal adolescents and adults may have chloride up to 60mmol/l and va lues of 40 \200\22360mmol/l should be regarded as borderline. If a sweat test in an adult i s borderline, a repeat sweat test after administration of 9 alpha \202 udrocor- tisone fo r 48hrs (3mg/m2/day) will reduce sodium levels in non-CF but not CF. Using the conventional method of collection, at least 100mgs of sweat are necessary and 30 L if the Macroduct sy stem is used. As CF is a diagnosis with serious implications Screening More patients are now being diagnosed in the neonatal period due to screening. So me countries in the deve loped CHAPTER 11.1 Cystic \201 brosis diagnosis 233 for both patients and family, tests should be carried out in duplicate. There are reports o f false positive sweat tests. The causes were listed by Wallis (Table 11.1.1). mutations does not always mean classical CF and the patient may have mild disease presentin g with nasal polyps, male infertility or pancreatitis. \210\22230 Table 11.1.1 Some rare causes of false positive sweat tests A I LC \210\22225 ) V m Adrenal insuf \201 ciency Glycogen storage disease \210\22220 ( D P Malnutrition Hypothyroidism and hypoparathyroidism \210\22215 \210\22210 Eczema Nephrogenic diabetes insipidus (a) A Fucosidosis Nephrosis \210\22250 \210\22245 \210\22240 \210\22235 \210\22230 \210\22225 \210\22220 \210 \22215 \210\22210 \210\2225 0 LC I Glucose-6-phosphate de \201 ciency HIV infection Modi \201 ed from Wallis (2007) ) V m ( D P Nasal potential difference (PD) The PD across the nasal epithelium is more negative in CF p atients than controls. The technique requires a co-operative patient and is not useful in t he presence of sinusitis or nasal polyps. One electrode is put on the \202 oor of the nos e and the reference electrode on the arm (Fig. 11.1.2). 0 5 10 Time (min) 15 (b) Fig. 11.1.3 Transepithelial nasal PD measurements. In a normal subject (a) the amiloride (A ) response is small followed by a marked low chloride (LC) and isoprenaline (I) response, i n contrast to a CF patient (b) where the amiloride response is large but with very little r esponse to low chloride and isoprenaline. Imaging the lungs and paranasal sinuses CT scans of the lung and sinus may indicate bronchi al wall thickening and/or parenchymal lung disease. Sinuses are frequently abnormal and pol yps are common. Microbiology Sputum analysis frequently shows pathogens, the most commonly isolated are Sta phylococcus aureus and Pseudomonas aeruginosa. Lung function testing In older children and adults, air \202 ow obstruction may be demonst rated in large or small airways. Patients with severe disease will be hypoxic as measured b y blood gasses or oximeter. Fig. 11.1.2 Transepithelial nasal potential difference (PD) measurement. An exploring elect rode is placed on the \202 oor of the nose and a reference electrode over an area of abra ded skin on the forearm. Nasal PD measurements are then taken in the presence of different solutions perfused onto the nasal mucosa. Semen analysis 98% of males will have azoospermia which is due to mal- development of the v as deferens. In CF there is a more negative basal potential difference (due to sodium hyperabsorption), a greater response to amiloride and little response to perfusion with a chloride free solut ion followed by isoprenaline (Fig. 11.1.3). The technique is not easy and should only be pe rformed by experienced operators. It can in some cases clarify the diagnosis. Further reading Alton EW, Currie D, Logan-Sinclair R, et al. Nasal potential differ- ence: a clinical diagnostic test for cystic \201 brosis. Eur Respir J 1990; 3(8): 922 \200\2239 26. Andersen DH. Cystic \201 brosis of the pancreas and its relation to celiac disease. A cli nical and pathological study. Am J Dis Child 1938; 56: 344 \200\223399. Mutation analysis The identi \201 cation of two disease-causing mutations in the CF gene c onfirms the diagnosis. However, over 1500 abnormalities in the gene have been identi \201 ed and it is not possible to test for them all. A positive test will therefore con \201 rm the diagnosis but if no mutation is identi \201 ed the diagnosis is not excluded and a sw eat test is still required. The commonest mutations are ZF508 (75%), G551D (3.4%), G542X (1 .8%), R117H (1.3%), 621+1G lT (1.3%), Z1507 (0.5%), and N1303K (0.5%). The presence of two Chat \201 eld S, Owen G, Ryley HC, et al. Neonatal screening for cystic \201 brosis in W ales and the West Midlands: clinical assessment after \201 ve years of screening. Arch Di s Child 1991; 66(1:Spec No): Spec-33. Crossley JR, Elliott RB, Smith PA. Dried-blood spot screening for cystic fibrosis in the ne wborn. Lancet 1979; 1(8114): 472 \200\223474. Dodge JA, Lewis PA, Stanton M, et al. Cystic \201 brosis mortality and survival in the UK : 1947-2003. Eur Respir J 2007; 29(3): 522 \200\223526. N SIMMONDS & M HODSON 234 In: Hodson ME, Geddes DM, Bush AB (eds) (2007). Cystic Fibrosis. London: Hodder Arnold: 49 \200\22358. Farrell PM, Kosorok MR, Laxova A, et al. Nutritional bene \201 ts of neonatal screening fo r cystic \201 brosis. Wisconsin Cystic Fibrosis Neonatal Screening Study Group. N Engl J Med 1997; 337(14): 963 \200\223969. Rosenstein BJ, Cutting GR. The diagnosis of cystic \201 brosis: a con- sensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr 1998; 132(4): 589 \200\223595. Hill CM (1998). Diagnosis. Practical Guidelines for Cystic Fibrosis Care. Edinburgh: Churchill Livingstone. Southern KW. The challenge of screening newborn infants for cystic \201 brosis. In: Hodso n ME, Geddes DM, Bush AB (eds) (2007). Cystic Fibrosis. London: Hodder Arnold: 109 \200\223 116. Hodson ME. Treatment of cystic \201 brosis in the adult. Respiration 2000; 67(6): 595 \200\223607. The diagnosis of cystic \201 brosis: consensus statement. 96 Mar; Cystic Kaplan E, Shwachman H, Perlmutter AD, et al. Reproductive failure in males with cystic \201 brosis. N Engl J Med 1968; 279(2): 65 \200\22369. Knowles MR, Durie PR. What is cystic \201 brosis? N Engl J Med 2002; Fibrosis Consensus Conferences, 1996. Wallis C. Diagnosis of cystic \201 brosis. In: Hodson ME, Geddes DM, Bush AB (eds) (2007) . Cystic Fibrosis. London: Hodder Arnold: 99 \200\223108. 347(6): 439 \200\223442. Nissim-Ra \201 nia M, Kerem B, Kerem E. Molecular biology of cystic \201 brosis: CFTR pr ocessing and functions, and classes of mutations. This page intentionally left blank A JONES & K WEBB 236 11.2 Managing acute infective exacerbations Principals of care for acute exacerbations Patients with CF have better outcomes for nutrit ion and pulmonary function the two best prognostic predictors for survival when care is del ivered by a CF center. All adults with CF with an acute exacerbation should be treated by a n experienced multidisciplinary team (MDT) based in a CF center. There are recognized guide lines for antibiotic management of acute exacerbations in cystic \201 brosis. neutrophil and antibiotic penetration and an explanation as to why infective exacerbations in CF can be controlled but not cured. Chronic infection with PA is associated with a sharp er decline in lung function over time and an increased mortality. Repeated courses of IV an tibiotics result in increased antibiotic resistance. Despite this in vitro antibiotic resis t- ance the patient usually respond in vivo to IV antibiotic combinations. Bacterial genoty ping in CF centers has shown the emer- gence of transmissible strains of PA within pediatri c and adult CF centers in Europe and Australia. Transmissible strains of PA occur more comm only in sicker hospitalized patients and have an increased antibiotic resistance. CF center s have adopted a policy of segregation for inpa- tients and outpatients with transmissible strains of PA. Burkholderia cepacia complex. This bacterial pathogen can be divided into di fferent species by phenotypic and geno- typic testing. These different species are commonly called genomovars. Seventeen genomovars are currently recog- nised. The importance of this division is the association of increased pathogenicity with certain genomovars. Patients i nfected with the B cepacia complex have more severe infective exacerbations than those with PA. Some strains of the B cepacia complex are highly transmissible Chronic infection with the B cepacia complex results in a greater morbidity and mortality than infection with PA. Infection with the B cepacia complex can result in a reduced survival of two decades compar ed with usual mean sur- vival \201 gures. The cepacia syndrome is much feared. It is asso ciated with an infective exacerbation which progresses to a necrotising pneumonia (Fig. 11. 2.1) and generalized sepsis. At this stage, it becomes untreatable with any antibiotic comb ination and progresses to death within weeks. It is usually caused by Burkholderia cenocepa ca (genomovar 3) but can occur with other strains of the B cepacia complex. This syndrome d oes not occur with PA. Epidemiology There is debate as to what constitutes the precise de \201 ni- tion of an acu te exacerbation in cystic \201 brosis. Infective exacerbations increase with age. Repeate d infective exacerbations in CF adults are associ- ated with a linear decline in lung funct ion. Infective exacerbations are a marker of disease severity, a measured variable in studi es of survival and an outcome measure in clinical trials. Pathology and etiology of acute exacerbations The basic defect in cystic \201 brosis is a mutation in CFTR (the cystic \201 brosis transmembrane regulator protein). The resulting basic defect is chloride impermeabilty. The basic defect is expressed in all ductal system s of the body and explains why cystic \201 brosis is a multi-organ systemic disease. The basic defect impairs the local host defenses in the air- ways and sinuses resulting in chro nic infection with charac- teristic bacterial pathogens. Infective exacerbations are more c ommon during the winter months and can be initiated by the usual respiratory viruses; in \202 uenza A and B, RSV and the common cold viruses. During an acute exacerbation there is an increase in bacte- rial pathogens, matched by an exuberant self damaging host in \202 a mmatory response in the airways consisting of neutrophil elastase, tumor necrosis factor, v arious inter- leukins (IL8, IL 6, IL1) and leukotriene B4. Microbiology of infective exacerbations Multiple bacterial pathogens can be isolated from a single sputum sample. It is important to decide which is the dom- inant pathogen causing a n acute exacerbation. CF bacterial pathogens require selective media for culture, grow very slowly and have multiple antibiotic resistance Culture of bacterial pathogens from CF pati ents should be undertaken by a specialist CF microbiology laboratory. Genotyping of Pseudom onas aeruginosa and Burkholderia cepacia from CF patients on at least one occasion is man- datory. This information will decide the outpatient clinic and inpatient segregation for th at individual patient. Bacterial pathogens causing an acute exacerbation Pseudomonas aeruginosa (PA) is the most c ommon patho- gen, infecting 80% of CF adults. PA has a characteristic phe- notype producing a protective mucoid exopolysacharide. This mucoid phenotype provides a defense against Fig. 11.2.1 Bilateral consolidation typical of necrotising B. cepacia complex pneumonia. CHAPTER 11.2 Managing acute infective exacerbations 237 \200 Chest pain (pleuritic or musculoskeletal from coughing). Anorexia/weight loss. CF adults infected with the B. cepacia complex have been ruthlessly segregated from other C F patients for many years. This action has resulted in a decline of the incidence (decrease d cross infection) and decreased prevalence (increased mortality) of B. cepacia complex inf ection. Patients infected with B. cenocepacia (genomovar 111) are considered unsuitable for transplantation due to poor results after surgery. Staphylococcus aureus and Haemophilus i n \202 uenza: these bacterial pathogens previously were responsible for severe infective e xacerbations in children.Treatment with long- term prophylactic antibiotics has considerabl y diminished their pathogenic potential. S. aureus ((51%) and H. in \202 uenza (16%) are c ommonly cul- tured in sputum without any change in clinical status or need for therapeutic intervention. Methicillin-resistant Staphylococcus aureus (MRSA): MRSA is increasing in pat ients attending centers and is usually acquired from the hospital environment. There is ver y little evidence that it causes infective exacerbations Signs Patient looks unwell with a tachycardia and dyspnoea. There may be very few signs on auscultation despite a severe infective exacerbation. CF patients (unlike patients with pri mary ciliary dyskinesia) rarely wheeze during infective exacerbations. Increased inspirator y crackles heard usually over the apices of the lungs and at the mouth. Presence of a pleur al rub. These are more common in CF patients than any other respiratory disease (apart from systemic lupus erythematosus). There is often a difference in intensity of the breath soun ds between the two lungs in an individual patient making it very dif \201 cult to diagnose a pneumothorax with con \201 dence. A pneumothorax may be dif \201 cult to con \201 rm without a chest radiograph but suspicion of a tension pneumothorax may require a lifesaving immediate intercostal drain with no time to do a chest radiograph. Non-bacterial pathogens and infective exacerbations Non-tuberculous mycobacteria (NTM): Abo ut 4% of CF adults have positive cultures for non-tuberculous myco- bacterium (atypical). P ositive cultures are often sporadic and therapy is not indicated. Multiple positive culture s and repeated smear positivity may indicate active disease. Active disease is more often a ssociated with the fast grow- ing NTB (M. abscessus and M. chelonae) Active disease due to NTM can be demonstrated on CT scanning. Infective exacerbations are usually caused by PA an d it is dif \201 cult to evaluate the exact contribution of NTM to infective exacerbations when isolated repeatedly. Aspergillus spp.: the fungus Aspergillus fumigatus has been foun d in the sputum of 60 \200\22380% of CF patients. Chronically infected CF lung is an ideal environment for this organism Allergic bronchopulmonary aspergillosis (ABPA) as de \201 ne d by consensus criteria has a prevalence of about 10 \200\22315% in CF patients and is incr easing as survival improves. ABPA contributes signi \201 cantly to infective exacerbations and accelerates decline in lung function. ABPA is probably a signi \201 cant co-factor wi th PA in magnifying the severity of an infective exacerbation. Investigations Simple spirometry. If the patient has chest pain do not perform spirometry u ntil a current chest radiograph has been reviewed. The FEV1 is remarkably reproducible for an individual patient. A reduction in FEV1 greater than 10% in the con- text of the above s ymptoms and signs denotes an infective exacerbation. Values for FVC are more variable with infective exacer- bations Blood gasses (arterialised capillary blood sample) will decide ox ygen requirements (percentage and \202 ow rate) if the patient is hypoxic and the potenti al need for nasal ven- tilation if there is an acute rise in carbon dioxide levels. Chest r adiographs usually do not show many new changes with a moderate infective exacerbation. A c hest radiograph should always be done to exclude \200 A small pneumothorax: can be dif \201 cult to detect on a plain radiograph if the pneumoth orax has a posterior location. Rib (cough) fractures in the presence of chest wall pain. Ri ght upper lobe collapse (more common than left) due to sputum plugs or ABPA. Pneumonic cons olidation typical of the onset of the cepacia syndrome in a patient chronically infected wi th the B. cepacia complex. \200 Diagnosing an infective exacerbation There has been considerable debate as to how an infect ive exacerbation should be de \201 ned and which diagnostic crite- ria should be employed. However, the physician who reviews the CF patient will have considerable knowledge of the usual clinical status and will easily detect both obvious and subtle decline in health due to an infective exacerbation. Sputum culture is always repeated at time of a new infec- tive exacerbation to exclude new growth of pathogens such as B. cepacia complex and MRSA. Change in antibiotic resistant pat terns may indicate acquisition of a transmissi- ble strain of PA. Hematological investigati ons Sequential measurement of C reactive protein (CRP) pro- vides a valuable indication of the severity of the infection and response to treatment. Blood glucose: 30% of adult CF pat ients have insulin dependent diabetes. Infective exacerbations are more frequent in diabeti c CF patients. Diabetic control is lost during an exacerbation due to infection and treatme nt (corticosteroids). Continuous blood sugar monitoring is Symptoms of an infective exacerbation \200 Increased coughing especially at night. \200 Exhaustion/lack of energy. \200 Increased sputum quantity or decreased with sputum reten tion. Thicker sputum. Bloodstained sputum. Dyspnoea and an increased respiratory rate. \200 \200 A JONES & K WEBB 238 best clinical response. Occasionally triple antibiotic therapy is used for multi-resistant PA. Pan antibiotic resistance occurs with B cenocepacia and makes a suitable antibiotic cho ice extremely dif \201 cult. Triple antibiotic therapy based upon best previous clinical r esponse and prolonged treatment is usually required. Pregnancy. During pregnanacy there is an increased requirement for IV antibiotics. The penicillins, cepha- losporins and monobact ms are safe for IV use. Although IV aminoglycosides are safe if blood levels are closely mo ni- tored, they are best avoided due to potential oxtotoxicity upon the fetus during the se cond trimester. Antibiotic allergy to antibiotics with repeated IV courses is becoming a hu ge problem. It is severely limiting choice of suitable antibiotics. Serious allergic reacti ons are common and anaphylactic reactions are not uncommon. It is impor- tant to document s peci \201 c antibiotic allergy. Patients should be provided with an Epipen (adrenaline) and taught how to self inject. It may be necessary to desensitize patients to useful antibi otics to such as ceftazidime to which they have become allergic. They will need admission t o hospital for this procedure. important for management. CF patients can become dia- betic for the \201 rst time during an infective exacerbation. Blood cultures should be done if the patient is pyrexial. Persis tent temperatures are unusual with an infective exacer- bation due to PA in CF. The usual c ause of a persistent tem- perature is an infected permanent IV access device (PORT) or the development of the cepacia syndrome. Management of an infective exacerbation The delivery of care for an infective exacerbation should be provided at a CF center by a multidisciplinary team. CF patients can become unwel l rapidly with an hour infec- tive exacerbation and a CF center should have a 24-hour open access self admission policy for patients. During the week they should be seen on the same day. At other times they should be able to ring the ward directly for advice and potential admission. Beds for CF patients should be ring-fenced and used only for CF patients. Usuall y the adult CF center will be the only one in the Region and the patients will have nowhere else to go to receive their specialist care. As the CF adult population increases the CF b eds at a center usually have maximum bed occupancy leading to prioritization of the sicker patients for admission. At the start of an infective exacerbation, a clinical decision will need to be made as to whether treatment is under- taken at home or in hospital. Evidence h as shown that clinical outcome is better when an infective exacerbation is treated in hospi tal rather than home. CF patients often prefer home treatment. The sickest CF patient can b e treated at home receiving IV antibiotics, nasal ventilation, continuous oxygen, and enter al feeding if there is suf \201 cient social support and satisfactory treatment adherence. Physiotherapy and airway clearance Physiotherapy delivered to a sick patient by an experien ced physiotherapist skilled in airway clearance techniques and the intricacies of nebulised drug delivery is crucial for patient recovery. Clearance of thickened airways secretions c an be improved during an infective exacerbation with judicious use of nebulised drugs such as rhDNase and hypertonic saline. Nebulised bronchodilators prior to physiotherapy have an important role in airway clearance. The use of overnight IV fluids such as saline or IV ami nophylline are useful adjuncts to maintaining airway clearance especially if the patient is sweating, pyrexial or diabetic. Mobility is crucial. As the patient recovers, mobilization and gentle exercise under physiotherapy supervision using a saturation monitor and oxygen will also enhance airway clearance. Treatment of an infective exacerbation IV antibiotics Each patient will have a portfolio of previous sputum cultures facilitating best choice of antibiotic treatment. There will be r ecords of best responses to IV antibiotics used for previous infective exacerbations. There should be a low threshold for starting a course of IV antibiotics. A treatment course shou ld be for 10 \200\22314 days. Two antibiotics should be used in combination. Monotherapy is associated with the development of antibi- otic resistance. The 2 antibiotics used should have a different mechanism of action. The usual combination is an aminoglycoside (kill- ing related to peak levels) and a beta lactam (killing related to constant blood level over 24 hours). Increasingly aminoglycosides are given as a once daily dose to achieve maximum con centration dependent killing and reduce side effects. Beta lactams are given 3 \200\2234 ti mes a day. There is a relatively wide choice of IV antibiotic for combi- nation usage. Larg e doses of antibiotics are required due to the enhanced metabolism of all drugs in CF patie nts. Oxygen delivery Repeated blood gasses are an essential component of inpa- tient management of an infective exacerbation. CF patients have a high inspiratory \202 ow. Correct oxygen delivery with an appropriate high \202 ow rate is important for safety and comfort. Safe delivery of oxygen is important. Oxygen should be delivered with a \201 xed concentratio n mask rather than nasal cannula during an infective exacerbation and espe- cially overnigh t where uncontrolled oxygen delivery can result in carbon dioxide retention. Steroids The bene \201 cial role of oral corticosteroids during an infec- tive exacerbatio n is uncertain. High doses can cause onset of diabetes and loss of diabetic control in esta blished insu- lin dependent diabetes Diabetes control Infective exacerbations are more common in the 30% of diabetic patients at tending a CF clinic. Insulin resistance increases during an infective exacerbation and high er doses of insulin are required or the institution of an insulin pump. Problem areas Antibiotic resistance is increasing with repeated courses and with the rising prevalence of transmissible PA. Choice of IV antibiotics is usually made according to the previous CHAPTER 11.2 Managing acute infective exacerbations 239 Pneumothoraces re-expand slowly in CF patients as the lungs are stiff due to \201 brosis and patience is required. When the lung has re-expanded a pleurodesis should be performed b efore the tube is removed. Pleurodesis with a 100ml of the patients own blood is common pra ctice. Talc pleurodesis is effective but may compromise the patient as a potential transpla nt candidate. Failure of the lung to re-expand requires referral to an experienced thoracic surgeon. The procedure of choice is an apical pleurectomy and surgical pleurodesis perform ed under videoassisted thoracoscopy (VATS). Occasionally, the patients may be so compromise d that they are un \201 t for surgical intervention. Upper lobe collapse is uncommon and u sually on the right side. It is due to airways impaction of purulent secretions. ABPA as a cause should be excluded with standard diagnostic tests. Prompt therapy should be directed at re-expanding the collapsed lobe as chronic collapse will result in permanent loss of lun g function. Therapeutic measures include physiotherapy with inter- mittent positive pressur e breathing to the collapsed upper lobe. Bronchoscopy ( \201 breoptic) can be used to extr act impacted mucous plugs and install rhDNase directly into the lobe. Anitifungal drugs (it raconazole/voriconazole) can be prescribed if ABPA has been diagnosed. Nutrition CF patients constitutionally have a high energy expendi- ture which is elevated f urther during an infective exacerba- tion and wasting can occur rapidly and recovery delaye d. Commencement of enteral feeding either nasogastric or with the insertion of a feeding ga strostomy will be required. Complications Haemoptysis: Small amounts of blood mixed with sputum can be resolved ver y q uickly with IV or oral tranexamic acid (500mg \200\2231g QDS) continued for 5 days. A large haemoptysis (300 \200\223400ml of fresh blood) is an indi- cation for bronchial artery emb olisation which is a skilled procedure undertaken by an experience interventional radiologi st. A life-threatening haemoptysis is one of the few indications for endotracheal intubatio n and ventilation to maintain air- way patency. IV vasopressors should be commenced. Terlip ressin 2mgm is given as a bolus intravenously and then 2mg 4-hourly until embolisation can be undertaken. After embolisation the patient should be extubated as quickly as possible an d respiratory support provided with non-invasive ventilation (NIV). Fractured ribs are caus ed by coughing during an infective exacerbation are a potentially lethal complication. The associated excruciated pain (requiring opiates) inhibits coughing and deep inspiration and optimum airway clearance. Effective treatment is with intramuscular calcitonin. Dose is 50 \200\223100 units per day for 10 \200\22314 days. Response is usually within 3 \200\2235 da ys. Pneumothoraces: these are associated with and cause infective exacerbations. They can b e bilateral. A pneumothorax with an air rim of greater than 2cm will usually require an int ercostal drain connected to an under- ater drainage system. The tube should be large bore a nd inserted either in the second intercostal space anteriorly or in the 5 \200\2236th inter costal space in the mid-axillary line. Due to pleural disease or tethering from previous pn eu- mothoraces a further pneumothorax may be both locu- lated and posterior and a CT scan i s required to de \201 ne the size and location (Fig. 11.2.2.). Intercostal drainage may ne ed to be done with radiological control. NIV and acute respiratory failure As a result of an infective exacerbation sick CF patients can fatigue rapidly and develop type 2 respiratory failure. It is impossible to oxygenate them safely and adequately at night even with controlled oxygen therapy. The acute introduc tion of NIV can be lifesaving in these circum- stances. The bene \201 ts are reducing the work of breathing at night, safe oxygenation and increased sputum clearance. Monitoring treatment responses to an infective exacerbation An MDT should review twice a we ek the response to treatment of each patient with an infective exacerbation. Each member sh ould have a signi \201 cant contribution to the portfolio of each patient \200\231s manage ment. The best objective markers of improvement are reduction in CRP and sputum quantity an d an improvement in simple spirometry and body weight towards previous best base- line meas urements. Repeat blood gasses and measurements of oxygen saturations. Qualitative measures of improvement are decline in breathlessness, increased exercise tolerance and patients sel f expression of improvement in well being. Failure to improve after \201 rst week of an infective exacerbation Consider changing the patient to a different antibiotic combination after review of most recent sputum culture. Decline in sputum production with deteriorating lung func- tion indicates retained secretio ns. Repeat chest radiograph to exclude development of a small pneumothorax or lobar col- la pse. If no change on chest radiograph introduce or increase pulmozyme to twice a day, add i n hypertonic saline. Review airway clearance techniques. 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