223 Chapter 10 Bronchiectasis Chapter contents 10.1 Bronchiectasis (etiology) 224 10.2 Chronic disease management 228 D SMITH 224 10.1 Bronchiectasis (etiology) Overview Bronchiectasis is fundamentally an anatomical diagnosis describing abnormal perman ent dilatation of airways. It may be suspected clinically in patients with chronic cough an d purulent sputum production and con \201 rmed by plain or cross-sectional radiology of th e chest. Radiological bronchiectasis without clinical symptoms is an increasingly common \201 nding of uncertain signi \201 cance. Table 10.1.1 Classi \201 cation of recognized causes and associations of bronchiectasis Causes of bronchiectasis Congenital structural defects Tracheobronchomegaly (Mounier \200\223Khun syndrome) Defective cartilage (Williams \200\223Campbell syndrome) Pulmonary sequestration Elhers \200\223Danlos syndrome Marfan \200\231s syndrome Tracheomal acia Epidemiology No cross-sectional population studies exist but for a DGH population of 250,00 0 about 100 \200\223200 patients could be seen by a respiratory physician with a special in terest. The extent of severe disease in developed countries has declined since the advent o f vaccination programs, the decline in tuberculosis, widespread antibiotic use and improvem ent in living conditions. Balanced against this is an increasing rate of diagnosis of milde r disease consequent on the increasing availability of CT scanning in the last 25 years. Th is has been described as the era of \200\230modern bronchiectasis \200\231. Obstruction Tumor Foreign body External lymph node Impaired mucociliary clearance Cystic \201 brosis Ciliary dyskinesia Young \200\231s syndrome (bronchiectasis, sinusitis and azoospermia) Pathophysiology In the established bronchiectatic airway the key features are those of dila tation with damage to the structural com- ponents of the airway wall (elastin, muscle and c artilage). In addition there is \201 brosis that may extend into the adjacent lung parenc hyma. Chronic in \202 ammation with lymphoid fol- licles in airway walls and neutrophils i n the lumen drives overproduction of abnormally viscid mucus that is poorly cleared, result ing in stagnation and a fertile medium for bacterial colonization and persistence. This in turn encour- ages continued in \202 ammation and cytotoxic damage, a con- tinuing \200 \230vicious circle \200\231. The initial factor beginning the process of chronic in \202 a mmation may vary, for example an exogenous insult such as toxic gas exposure or foreign bod y inhalation or an endogenous defect of host defenses either congenital or acquired. Howeve r, what seems clear is that infection plays a key role both in the development and persiste nce of the disease. Immune de \201 ciency Common variable immunode \201 ciency Selective immunoglobulin de \201 ciency Functional n eutrophil defects Human immunode \201 ciency virus Excessive immune response Allergic bronchopulmonary aspergillosis Lung transplant rejection Chronic graft versus host disease Post-infective Tuberculosis Whooping cough Non-tuberculous mycobacteria Pneumonia Measles Adenovirus Swyer \200\223James syndrome Post- in \202 ammatory pneumonitis Aspiration Inhalation of toxic gasses Miscellaneous Diffuse panbronchiolitis Etiology Although the list of conditions recognized as causing bron- chiectasis is long (se e Table 10.1.1), in clinical practice the majority of cases are of unknown etiology. The mo st commonly identi \201 ed cause is previous severe pulmonary infection, including tubercu losis. Other relatively frequently identi \201 ed causes (up to 10% in some series) includ e ciliary dysfunction, immune deficiency (Stead) and allergic bronchpulmonary aspergillosis (ABPA). Table 10.1.2 shows causes and associations from 2 recent UK studies in tertiary re ferral centers (Pasteur, Shoemark). These results are a consequence of quite intensive inve sti- gation of a selected patient group; \201 ndings in a DGH popu- lation are likely to be different. In practice, investigation into etiology should be limited to identifying cau ses that might lead to speci \201 c therapeutic interventions over and above conventional treatment of the bronchiectasis and/or provide additional prognostic information for the pa tient and their family. Clues as to etiology may come form the history, examination, imagin g and microbiological investigations. Associations Rheumatoid arthritis In \202 ammatory bowel disease Systemic lupus erythematosis Sjogren \200\231s syndrome Ankylosing spondylitis Relapsing polychondritis Yellow nails syndrome (y ellow nails, pleural effusions and lymphoedema) Microbiology Most published studies of non-CF bronchiectasis in adults show similar microbi ological \201 ndings. The most commonly isolated organism is Haemophilus in \202 uenzae. Pseudomonas aeruginosa is present in about a fourth of patients in most series and affects patients with more severe disease. Moraxella catarrha lis and Streptococcus pneumoniae als o appear, as do anaerobic organisms. Staphylococcus aureus is a less common pathogen whose isolation should prompt consideration of CF as a cause. Aspergillus spp. may be cul- tured from some patients and should prompt consideration CHAPTER 10.1 Bronchiectasis (etiology) 225 \200 \200 \200 History of a previous severe infective episode. Family history (including infertility). Sym ptoms of gastro-oesophageal re \202 ux disease. Asthmatic features in the history (ABPA). Table 10.1.2 Frequency of causes and/or associations of bronchiectasis from 2 large UK stud ies (Pasteur, Shoemark) Cause Frequency Many patients will have had symptoms for most of their life that they accept as normal; per sistence in questioning about sputum frequency, volume, color and taste (foul taste suggest ive of anaerobic infection) are important in establishing a baseline. Equally important is an appreciation of the frequency and nature of exacerbations and their response to speci \201 c antibiotics. Past experience of physiotherapy training and the current practice of t he patient are useful to establish at the outset. Some consideration of the impact of disea se on the patient \200\231s quality of life is always worthwhile; many patients curtail soc ial activities because of embarrassment about their cough and sputum. Ideopathic 26-53% Post-infective 29-32% Ciliary dysfunction 1.5-10% Immune de \201 ciency 7-8% Allergic bronchopulmonary aspergillosis 7-8% Aspiration 0-4% Young \200\231s syndrome 3% Cystic \201 brosis 0-3% Rheumatoid arthritis 2-3% In \202 ammatory bowel disease 1-3% Panbronchiolitis <1-2% Examination The majority of patients will have few, if any, physical signs. Crackles and cl ubbing although classical are rare in mod- ern bronchiectasis. Most commonly a few coarse c rackles may be heard over the site of disease. In older patients there may be signs associa ted with previous surgical inter- ventions for the bronchiectasis itself (lung resection) o r for therapy of tuberculosis or other infections. Congenital <1-2% Atypical Mycobacterial 0-2% of ABPA as a causative factor or aspergilloma as a compli- cation. A proportion of patients will not reveal any pathogenic organisms on some samples. Burkholderia cepacia has been re ported in patients with non-CF bron- chiectasis. Isolation requires special culture media a nd should be speci \201 cally requested in patients with unex- plained deterioration. Occa sional samples should also be sent for mycobacterial culture, especially in cases with poor response to conventional antibiotics, haemoptysis or fever. Longitudinal studies suggest t hat, for the majority of patients, sputum isolates show consistent \201 ndings over time. This supports the usefulness of knowing a patient \200\231s microbiological history in pre dicting the likely organism causing an exacerbation. Radiology (Figs. 10.1.1 \200\22310.1.3) Conventional plain CXR is relatively insensitive; H RCT imaging is the current gold standard. Key CT features include internal airway diameter greater than the adjacent artery (dilatation), failure of airway tapering and thickening of airway walls. In addition mucus plugging of small airways may give rise to a \200\230tree in bud \200\231 pattern. Distribution of dis- ease may give clues as to the etiology. Prox imal or central bronchiectasis suggests ABPA as a possible cause; upper lobe predominance s hould prompt consideration of cystic \201 brosis. Localized disease requires exclusion of an obstruc- tive lesion by fibreoptic bronchoscopy. Most patients AUTHOR \200\231S TIP Characterizing patients as pseudomonas positive or negative is helpful in clinical management since antibiotic strategies differ between the groups. The new patient History, examination and imaging establish a diagnosis of bronchiectasis. S ubsequent investigations serve two pur- poses; to look for an underlying cause (once only) and to guide and monitor ongoing treatment (repeated testing). History The symptom complex that should lead to consideration of a diagnosis of bronchiecta sis is that of chronic cough with purulent sputum production. There will nearly always be a history of episodic worsening in symptoms often with additional features such as general m alaise, joint pains, increasing breathlessness and occasional haemoptysis. Some patients wi th bronchiectasis may produce little or no sputum between exacerbations. Additional histori cal features may suggest possible aetiologies. Important historical features: \200 Age at onset of symptoms. \200 Associated upper air way features (sinusitis, middle ear infection). Fig. 10.1.1 CT scan showing dilated branching airways, some \201 lled with sputum, in the right upper lobe together with tree-in- bud appearances in the right lower lobe indicating small airway involvement. D SMITH 226 clinical bronchiectasis. Similarly airway dilatation occurring in areas of lung \201 bros is, usually termed traction bron- chiectasis, rarely gives rise to signi \201 cant symptom s of its own accord. Initial investigations For all patients: \200 \200 \200 \200 \200 \200 \200 Blood count for eosinophilia. ESR or CRP. Serum immunoglobulins. IgE RAST to aspergillus. S erum IgG precipitins to aspergillus. Skin prick sensitivity to aspergillus. Sputum culture. For selected patients with suggestive features: \200 Oesophageal studies (aspiration susp ected). \200 Cilial studies (early onset of lifelong symptoms, middle ear and sinus sympt oms). CF genotype sweat test (upper lobe predominance, infertility, GI symptoms, S. aure us in sputum). Seminal analysis (sinusitis and infertility). Detailed immunological studies (recurrent infections at multiple sites). Fibreoptic bronchoscopy (localized disease on CT ). Fig. 10.1.2 CT scan showing patchy consolidation in the right middle lobe, cystic bronchiec tasis in the right lower lobe, cylindrical bronchiectasis in the left lower lobe and periph eral nodularity in the left lower lobe indicating small airway involvement. \200 AUTHOR \200\231S TIP IgG subclass testing, auto-immune studies and alpha-1- antitrypsin lev els are not clinically helpful. will have diffuse disease with a lower lobe predominance. A tree in bud pattern in associat ion with nodules and cavi- tation is suggestive of atypical mycobacterial infection, especi ally M. avium complex. Some patchy consolidative change may also be seen especially if imag ing is done in the context of an acute exacerbation. Comparison with any previous imaging w ill allow some appreciation of disease progression; it is always worth ask- ing about previ ous scans, CXR and bronchography (which patients particularly remember). A degree of airway dilata- tion often occurs in the context of pneumonic consolida- tion as a temporary pheno menon, this does not constitute Lung function Although diagnostically lung function testing is of no great value, serial mo nitoring of spirometry helps to identify patients with disease progression that should prom pt review of therapy. Reversibility testing helps to identify patients who may bene \201 t from bronchodilator therapy. Most patients will have obstructive spirometry although norma l results are not uncommon. Physiotherapy assessment An initial assessment by a respiratory physiotherapist with expert ise in bronchiectasis is always worthwhile for a new patient. Although many patients with l ifelong symptoms will have received physiotherapy instruction in the past this is often rem embered by patients as something that is done to them rather than by them. There are a vari ety of tech- niques taught by physiotherapists to aid sputum clearance including the active cycle of breathing, postural drainange and autogenic drainage. In addition a number of mod ern devices are available that are a useful adjunct or replace- ment for conventional physi otherapy including the Flutter and the Acapella. A detailed assessment will allow the patie nt and physiotherapist to select the technique(s) that best \201 ts with their lifestyle and abilities. It is always worth encouraging partners to attend these sessions. A second a ssessment at an interval is useful to assess compliance and deal with problems that may hav e arisen. Reinforcement of the bene \201 ts of physiotherapy by medical staff needs to be frequent. Patients typically settle into a pattern of perform- ing physiotherapy once or tw ice a day for periods of about 10 \200\22315 minutes on each occasion. Those with higher sp u- tum volumes may bene \201 t from more sessions. Fig. 10.1.3 Prone HRCT image showing varicose bronchiectasis in the right lung, enhanced in this image by ground glass shadowing in the surrounding lung tissue. CHAPTER 10.1 Bronchiectasis (etiology) 227 Monitoring progress The above initial assessment will identify a wide range of disease seve rity amongst patients with bronchiectasis. For those at the milder end of the spectrum with normal lung function, infrequent exacerbations and few if any chronic symptoms, a short pe riod of surveillance in secondary care to ensure stability and educate the patient in the m anage- ment of exacerbations is probably adequate. Those with lung function abnormality, co nstant symptoms and more frequent exacerbations will bene \201 t from long term secondary care follow-up. Typically this will include all patients with Ps. aeruginosa infection. Pat ients should have access to a specialist clinic at short notice and be able to get telephon e advice easily. During routine follow-up visits spirometry should be per- formed and a spu tum sample sent. Enquiry into frequency of exacerbations and response to antibiotics togeth er with any change in baseline symptoms will provide an assess- ment of disease stability. Jones AM, Dodd ME, Webb AK, et al. Burkholderia cepacia: current clinical issues, environme ntal controversies and ethical dilemmas. Eur Respir J 2001; 17: 295 \200\223301. King PT, Freezer NJ, Holmes PW, et al. Role of CFTR mutations in adult bronchiectasis. Thorax 2004; 59: 357 \200\223358. King PT, Holdsworth SR, Freezer NJ, et al. Microbiologic follow-up study in adult bronchiec tasis. Respir Med 2007; 101: 1633 \200\2231638. Pasteur MC, Helliwell SM, Houghton SJ, et a l. An investigation into causative factors in patients with bronchiectasis. Am J Respir Cri t Care Med 2000; 162: 1277 \200\2231284. Patterson JE, Bradley JM, Hewitt O, et al. Airway clearance in bronchiectasis: a randomized crossover trial of active cycle of breathing techniques versus Acapella. Respiration 2005; 72: 239 \200\223242. Shoemark A, Ozerovitch L, Wilson R, et al. Etiology in adult patients with bronchiectasis. Respir Med 2007; 101: 1163 \200\2231170. Stead A, Douglas JG, Broadfoot CJ, et al. Humoral immunity and bronchiectasis. Clin Exp Immunol 2002; 130: 325 \200\223330. Thompson CS, Harrison S, Ashley J, et al. A randomized crossover study of the Flutter and t he active cycle of breathing technique in non-cystic \201 brosis bronchiectasis. Thorax 2 002; 57: 446 \200\223448. Further reading Fowler SJ, French J, Screaton NJ, et al. Nontuberculous mycobacte- ria in b ronchiectasis: prevalence and patient characteristics. Eur Respir J 2006; 28: 1204 \200\223 1210. J FRENCH & D BILTON 228 10.2 Chronic disease management Bronchiectasis is a chronic airway disorder characterized by bronchial wall thickening and dilatation associated with clinical symptoms of persistent cough productive of spu- tum and general malaise. The clinical course is punctuated with acute exacerbations associated wit h an increase in sputum purulence and vol- ume and worsening malaise. of oscillating positive expiratory pressure devices (Acapella or Flutter) is effective and preferred by some patients. Bronchodilator therapy is helpful for patients with evi- dence of reversible air \202 ow obstruction. Mucolytic and hyperosmolar therapies have been pro- posed as useful adjuncts to physical techniques of airway clearance. Recombinant human DNa se (rhDNase) has been studied and found to be of no bene \201 t and indeed increased decli ne in lung function and exacerbations. Thus rHDNase is not recommended for regular use. Stu dies of hypertonic saline and inhaled dry powder mannitol are ongoing. Aims of treatment \200 Survival. The advent of the antibiotic era signi \201 cantly altered survival in bronchiec tasis. There is now debate regarding survival data suggesting that bronchiectasis may not c onfer reduced survival compared to an age matched population. Thus treatments are not now s pe- ci \201 cally aimed at improving survival. Preserving lung function. Persistent infect ion in the air- ways is associated with a vigorous neutrophil dominated in \202 ammatory r esponse with an abundance of proteo- lytic enzymes which destroy the airway wall. The avera ge loss of lung function has been shown to be of the order of 50ml of FEV1 per year. By con trolling infection we aim to preserve lung function. Prevent exacerbations. Exacerbations a re unpredictable and result in reduced quality of life.There is clear evi- dence of a stron g correlation between the number of exacerbations per year and reduction in quality of life . An exacerbation in patients with chronic Pseudomonas aeru- ginosa infection may precipita te a hospital admission. Reduce symptoms and improve quality of life.There is good evidence that people feel better when they have less sputum and their life is less disturbed by exa cerbations. Reducing bacterial load Patients with bronchiectasis feel better when they have less sputum and less purulent sputum. Mucoid sputum has far less free elastase and myeloperoxidase tha n purulent sputum and is potentially less harmful to the airways. Antibiotic therapy is aim ed at reducing airway bacterial load and improving the amount and color of the sputum. Bact erial eradication is not always possible because of structural damage and disordered local defenses. Sputum culture is used to characterize the infecting organ- isms so that an appro priate antibiotic management plan can be put in place for each individual. The approach to a patient with purulent sputum is shown in Fig. 10.2.2. Patient with purulent sputum Principles of treatment Having ensured that treatment for the underlying cause is establish ed (i.e. immunoglobulin for immunode \201 ciency), the focus on chronic management is focu sed on targeting the underlying pathophysiological pathway known as the vicious cycle. Culture sputum Treat infecting organism with high-dose oral antibiotics Treatment failure Treat with IV antibiotics to achieve treatment success Treatment success Impaired mucociliary clearance Inflammation causes airway damage Follow to relapse Bacterial persistence Early relapse Less than 8 weeks Late relapse Fig. 10.2.1 The vicious cycle Improving airway clearance People with bronchiectasis should receive instruction from a phy siotherapist so that they can perform airway clearance techniques independently at home. Th e particular tech- nique should be tailored according to information regarding affected lob es from the CT, disease severity, sputum vol- umes, and patient preference. The most common ly used technique in the UK is the active cycle of breathing, but use Treat with successful agent for exacerbations only Treat with successful agent and establish on maintenance antibiotic therapy Fig. 10.2.2 Approach to antibiotic therapy for a patient with chronic purulent sputum CHAPTER 10.2 Chronic disease management 229 The principle is to carry out an initial \200\230clear up \200\231 with an antibiotic targ eted at the infecting organism and to con- tinue it for a minimum of 2 weeks but longer if necessary to reduce the bacterial load and render the sputum color as near to mucoid as pos sible and the sputum volume to the minimum possible. Treatment success is de \201 ned as a reduction in sputum vol- ume and a change in sputum color to mucoid. The sputum may still culture a potential pathogen but if the patient is well and the sputum is mucoid this is no t treatment failure. Once treatment success is secured the antibiotic therapy is discontinu ed in order to establish the time to relapse. Patients can monitor sputum color and volume at home and are instructed to contact the clinic in the event of a relapse. If relapse to t he original state, (ie: purulent sputum in increasing volumes associated with malaise), occ urs early (within 6 or 8 weeks) and there is a history of recurrent frequent exacerbations then after further treatment with the successful agent maintenance antibiotic therapy shoul d be instituted appropriate to the infecting organism. This approach holds whether the infe cting organism is Haemophilus in \202 uenzae or Pseudomonas aeruginosa (PA). Patients who have chronic infection with PA are much more likely to require intravenous antibiotics to g ain dis- ease control in the \201 rst place and maintenance therapy is likely to be nebul ised Colomycin. Key points De \201 nition of relapse/exacerbation \200 \200 \200 \200 Increase in cough. Increase in sputum volume. Increase in sputum purulence. Increase in mal aise. Treatment of relapse \200 \200 \200 Institute antibiotic therapy. Send sputum for culture. Adjust therapy later based on sputum culture if lack of response. Anti-in \202 ammatory therapy There are theoretical reasons why inhaled steroids should be useful in the chronic treatment of bronchiectasis. The host response to chronic bacterial persistence in the air- ways contributes to airway damage. Clinical studies have been less convincing and inhaled steroids are not recom- mended outside of routine treatment of any c oexistent asthma. There is one notable exception. Bronchiectasis associated with ulcerative colitis is exquisitely sensitive to oral steroid therapy and control of symptoms is mainta ined with inhaled steroid therapy. Immunomodulatory therapy Azithromycin has been shown to produce bene \201 ts in cystic \201 brosis in terms of improvement in lung function and reduction in exacerbations. Azithr omycin works through a number of pathways includ- ing disruption of bacterial quorum sensin g proteins, reduc- tion of production of bacterial virulence factors and reduction of produ ction of host epithelial and phagocytic cell in \202 ammatory cytokines. Large scale studi es in non CF bronchiectasis are lacking but pilot data suggests azithromycin may be useful. Because of absence of long term safety data and randomized clinical trials its use is con \201 ned to dif \201 cult cases unresponsive to usual maintenance antibiotic therapy in t he context of infection with Pseudomonas aeruginosa. Sputum culture Antibiotic therapy Haemophilus in \202 uenzae Doxycycline 100mg OD Amoxicillin 500mg BD Streptococcus pneumoniae Penicillin V 500mg BD Trimethoprim 200mg BD Staphylococcus aureus Flucloxacillin 500mg BD Pseudomonas aeruginosa Nebulised Colomycin 2 mega units BD Fig. 10.2.3 Potential therapies for maintenance antibiotic regimen Key points There are important caveats to the use of long-term azithromycin. \200 AUTHOR \200\231S TIPS Maintenance antibiotics in bronchiectasis Consider if: \200 Azithromycin must not be used until infection with non-tuberculous mycobacteria (NTM)is exc luded. Patients must be warned regarding possible oto-toxicity and to stop therapy immediat ely if they develop tinnitus. Frequent oral antibiotic courses or greater than four exacerbations per year. Rapid relapse (less than 8 weeks ) after a course of antibiotics. More than two admissions to hospital f or IV antibiot- ics in a year. Patient education Management of patients with bronchiectasis should become a partnership be tween the health professionals and the patient. The patient should be involved in de \201 ning a management plan having agreed on what they consider to be successful treatment. They can then be involved in decisions regarding the need for long term maintenance therapy and the choice of agent. Furthermore they can be involved in a decision to stop maintenance th erapy if they have remained well and exacerbation free for over a year. Patients who remain well for 3 months or longer without relapse can then simply be given a supply of the successful antibiotic agent to use again in the event of an exacerbation. It is important for the patient to provide a sputum sample at the beginning of an exacerbation and inform the GP or practice nurse that they are starting antibiotics. Hence the infectin g organism is con \201 rmed and in the event of antibi- otic failure an appropriate second -line antibiotic can be selected. J FRENCH & D BILTON 230 It is important that each patient has a clear understanding of the following. \200 In the event of worsening symptoms and/or decline in lung function it may be helpful to re- evaluate the HRCT appear- ances as part of a broader strategy of reinvestigation. The HRCT is useful in the setting of a new growth of NTMa in establishing its signi \201 cance. The chest radiograph should be performed during exacer- bations requiring hospital admission a nd other exacerba- tions associated with chest pain or haemoptysis. Individual management plan including a plan for manage- ment of an exacerbation. Recognitio n of an exacerbation (symptoms defined earlier). Requirement to send sputum for culture in the event of an exacerbation before starting antibiotics. How to access advice from health professionals if not responding to management plan. Requirement for annual \202 u vaccine . Requirement for follow up and assessment. Vaccinations It is recommended that patients with bronchiectasis have an annual vaccination against in \202 uenza. The pneumococcal vaccine is used as an initial test of func- tiona l antibody production. If a bronchiectasis patient who is initially immunocompetent suffers decline with more fre- quent and severe exacerbations in particular with pneumo- coccal in fection it is worth retesting speci \201 c antibody levels. \200 Monitoring and follow up Patients with bronchiectasis require long-term follow-up to ensure that their infections are adequately controlled and their lung function is maintained. Not all patients require long-term follow up in secondary care if they have a satisfactory man agement plan. The following patients are at risk of more rapid decline or frequent hospital admis- sions and warrant follow up in secondary care. \200 Other infections in bronchiectasis NTM are known to cause bronchiectasis and to complicate pre-existing bronchiectasis. Infection with Mycobacterium avium intracellulare is the most common in this setting. There is a characteristic appearance on HRCT of nodular bronchiecta sis with \202 orid tree in bud appearance when there is active infection. Treatment is di f \201 cult requiring lengthy courses of multiple drugs often associated with side effects and toxicity. The decision whether or not to treat NTM infection in the context of bronchi ectasis depends on whether the same organism is repeatedly isolated, whether there is evi- dence of clinical deterioration and whether there is evidence of ongoing damage on the HRCT . It is recommended that treatment is supervised by specialists. Patients with bronchiectasis in the context of rheuma- toid arthritis. Patients with Pseudo monas aeruginosa infection. Patients with immunode \201 ciency and bronchiectasis. Patient s with primary ciliary dyskinesia. Patients with frequent exacerbations requiring hospital admission. \200 \200 \200 At follow up the following should be checked \200 Current sputum color and estimation of daily sputum volume. Spirometry to assess stability or decline in FEV1. Frequency of exacerbations since last seen. Effectiveness of antibiotic therapy in treating exacerbations. Effectiveness of maintenance therapy (if applicable) in preventing exacerbations. Sputum culture (patient should be encouraged to bring a sample t o clinic). Patient \200\231s concordance with treatment including physiotherapy. Patient \200\231s understanding of bronchiectasis and the management plan. \200 \200 \200 Further reading Barker AF. Bronchiectasis. New Eng J Med 2002; 346(18): 1383 \200\2231393. Crockett AJ, Cranston JM, Latimer KM et al. Mucolytics for bron- chiectasis. Cochrane Datab ase Syst Rev (England) 2000; 2: pCD001289. Davies G, Wells AU, Doffman S, et al. The effect of pseudomonas aeruginosa on pulmonary fun ction in patients with bronchiecta- sis. Eur Respir J 2006; 28: 974 \200\223979. Fowler SJ, French J, Screaton NJ, et al. Nontuberculous mycobacte- ria in bronchiectasis: p revalence and patient characteristics. Eur Respir J 2006; 26: 1204 \200\2231210. A change in frequency or severity of exacerbations should prompt further evaluation of the sputum bacteriology. Furthermore a decline in lung function, general well being and quality of life should prompt reassessment and investigation. Jones AP, Rowe BH. Bronchopulmonary hygiene physical therapy for chronic obstructive pulmon ary disease and bronchiectasis. Cochrane Database Syst Rev (England) 2000; 2: pCD00045. Kolbe J, Wells A, Ram FS. Inhaled steroids in bronchiectasis. Cochrane Database Syst Rev (England) 2000; 2: pCD000996. Use of radiology in long term monitoring The HRCT is used to establish the diagnosis of bro n- chiectasis. There is no requirement to repeat this on a regular basis if the patient rem ains well and exacerbation free with stable lung function. Noone PG, Leigh MW, Sannuti A, et al. Primary ciliary dyskinesia. Am J Respir Crit Care Med 2004; 169: 459 \200\223467. Vendrell M, deGracia J, Rodrigo MJ, et al. Antibody production de \201 ciency with normal IgG levels in bronchiectasis of unknown etiology. Chest 2005; 127(1): 197 \200\223204. 231 Chapter 11 Cystic \201 brosis Chapter contents 11.1 Cystic \201 brosis diagnosis 232 11.2 Managing acute infective exacerbations 236 11. 3 Chronic disease management 242 11.4 Cystic \201 brosis genetics 248 11.5 Extra-pulmonar y manifestations of cystic \201 brosis 252 N SIMMONDS & M HODSON 232 11.1 Cystic \201 brosis diagnosis Introduction CF is caused by mutations in the cystic \201 brosis transmem- brane conducta nce regulator (CFTR). Over 1500 abnor- malities in this gene have been identified. The gene regulates chloride and sodium transportation in secretory epi- thelial cells. Abnormalitie s in the gene cause multisystem disease including respiratory disease which is the major ca use of morbidity and mortality, and also pancreatic dys- function leading to malabsorption. Liver disease, diabetes mellitus, osteoporosis, infertility in males, small bowel obstruct ion, joint disease, vasculitis, sinusitis, and nasal pol- yps may also occur. There is a hi gh level of sodium and chloride in the sweat which is the basis of the main diag- nostic te st for this condition. In 1938 70% of patients died within the \201 rst year of life but now the median survival is to 36 years in developed countries. In view of the mortality and morbidity associated with this condition it is essential that cases are not missed and app ropriate treatment is given. On the other hand a mistaken diagnosis could have a disastrous effect on an individual and their family. Diagnostic procedures therefore must be robust. 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.