David Currie. May, 2002. Differential diagnosis of cystic fibrosis bronchiectasis [online]. Dewsbury and District Hospital, Dewsbury, UK. Available from http://www.cysticfibrosismedicine.com
Bronchiectasis is defined by pathology (1) and radiology (2) as the abnormal dilatation of bronchi. Limited bronchial dilatation may be found in patients with chronic bronchitis (3) and not regarded as sufficient to justify the label of bronchiectasis. Traction bronchiectasis such as in fibrosing alveolitis which is not associated with purulent sputum production should be ignored.
There are six common patterns of symptoms:
Bronchial sepsis without bronchiectasis
There is no evidence of bronchiectasis in some patients presenting with daily purulent sputum, prolonged purulent bronchitis and recurrent purulent bronchitis. An abstract describing a small group of such patients where the cause is unknown has been published (4). Other such patients will have the same underlying causes as those who have evidence of bronchiectasis and are at risk of developing radiological evidence of bronchiectasis in the future. Chronic bronchial sepsis has been proposed by Professor Cole as a term to describe all patients experiencing troublesome purulent sputum production, with or without bronchiectasis (5).
The prevalence of bronchiectasis on mass miniature radiography was found to be 0.8 per 1000 in 1946 and 1.1 per 1000 in 1956 (9). However this will significantly underestimate prevalence as plain CXR has a sensitivity for bronchiectasis of only 37% at lung level (10). In Dewsbury & District Hospital, which serves an area of 165,000 population, 160 patients were disease-coded with bronchiectasis over a six year period between 1992 & 1998. Throughout this time interval high resolution(HR) CT scans was being used as the standard method for confirming the diagnosis. A study 11 of 110 patients who had presented to their general practitioner with an exacerbation of COPD were assessed two months later with HRCT. Nine(8%) had cystic or varicose bronchiectasis and 83% of these patients were expectorating purulent sputum in the stable state. A further 22(20%) with less marked tubular dilatation could not be differentiated on clinical grounds or sputum characteristics from the rest of the population; the relevance of the CT finding in this group is uncertain.
Any age with mean of 23 years (12)
Slight female predominance (12)
Causes of chronic bronchial sepsis including bronchiectasis (13)
* defined as bronchiectasis or chronic bronchitis with chronci sinusitis in men with obstructive azoospermia in whom there is no defect of ciliary function and no evidence of cystic fibrosis. It may be caused by mercury poisoning from teething powders and worm medication(21). The UK frequency of Young's syndrome has fallen dramatically in those born since 1955 when these preparations stopped being used.
How to investigate bronchiectasis?Chest X-ray - CXR has only a 37% sensitivity at lung level (10)
High Resolution Computed Tomography (HRCT) - Scan of Thorax 2-3mm slice width with appropriate protocol for good definition of the lungs. The criteria for the diagnosis of bronchiectasis (2) are lack of tapering, visibility of bronchi within 1cm of the pleura and bronchial dilatation (bronchial diameter larger than the accompanying pulmonary artery; avoiding CT slices close to bronchial bifurcation). Radiation dose of scan using 3mm slice width every 10mm equivalent of up to fifty CXRs to the breasts (26). Reduce the radiation dose by modifying the protocol, if exclusively for evidence of bronchiectasis, for example 2mm slices every 20mm). Only perform CT when likely to inform decisions and alter the management, for example with respect to aetiology, surgical resection, physical therapy, and as a baseline to monitor disease progression. CT incidentally demonstrated mediastinal lymph nodes larger than 1cm diameter in 29% of 42 patients being scanned to confirm a diagnosis of bronchiectasis (27). However, always consider more serious causes for lymph node enlargement in the presence of bronchiectasis. Haemoptysis in clinical picture of bronchiectasis should widen differential diagnosis to include malignancy and indicate need for additional 7 or 10mm width contiguous CT slices and bronchoscopy.
Fertility and azoospermia - Fertility in males, as judged by fathering children or the presence of normal numbers of motile spermatozoa in semen, rules out CF and Young's syndrome and makes primary ciliary dyskinesia (PCD) much less likely. Obstructive azoospermia occurs in cystic fibrosis and Young's syndrome and in primary ciliary dyskinesia (PCD), the classical abnormality is immotile sperm with normal numbers. In a report (37) from the Royal Brompton Hospital of nine men with PCD, 3 had the classical abnormality, 3 azoospermia and 3 had children or normal seminal analysis.
Mucociliary clearance - If prominent upper respiratory tract symptoms in childhood, check nasal mucociliary clearance (NMCC), (38) by placing a 1mm diameter piece of saccharin tablet on the inferior turbinate, just posterior to the tip and recording the time taken for the patient to taste the saccharin. Do not inform the patient of the substance used, to avoid food or drink during the test and preferably to sit with head tilted slightly forwards. If NMCC > 60minutes, contact a specialist centre equipped to measure nasal nitric oxide. Nasal NO is very low in primary ciliary dyskinesia (39). Patients with low nasal NO should require measurement of ciliary beat frequency and electron microscopy at a specialist centre.
Immunoglobulin (Ig)s - Ig G, A, M and G subclasses recommended in all cases looking for low values of total IgG (= low IgG1 subclass), or IgG2 subclass (40) with a view to replacement immunoglobulin therapy. Isolated IgA deficency occurs in about 7% of the normal population and is of doubtful significance in bronchiectasis.
Bronchoscopy - Fibreoptic procedure to look for a foreign body or endobronchial pathology (eg carcinoid or other slow-growing tumour) especially if unilateral disease or any proximal bronchial narrowing on CT scan. Also following haemoptysis for the same reason, but also to exclude endobronchial malignancy. There should be a low threshold for repeat bronchoscopy in smokers with further haemoptysis.
Aspergillus fumigatus - Skin test ( or serum RAST for Aspergillus fumigatus specific IgE) to look for Allergic Bronchopulmonary Aspergillosis (ABPA), for example, if bronchiectasis or purulent sputum associated with asthma or seasonal (spring & autumn) periods of disease activity. ABPA is characterised by the combination of symptoms suggestive of an infective exacerbation and those of asthma. Repeat CXRs (17) during acute episodes may demonstrate shadows indicative of proximal bronchial inflammation and plugging by fungus or peripheral shadowing, between acute episodes of symptoms the same CXR abnormality may be present from silent acute episodes or there may be evidence of proximal bronchiectasis. CT scan will help identify proximal bronchiectasis (41). Blood eosinophilia usually between 1 and 5/nl during acute episodes. Immunoglobulin G precipitins to Aspergillus to a few antigens compared with high levels to multiple antigens in the presence of Aspergilloma.
Sweat testing - In adult patients with chronic bronchial sepsis is still a good screening test for cystic fibrosis. If abnormal, a repeat sweat test after oral fludrocortisone suppression (42) may limit the number needing to go forward to genetic blood testing. Those with sweat sodium or chloride levels of 70mmol/l or higher should be checked for the presence of common and rarer genes associated with cystic fibrosis. (for more details see CF section-making the diagnosis)
Transepithelial nasal potentials - At a specialist centre may be helpful where doubts remain. (Refer to section on diagnosis of cystic fibrosis)
24 hour sputum volume (28) Fresh four-hour morning sample of sputum for purulence (28) - judge the proportion of the sample which is coloured yellow or green (ie purulent), the colour (yellow or green and intensity of colour). The remainder of the sample is either mucoid sputum (white or clear and viscous) or clear liquid denoting saliva or theoretically periciliary fluid. Purulent sputum implies a higher level of disease activity and in patients with bronchiectasis is usually indicative of the presence of neutrophils (29) & a higher level of disease activity, although eosinophils may also cause purulence (30). The liquid cleared from the mouth after coughing up mucus from the lungs is potentially a mixture of periciliary fluid, mucoid and purulent sputum and saliva. There is also the possibility of contamination with post nasal discharge from the nose and sinuses and gastro-oesophageal reflux liquid. 24 hour purulent sputum volume (28) - by multiplication of the proportion of purulence in the morning sample by the 24 hour sputum volume, this useful estimate of disease activity is derived.
Sputum culture - One sample cultured early in the disease; ideally during a phase of purulent sputum expectoration when the bacterial flora of the sputum has not just been altered by antibiotics. Only culture intermittently thereafter. Sputum culture is useful for the detection of bacteria other than the expected Haemophilus influenzae. These bacteria may guide antibiotic choices, for example, Moraxella catarrhalis with expected resistance to amoxycillin or the arrival of Pseudomonas aeruginosa. The presence of Staphylococcus aureus, uncommon in non-CF bronchiectasis, needs reconsideration of Cystic Fibrosis or an atypical variant or ABPA(32) Absence of bacteria does NOT mean the disease is inactive. Microbiology laboratories selectively do not report certain bacteria
ESR, CRP - seldom necessary
Serum elastase - research tool (31) role not established
Immunoglobulin G, A & M - high levels in some patients (28)
CXR -Allergic Bronchopulmonary Aspergillosis (17) Pneumonia - a rare cause of lower respiratory tract infection in bronchiectasis
White blood cell (WBC) scanning (33) - autologous 111In labelled WBC (unproven role).Up to 50% of labelled WBC pass through the lungs to be expectorated in the sputum. Expectoration of >7.5ml purulent sputum in 24 hours has been associated with a positive WBC scan. Lung damage: baseline & surveillance to look for progression of disease Symptoms - worsening symptoms require search for progression of disease
Full pulmonary function tests - as baseline, repeat if suspicion of progression. Most patients have an obstructive ventilatory defect (12,28,34,35) although a restrictive defect may also be present (36). Spirometry - FEV1/FVC to monitor in cases with active disease annually and more frequently, if necessary. Spirometry seldom deteriorates during episodes of acute bronchitis in CF-unrelated bronchiectasis in contrast to CF
CT scan thorax - limit repeat scans and radiation dose (refer to diagnosis section) Determining the cause of bronchiectasis?
In CF-unrelated bronchiectasis many problems are similar to those of patients with cystic fibrosis. However the relative importance of the problems is different.
Key Problems
Background symptoms (both respiratory and generalised)Acute exacerbation of symptoms (episodes of acute bronchitis)Risk of progression of disease (background symptoms & lung damage)Adverse effects of treatment (eg from antibiotics or physical therapy)Objectives of treatment:
Education
The patient needs good general education about bronchiectasis. Patients are often first seen late by an interested health professional many years after developing the disease. The patient's experience of the disease needs to be recorded including responses and attitude to treatment. Open questions to explore these experiences are important. Patients with radiologically-proven established bronchiectasis need to know that unless complete surgical resection is possible, the abnormal areas of bronchiectasis will always be present and the strategy developed for management will need to flexible but lifelong. In contrast patients with recent prolonged purulent bronchitis and/or no radiological change are more likely to have reversible symptoms. Inform the patient of the four areas for setting treatment objectives: background symptoms, acute episodes of acute bronchitis, risk of progression and adverse effects of therapy). It is for the patient informed by the health professional to decide the goals of treatment after considering the evidence and professional recommendations.
Patient choices of treatment outcomes
There is a range of patient choices of treatment outcomes in each problem area. There is more freedom of choice for a patient with CF unrelated bronchiectasis than with cystic fibrosis because there is a much lower risk of disease progression.
Disease progression
The risk of disease progression in bronchiectasis is a difficult area for the health professional to explain to the patient in the absence of evidence of progression or a proven risk factor for progression (only proven factor is cystic fibrosis). The 'vicious circle' hypothesis proposed in 1984 by Professor Cole (43) may help the patient to understand the risk by demonstrating a possible way that four features of patients with bronchiectasis may interact to worsen symptoms and lung damage.
Many patients with years of living with the disease will believe that their disease is not progressing and as a consequence the risk of progression may not influence their decisions about treatment. The risk of progression is easier to explain to those who have already experienced symptomatic progression, poor lung function and symptoms of damage (breathlessness not due to asthma). However it is wrong for health professionals or patients to assume that there is no risk of progression in patients with CF unrelated bronchiectasis. The risk of progression is relevant between 15 and 20% in two series (12, 44).
A longitudinal study (12) of patients with CF-unrelated bronchiectasis showed that the disease was associated with premature death in 16% at a mean age 53 years. This retrospective study set out to include all patients in a ten year period from 1963-72 who had bronchography at Edinburgh City Hospital or at the thoracic surgical unit and lived within the city of Edinburgh. In this way it achieves a relatively comprehensive review of bronchiectasis requiring hospital referral. There were nineteen deaths, twelve others with worsening of disease and four were not working due to the disease in a population of 116 patients followed for 5 to 15 years. Progression or death occurred equally in three groups of different initial disease severity, although death was significantly associated with worse initial FEV1. FEV1 was monitored longitudinally in 71 of these patients: reduction of more than 50ml/year in 14 (20%), 50ml/year in 43 (60%) and no change or an improvement in the remainder (20%). Normal decline in FEV1 30ml/year (45).
In the second study (44), evidence of radiological progression of disease was found in 15 of 84 (18%) consecutive patients admitted to Brompton Hospital, a tertiary unit with a particular interest in the disease. The most recent radiology was compared with the earliest. Progression was demonstrated on serial plain chest radiography in 14 and bronchography in one. Only one patient had undergone serial bronchography and 32 had serial CT scans but the maximum interval between CT scans was only two years. .
Treatment options for established disease
Disease may be judged as established by the presence of irreversible bronchiectasis on CT scan and/or prolonged symptoms.
Surgery: resection - Role limited to selected patients who are symptomatic from purulent sputum expectoration or other complication (eg haemoptysis or lung abscess) despite antibiotics and other medical therapy. Ideally patients should have sufficently localised disease to permit complete resection, excluding those with any factor predisposing to the later development of bronchiectasis in other areas. Take care to exclude the presence of inflammation, microbial colonisation or sub-radiological damage in other areas. Possible role for 111In labelled white blood cell scan (33).
A further small number will be resected incidentally for diagnosis and treatment of masses suspicious of malignancy on CT (46).
Surgery: transplantation - For patients with a life expectancy of less than two years and no significant co-morbidity (47). (See transplant section for a recent review)
Immunisation - against influenza annually and against Pneumococcus at frequency in line with current advice from Department of Health (48). Seek advice from immunologist for patients with immune deficency.
Antibiotics - personal hierarchy In different clinical situations.
Unfortunately there are very few randomised double-blind placebo-controlled studies of antibiotic therapy in bronchiectasis. In my view antibiotics should be used to achieve particular agreed objectives. In short course the objective is usually to convert purulent sputum to mucoid or no sputum. Prolonged courses may aim to maintain sputum mucoid or absent and reduce or prevent acute exacerbations.
For background symptoms and acute episodes of bronchitis in bronchiectasis
The key bacteria are Haemophilus species (usually influenzae, although influenzae & parainfluenzae are not routinely distinguished from each other) and later Pseudomonas aeruginosa (49). Often the microbiological report will state "no bacterial growth", which should not stop use of antibiotics if sputum is purulent. If P. aeruginosa is isolated, antibiotics with antibacterial activity against this bacteria are usually necessary. I prescribe antibiotics in pairs for purulent sputum unresponsive to all oral antibiotics except quinolones. The theoretical rationale for selecting antibiotic pairs is to delay the development of bacterial resistance and increasing difficulty and ultimately inability to render sputum mucoid. There are only limited pairs of antibiotics at this stage. I always prefer to use an "anti-Pseudomonal" penicillin with oral ciprofloxacin or an aminoglycoside. If any of these have been used as oral or intravenous single agents in the past there is a substantial risk that bacteria in the purulent sputum will already be resistant to one of the antibiotics. In my experience laboratory resistance patterns are of surprisingly little help in choosing antibiotic pairs.
If sputum is unresponsive to oral antibiotics after one to two weeks, I would switch to an alternative. Ideally I would arrange for a sputum culture to be sent in an antibiotic-free interval, in readiness for switching to a third antibiotic. Occasionally these sputum cultures indicate bacteria or resistance patterns that justify a change of antibiotics , usually only if sputum is unresponsive or there is a simple alternative. For example, substitution of coamoxiclav in place of amoxycillin if Moraxella catarrhalis or an amoxycillin resistant strain of Haemophilus influenzae are grown.
Prolonged courses of antibiotics
Only use for background symptoms and with the objective of reducing the severity of acute bronchitis in CF-unrelated bronchiectasis.
For background symptoms in penicillin-allergic patients
Remember that only 10% of patients reporting penicillin allergy are truly allergic. In view of this fact and the superiority of penicillins in the control of bronchiectasis, consider giving a test dose of penicillin to the patient with an intravenous cannula in-situ and in an area staffed and equipped for recuscitation.
Choosing and tailoring antibiotic treatment for individual patient
This is a personal view after over 18 years caring for patients with purulent bronchiectasis. These patients usually have had several courses of antibiotics when first seen by a respiratory specialist. They often recall the antibiotics that have been effective in the past. An antibiotic may be regarded as effective if makes any difference to the symptoms of the disease. There is a wide range of effectiveness ranging from limited to a positive impact on acute episodes of bronchitis, to an effect on background symptoms or even leading to a reduction in the frequency of subsequent episodes of acute bronchitis.
If there is any evidence of recent disease progression, the objective should be the abolition of background symptoms and the minimisation of symptoms from acute bronchitis. This is equally important in the face of new prolonged purulent bronchitis in my view. Occasional sputum cultures are helpful for purulent sputum to look out for less common bacteria such as Moraxella catarrhalis and the first colonisation of sputum by Pseudomonas aeruginosa. As in patients with cystic fibrosis, Pseudomonas aeruginosa is found in patients with lung damage and seldom early in the course of the disease. As predicted by the laboratory antibiotic sensitivities, Pseudomonas aeruginosa patients are less responsive to high dose amoxycillin (28) and more often require therapy which includes antibiotics with the spectrum to kill Pseudomonas aeruginosa.
Select the objectives of treatment with the patient and choose the simplest antibiotic regimen, likely to be effective, from the hierarchy. A carefully designed open study (53) in patients with bronchiectasis assessed response to oral amoxycillin in conventional doseage (250mg three times daily) and followed in those whose sputum did not improve by higher doseage (3g twice daily), both prescribed for 14 days. All 14 patients, half with mucoid & half with mucopurulent sputum between episodes of acute bronchitis responded to the lower dose. Only 3 of 19 patients with purulent sputum between acute episodes responded, with reappearance of purulent sputum in a median of four days. Seven of 12 of these non-responders subsequently responded to the higher dose treatment, with a longer median time to reappearance of purulent sputum of forty days.
Treat with the chosen antibiotic for a maximum of two weeks. If there is no response after agreed interval switch to next antibiotic regimen in the hierarchy. If again no response, stop antibiotics and ideally after two days without antibiotic collect fresh sputum sample to send of assessment of purulence and bacterial culture. In difficult cases, monitor progress with 24hour & morning collections of sputum to measure purulent volume & degree of purulence (refer to investigation section of this article). Twenty-four hour purulent sputum volume discriminated most clearly between the treated and untreated groups in the controlled trial comparing long-term high dose amoxycillin against placebo (28). It proved more useful than sputum elastase level, colonising bacterial load in sputum, erythrocyte sedimentation rate and white blood count.
Long-term antibiotic therapy
Only antibiotics that reduce purulent sputum volume in short courses should be considered for use for prolonged periods.
Long-term oral high dose amoxycillin therapy is an option in selected patients. In the double blind randomised placebo-controlled study (28) of 32weeks treatment followed by 20 weeks additional monitoring under trial conditions, 38 patients with established purulent bronchiectasis impaired lung function (median FEV1 just over 50%) were recruited into the study. Nineteen received oral 3g amoxycillin twice daily. The study demonstrated that the treatment reduced purulent sputum volume and the time spent off sick from work or confined to bed. However it did not demonstrate improvements in patient general well-being whilst on the treatment and the frequency of episodes of acute bronchitis did not change. After a fortnight amoxycillin, nine of eleven responders to the prolonged course would have been identified on the basis of a reduction in purulent sputum volume by >50%. In this group of patients there were few adverse effects with high dose amoxycillin.
In a pilot double blind study (54) six patients with bronchiectasis and daily purulent sputum for many years were given three different regimens for one week each of amoxycillin and probenicid in different doses, in random order, placebo controlled for probenicid. The study suggested that similar serum levels of amoxycillin and clinical efficacy were obtained from oral amoxycillin 1g twice daily combined with oral probenicid as from oral amoxycillin 3g twice daily. Two of six patients experienced loin pain after probenicid.
Long term therapy with high dose amoxycillin has not been critically evaluated in patients with less severe disease, or in those with recent prolonged purulent bronchitis (not assessed by CT scanning, or prolonged purulent bronchitis after excluding radiological evidence of bronchiectasis by computed tomography.
Throughout there must be balancing of the benefits against the potential side effect of the chosen therapy. It seems prudent to restrict choice of long-term antibiotics to those with a satisfactory safety record, tolerance and efficacy in short course in the individual patient. Early publications (55) on use of antibiotics leave no doubt that antibiotics may cause adverse effects including vaginal and oral candidiasis, antibiotic-related diarrhoea and allergic reactions. In the study of long-term high dose Amoxycillin versus placebo (nineteen patients in each group, Reference 28) only the following new symptoms occurred more frequently in the antibiotic group: diarrhoea in seven patients on amoxycillin, three on placebo; sore throat, mouth or tongue in same numbers; genital candidiasis or urinary tract infection in four on amoxycillin ,one on placebo; similarly arthralgia or early morning stiffness in a four to one ratio.
Antibiotics predispose to the development of Pseudomembraneous colitis caused by Clostridium difficile toxin. However, C. difficile was not cultured in this study, which is the only one to assess faecal flora during long-term antibiotic therapy in bronchiectasis. Most of the coliforms cultured from the faeces were already resistant to amoxycillin. There was no significant increase in antibiotic resistance with antibiotic therapy. A study (56) of single intravenous doses of five different penicillins and eight different cephalosporins to six different healthy subjects showed emergence of C. difficile in 31% of subjects receiving cephalosporins and none of those receiving penicillins.
The first partially-controlled study (57) of antibiotic in a study of 62 patients including 38 with bronchiectasis is very salutary. The patients were treated with oral chloramphenicol( 1g ) two or three times weekly for periods of 2 to 6 months following an initial course of daily oral chloramphenicol or an alternative antibiotic. Thirty-six of the 38 patients with bronchiectasis experienced reductions in their daily sputum volumes by half or more. At the end of treatment fourteen patients were changed to placebo therapy while the remainder simply stopped the prolonged course of chloramphenicol. Relapse of symptoms occurred during the third month after stopping the antibiotic in most patients regardless of whether or not they had received the placebo medication. Two developed aplastic anaemia and one died as a result. The next year a further death from aplastic anaemia was reported in another study (58) to assess the value of long term chloramphenicol in bronchiectasis. The latter study was terminated prematurely and chloramphenicol was abandoned as a drug for prolonged therapy.
A study (59) of 197 patients with daily purulent sputum, of whom 26 had bronchiectasis received twice daily intramuscular therapy with either three different doses of cephaloridine(1,2 and 3g) twice daily for 14 days or combined penicillin(1.2g) for 14 days and streptomycin(500mg) for first 7 days. The treatment groups were well-matched despite patients known to be allergic to penicillin always being entered into the cephaloridine groups. The study showed that cephaloridine 2g was comparable to penicillin and streptomycin, 1g was worse and 3g superior. However, renal adverse effects precluded further use of this cephalosporin at high dose. In 1980s a study (60) of oral cefaclor 2g twice daily did not show any benefit compared with placebo in a double blind randomised trial in 22 patients with stable purulent bronchiectasis.
The Medical Research Council in 1957 conducted a major study (50) to assess the value of long-term oral antibiotics. It was a well-planned randomised double-blind, placebo-controlled multicentre study involving 122 patients. Thirty eight were prescribed penicillin, 44 oxytetracycline and 40 lactose(placebo) each 500mg four times daily for two days each week for one year. All patients had bronchiectasis proven by bronchography, respiratory symptoms for at least three months, and a total of at least 150ml of purulent or mucopurulent sputum from four 24hour sputum specimens collected at weekly intervals with a least 25 ml in the final collection. All groups showed a reduction in sputum volume greater for the purulent than the mucoid fraction during the year. The reduction in the oxytetracycline group was rapid and the purulent volume reduced to about half. The reduction in the penicillin and lactose groups was slower to about 70% of the original volume in each. There was a pronounced reduction in disability in the oxytetracycline group compared with the others expressed by numbers of days off work, days confined to bed, and episodes of fever. At that time the cost of long term oxytetracycline was felt to outweigh the benefit!
The only other double-blind placebo-controlled trial (61) at that time including patients with bronchiectasis (forty-five proven by bronchography out of a total of 67 patients) compared three oral antibiotics, namely tetracycline(500mg), combined(500mg) oleandomycin & penicillin, and penicillin G(250mg) alone. Each drug was prescribed four times daily for 3 to 22 months. The patients were assigned in rotation to each one of the four groups, occasionally placing a patient out of strict order to ensure that the groups remained similar for certain pre-treatment characteristics. Unfortunately, the mean pre-treatment 24hour sputum volume differed enormously and there was a wide range of disease severity enrolling both patients with background mucoid and purulent sputum. These differences mean that the clinical significance of the findings is uncertain, so the results are not included here.
The macrolide, erythromycin(500mg twice daily orally for 8 weeks) was compared with placebo in a double-blind randomised study (62) of 21 patients with steady-state idiopathic bronchiectasis. FEV1 , FVC & 24hour sputum volume significantly improved (p< 0.05), but there was no parallel improvement in sputum pathogens and inflammatory markers in the sputum. Roxithromycin (4mg/kg twice daily for 12 weeks), a semisynthetic macrolide not licensed in UK, reduced sputum purulence & leucocyte scores, and airway hyperreactivity, but did not improve FEV1 in a double-blind placebo-controlled study (63) in 25 children with bronchiectasis.
Long-term Ciprofloxacin for at least 90 days orally has been studied in an open retrospective report (64) about in ten patients with severe bronchiectasis. Seven patients improved but two became colonised by ciprofloxacin resistant Pseudomonas aeruginosa associated with clinical deterioration and one other reported a side effect.
Inhaled antibiotic therapy
Gentamicin 40mg twice daily nebulised in a hypotonic solution for three days was given to 16 of 31 patients with stable bronchiectasis & >30ml mucopurulent sputum/day in a double-blind randomised placebo-controlled study (65).The active treatment was associated with improved myeloperoxidase levels in sputum, sputum volume, PEFR, nocturnal oxygen desaturation, 6minute walking distances and subjective level of breathlessness. Serum Gentamicin levels in this study were peak between 1 & 2.5mg/l and almost undetectable trough levels.
A retrospective report was presented to the Yorkshire and Northern (UK) Thoracic societies of a consecutive series of eleven patients with bronchiectasis and prolonged daily purulent sputum prescribed 80mg nebulised gentamicin twice daily (66). The nebulised treatment was usually started after intravenous antibiotics had rendered the sputum mucoid, if previous short course intravenous antibiotics or long term oral antibiotics were not followed by a prolonged period of without daily purulent sputum. The results of this uncontrolled pilot study were: four responders, three patients with no obvious benefit or adverse effect, and the drug caused breathlessness in four (two with the test dose and two subsequently). The lengths of follow-up on long-term inhaled gentamicin were between 15 and 31 months (six patients). A cautionary case report describes a near fatal episode of bronchospasm following first inhalation of gentamicin (67).
After intravenous antibiotics to stabilise respiratory status, seventeen patients, colonised by Pseudomonas aeruginosa, were randomly allocated to a 12-month treatment with inhaled ceftazidime and tobramycin (group A) or a symptomatic treatment (group B) in Spain (68). One patient from group A abandoned inhaled treatment because of bronchospasm and one from group B died before the end of the study. The remaining fifteen (7 A, 8B) completed the study. The number of admissions and days of admission were different at p< 0.05. However, there were no differences in spirometry, arterial blood gases, oral antibiotic usage and antibiotic resistance at the end of the study.
An important placebo-controlled, double-blind, randomised study (41) of nebulised tobramycin 300mg twice daily for four weeks followed by two weeks without treatment enrolled 74 patients (37 in each group) with bronchiectasis and sputum colonised by Pseudomonas aeruginosa. At week four, there was a mean decrease in Pseudomonas density in sputum of 4.5 log10 in the tobramycin group compared with no change in the placebo group. At week six, Pseudomonas was undetectable in sputum of 35% of the tobramycin group and still present in all placebo group. Improvement in medical condition in 62% in tobramycin group and 38% in placebo group (odds ratio 2.7, 95% confidence interval 1.1 to 6.9). More patients in the tobramycin group reported increased cough, dyspnoea, wheezing and non-cardiac chest pain, but the symptoms did not limit therapy and there was no change in lung function after four weeks in either group.Tobramycin-resistant strains developed in 11% of tobramycin group and 3% of placebo group (p=0.36). An abstract has been published on the inhalation of tobramycin (TOBI) as maintenance treatment for similar patients (69). I shall chase up O'Donnell abstract for more detail.
Colomycin is licensed by aerosol, as an adjunct therapy in patients already receiving standard antibiotic therapy. To my knowledge, there is only one study (70) which included patients with non-cystic bronchiectasis (four out of 20 patients, sputum growing a mixture of Klebisella, Serratia, Aerobacter and Pseudomonas). The antibiotic was administered in two different doses (50 & 100mg, equivalent doses in megaunits are not stated) thrice daily for seven days. There were no toxic effects and all serum colistimethate levels were less than 250mg/l indicating that no significant absorption had taken place.
Physical therapy is indicated for patients expectorating an eggcupful (20ml) or more, purulent sputum daily (per 24hours) despite appropriate antibiotic therapy. Physical therapy is not readily accepted by patients. Only 23 out of 50 patients attending a specialist respiratory clinic for sputum producers were performing adequate physical therapy (71). This group all agreed that they had been asked to do physical therapy and each would have received initial individual instruction. Seventeen patients had difficulty finding time for physical therapy, 15 found it distasteful and in 17 it caused discomfort and pain. Pain was attributed to shaking movements and percussion techniques, often applied by partner.
No long-term randomised study of physical therapy has been published. Most research to test the effectiveness of physical therapy assesses the rate of mucociliary clearance from the lungs and expectorated sputum volumes during single episodes of physical therapy compared with controls. On the basis of this research, physical therapy should be simplified to the components shown to increase mucus clearance. In brief a combination of postural drainage with a cycle of breathing, forced expiration technique and directed cough (72). In detail, in a position suitable for gravity-assisted drainage of mucus, a cycle of four deep breaths with relaxed expiration followed by a pause for relaxation and "diaphragmatic" breathing, then one or two forced expirations (huffs) followed by another pause for gentle breathing will loosen secretions, which are cleared by one or two coughs. The cycle is repeated as often as necessary.
Appropriate positions for gravity-assisted drainage in CF-unrelated bronchiectasis are best limited in number for simplicity and compliance. Five basic positions will drain upper lobes (one position), lingula, middle lobe and each lower lobe. If the appropriate position is difficult to achieve or uncomfortable details should be supplied about more suitable equipment, such as specially designed bed or a foam wedge.
Physical therapy should be discussed with the patient and the prescription modified to enhance compliance whilst keeping the essential elements. For example, each position must be maintained for a minimum of ten minutes and until no more sputum is cleared, but only those positions yielding sputum are included in the agreed regimen. Prescriptions for physical therapy will vary from none, only during episodes of acute bronchitis, to once or twice daily regularly for background symptoms intensified during acute bronchitis. Nasal and oesophageal symptoms, that deter patients undertaking physical therapy, are often treatable.
The objectives of physical therapy in CF-unrelated bronchiectasis are to improve symptoms by focusing sputum expectoration to treatment sessions. This will clear sputum from the lungs earlier than usual, reducing the volume of sputum available as a culture medium for bacteria and acting as a stimulus for host inflammatory response. As a result there may be a reduction in the total volume of sputum produced. In theory, physical therapy offers the chance of reducing the frequency of antibiotic courses and disease progression.
Case control study highlights a possible role for non-invasive ventilation in patients with severe hypercapnic respiratory failure (73).
Immunosuppressive and anti-inflammatory therapy
The rationale for this therapy is derived from the 'vicious' circle hypothesis(43). In patients with CF-unrelated bronchiectasis, there are only two published randomised double blind placebo-controlled studies of corticosteroids. The earlier study (74) in Northern Ireland was cross-over design in 20 patients. An 18% reduction in daily sputum volume (p<0.003), of the order of only 3g/day, was observed on treatment with inhaled beclomethasone 750mcg twice daily for six weeks compared with placebo. A small improvement in morning peak flow rate and forced expiratory volume in one second (p<0.03), but the absolute values were small. Symptom scores for cough improved significantly (p<0.02).
A more recent double-blind placebo-controlled randomised study (75) of fluticasone 500mcg twice daily inhaled via Accuhaler in 24 patients with stable idiopathic bronchiectasis in Hong Kong gave equivocal results. After four weeks there was no significant change in 24hour sputum volume, bacterial densities or tumour necrosis factor-alpha in sputum and no change in spirometry. However there was a significant decrease in sputum leucocyte density,interleukin-1beta & 8 and leukotriene B4.
There is insufficient evidence to justify regular inhaled corticosteroids routinely for patients with CF-unrelated bronchiectasis in the absence of asthma. However, in my view fortnight trial of oral corticosteroids (Prednisolone 30mg daily) is worthwhile, if purulent sputum volume is not readily responsive to antibiotics. This will assess the steroid responsiveness of the purulent sputum in the individual patient. An impressive response of respiratory symptoms to oral steroids was seen in a patient developing bronchiectasis after colectomy for Crohn's disease (76); and the abolition of purulent sputum by regular standard dose inhaled corticosteroids in two patients with bronchiectasis and ulcerative colitis without evidence of asthma (personal unpublished cases) may indicate a more definite role for corticosteroids in patients with inflammatory bowel disease.
Additional information on use of corticosteroids in other disorders associated with sputum production
In children with cystic fibrosis long-term oral steroids alternate days for three years showed significant benefits with respect to height, weight, lung vital capacity, forced expiratory volume in one second, peak expiratory flow rate, erythrocyte sedimentation rate and serum immunoglobulin G class (77). Yet there was no benefit in adults with cystic fibrosis after three weeeks higher dose(20-30mg daily) treatment (78).
Two large studies (79,80) using inhaled corticosteroids in chronic obstructive pulmonary disease, which did not show any reduction in the primary end point (rate of decline of FEV1), appeared to show a reduction in the frequency of bronchitis in the active groups. This secondary analysis has generated the hypothesis that inhaled corticosteroids may have a role in preventing or ameliorating acute bronchitis in smokers with COPD (79).
There are no studies of other immunosuppressants. However there is one interesting pilot study of non-steroidal anti-inflammatory drugs (81). Nebulised indomethacin (2.4mcg) three times daily for one week was given to 13 of 25 patients in a randomised, placebo-controlled study. Four patients in each treatment group had bronchiectasis, the others had chronic bronchitis or diffuse panbronchiolitis. The whole indomethacin group recorded an average reduction in sputum weight from 189 to 95g/day (p< 0.001) and reduced dyspnoea score (p<0.01) There was no change in sputum bacterial concentration, lung function or ESR. No parameters changed in the placebo group.
Specific therapy for individual causes
Panhypogammaglobulinaemia - intravenous immunoglobulins with guidance and supervision from Consultant Immunologist.
Inherited immune deficency or neutrophil dysfunction - seek expert advice of Consultant Immunologist.
Primary ciliary dyskinesia - more intensive therapy advised, based on the assumption that disease progression is more likely. Emphasis on the importance of physical therapy.
TB, HIV, Inflammatory bowel disease, Rheumatoid arthritis, Sarcoidosis - treat active associated disease. There is no evidence that control of Inflammatory bowel disease and Rheumatoid arthritis prevents problems with bronchiectasis. Bronchiectasis may precede, accompany or follow the development of these associated diseases.
Allergic bronchopulmonary aspergillosis(ABPA) - the objectives are control of asthma and prevention or limitation of damage from acute exacerbations of ABPA. Consider maintenance oral corticosteroids. Antifungal therapy of uncertain value (82) and remain a second-line choice, unless there is associated invasive Aspergillosis.
Psychological - reassurance, education, instruction from Physiotherapist and, if necessary referral to Clinical Psychologist.
Mucolytics and DNase - There are four randomised double-blind placebo-controlled studies of therapy to influence the character of mucus in patients with bronchiectasis (83,84,85,86). There was no benefit & potential harm from nebulised recombinant human (rh) DNase for 24 weeks tested in a population of 349 adult outpatients with stable bronchiectasis (background symptoms only at the time of enrolment) from 23 centres in North America, Great Britain & Ireland (83). The primary end-points were worse in the rhDNase group: pulmonary exacerbations were more frequent and decline in FEV1 from baseline was greater. Bromohexine (30mg capsules three times daily orally) has been compared with placebo in 88 in-patients with acute exacerbations of bronchiectasis in Italy (84). All patients received ceftazidime 1g intramuscularly daily during the first week. Those receiving bromohexine had less difficulty with expectoration of sputum and expectorated less sputum at day 16. In an earlier study of 60 patients with acute lower respiratory tract infection (40 with underlying bronchiectasis) received amoxycillin (500mg) or a combination tablet (bromohexine 8mg with amoxycillin 500mg) three times daily orally for seven days. The clinical response to treatment was better (p<0.01) as assessed by both the clinicians and the patients separately in a predetermined manner. The factors considered were: severity of cough, difficulty of expectoration, sputum purulence and sputum volume. In addition, the concentration of amoxycillin in the sputum measured after the first dose was significantly higher in the combination group (amoxycillin alone: 0.27 [SD 0.2]mg/l, with bromohexine: 0.67 [0.6]mg/l).
Several small single dose studies testing the effect of Hypertonic saline, Terbutaline, Water and 2-Mercaptoethane sulphonate on mucus clearance are discussed elsewhere (87). In another study (88), hypertonic saline has been shown to speed up the transport of sputum from humans with bronchiectasis, with or without cystic fibrosis, in-vitro along bovine tracheal rings depleted of animal mucus. The viscoelasticity of sputum, but not the bovine ciliary beat frequency, was markedly dependent on the concentration of saline over the pathophysiological range. The paper suggested that low mucus salinity and not (as generally assumed) its underhydration, contributes to its retention in bronchiectasis. The paper concludes that therapies that increase the osmolality of lung mucus might benefit patients with mucus retention. Inhalation of dry-powder Mannitol (300mg) increased mucus clearance (85), using a radioaerosol technique over 75minutes compared with the same 11 patients studied after no intervention and on control days (p<0.00001). On control days, patients reproduced the breathing manoeuvres and the number of coughs induced by mannitol. A 24hour study (86) in eight patients showed that on the day of inhalation of a single dose of mannitol less mucus was retained at 24 hours, compared with two control days.
Bronchodilator therapy and oxygen - following the British Thoracic Society guidelines for Chronic obstructive pulmonary disease(COPD, 89) is logical for the component of COPD due to bronchiectasis.
Bronchodilator, regular inhaled and courses of oral corticosteroids and other add-on therapies following with BTS guidelines for the management of asthma (90) for those patients with asthma in association with bronchiectasis.
Reversibility to bronchodilators is more common in patients with bronchiectasis than the general population. Airway hyperreactivity to histamine (91) and to metacholine (34) was present in 48% and 69% respectively of tested patients. In a study of 23 patients, nine recorded >15% improvement in FEV1 after the inhaled beta2 agonist fenoterol (92). A more recent study (93) in 24 patients with bronchiectasis in Malaysia showed reversibility, defined in the same way, in 32% to nebulised fenoterol (5mg) and the same rate to ipratropium bromide (500mcg). 20% responded to both drugs, 12% to only one of the two drugs.
Control of allied symptoms and exacerbating factors for sputum production
Nasal treatment - A careful history will identify the source of most secretions cleared from the mouth. In many patients the mucus expectorated is a combination of sputum (mucus from the lungs) and post-nasal discharge (mucus from the nose via the pharynx). Radio-opaque dye placed in the nose has been demonstrated in the lung the following day and visa-versa (94,95) Effective control of nasal symptoms with topical corticosteroids (96) may dramatically reduce the volumes of mucus cleared from the mouth and sometimes the level of breathlessness due opening up the nasal passages by reducing inflammation. However, it is important to refer to an ENT specialist if there is uncertainty about the diagnosis or risk of malignancy (for example blood in the post-nasal discharge or blood in the anterior nasal discharge from one nostril).
Oesophageal reflux and risk of lung aspiration of gastrointestinal secretions - Screen in the history for oesophageal reflux and features of aspiration (eg. nocturnal-onset episodes of acute bronchitis or cough on lying flat). Control of reflux and aspiration may be achieved using proton pump inhibitors or surgery. A three month trial with effective reflux symptom control may be helpful to establish if reflux is responsible for any of the respiratory and systemic symptoms. Oesophageal pH monitoring and upper gastrointestinal endoscopy are often useful to judge objectively the severity of the reflux and to guide treatment choices.
New prolonged purulent bronchitis
Manage the sputum expectoration and other symptoms as for established bronchiectasis with the objective of stopping sputum expectoration and reducing sputum production to normal, restoring mucus clearance and health. Undertake additional tests judiciously.
A snap shot of a selected group of patients with daily purulent sputum expectoration and bronchiectasis
In search of patients with daily purulent sputum expectoration and bronchiectasis in 1985 & 1986, the hospital notes of the whole population of patients coded for bronchiectasis at Brompton Hospital, London, between 1970 and January 1986 were screened. Five hundred and thirty-seven patients alive without major complications of the disease (eg respiratory failure) or other major illness (eg active tuberculosis) were identified. Patients with CF, ABPA and PCD were excluded.
Thirty six patients reporting daily production of 10ml or more purulent sputum were enrolled in a double blind placebo-controlled prolonged antibiotic study (28) and took the study treatment for more than six weeks. They were intensively studied prior to recruitment. This baseline data characterises a sample of patients with bronchiectasis expectorating purulent sputum daily. These patients were attending a tertiary referral centre specialising in respiratory disease. However many of the observations made in this selected group of patients are in my view valid for the wider population of UK patients with bronchiectasis in whom CF, ABPA and PCD have been excluded.
Bronchiectasis was demonstrated on thick section (10mm slice width ) CT scans to affecting three or more lobes in 22 out of the 36 patients. Thick section CT scanning was shown to have a sensitivity of 66% and specificity of 92% at the level of segmental bronchi compared with bronchography (12). The interpretation of CT was shown to be as subjective as bronchography (97). Thin section (2 or 3 mm slice width) has superceded thick section CT and bronchography for diagnosis (2).
Lung function was impaired in this group of 36 patients with a median FEV1 52% predicted (range 22-107%). Twenty-three patients had an obstructive ventilatory defect, two restrictive and two mixed obstructive and restrictive ventilatory defect.
Mucociliary clearance, judged by six hour clearance of inhaled radioaerosol, was slower than normal subjects (89%) in patients with bronchiectasis (61%), similar to that of patients with COPD with or without chronic bronchitis.
The 36 patients were asked to report symptoms in more detail following a standard doctor-administered questionnaire. Symptoms during episodes of acute bronchitis and background symptoms between episodes are tabulated below.
During episodes of acute Bronchitis these patients with Bronchiectasis experienced a multitude of general and respiratory symptoms which restricted lifestyle in thirty-three (92%). Between episodes of acute Bronchitis, the background symptoms restricted lifestyle in twenty-eight (78%) patients and as many as eleven (31%) felt unwell.
General symptoms between acute episodes are often overlooked and yet they are very important when considering treatment options. Sputum bacteriology between exacerbations Four samples of purulent sputum from each patient were collected in a morning over a four hour period and cultured on general and selective culture media (49). Moderate or large numbers of the following bacteria were isolated at least once in the following number of patients.
The overall colonising bacterial load was measured in 22 patients. It ranged from 2 x 10 6 to more than 10 10 bacteria per millilitre. Sputum load in 13 of 22 patients was between 10 8 and 10 9 bacteria/ml.
Inflammatory activity between exacerbations
In the group of patients with purulent bronchiectasis, the volume of sputum cleared over 24 hours was measured on two separate occasions between exacerbations. Fresh four hour morning collections of sputum were examined macroscopically and its characteristics were arbitarily defined as the same as the 24 hour collection. The 24 hour sputum volume ranged from 15 to 312ml with a median of about 30ml. The purulent component of the sputum was green (only one yellow sample out of seventy-two) and of mid- intensity ( ++ ) of colour. The 24 hour purulent sputum volume ranged from 2 to 113ml with a median of about 20ml. Purulent sputum volume best discriminated responders and non- responders to prolonged amoxycillin (28).
Elastolytic activity of sputum, probably a product of neutrophils, was raised between episodes of acute Bronchitis in these patients (28). Prior to antibiotic therapy during periods of background symptoms only, six had raised white cell counts in the blood. ESR was raised in 28 patients, median value 13mm in first hour, range from 1 to 68mm. Total Immunoglobulin (Ig) G levels were raised in 6/36, IgA in 17/36 and IgM none.
1 Reid LM. Reduction in subdivisions in bronchiectasis. Thorax 1950; 5: 233-47.
2 Hansell DM. Bronchiectasis. In: Webb WR ed. Imaging in obstructive pulmonary disease. Publ.: WB Saunders Co Ltd. 1998:107-28.
3 Simon G, Galbraith HJB. Radiology of chronic bronchitis. Lancet 1953; ii: 850-2.
4 Garbett ND, Currie DC, Cole PJ. Persistent purulent sputum without evidence of bronchiectasis. Am.Rev.Respir.Dis. 1987;135:A42.
5 Cole PJ. A new look at the pathogenesis and management of persistent bronchial sepsis: a "vicious circle" hypothesis and its logical therapeutic connotations. In: Strategies for the management of chronic bronchial sepsis. Editor: Davies RJ, Oxford: Medicine Publishing foundation:1-20.
6 MRC Report of committee on the aetiology of chronic bronchitis. Definition and classification of chronicbronchitis for clinical and epidemiological purposes. Lancet 1965; 1: 775-9.
7 Fleishner FG. Reversible bronchiectasis.AJR 1941; 46: 166-72.
8 Yamanaka A,Saiki S,Tamura S,Saito K. Problems in chronic obstructive pulmonary disease, with special reference to diffuse panbronchiolitis. Naika 1969; 23: 442.
9 Crofton J, Douglas A. Bronchiectasis: Chapter 24. In: Respiratory Diseases 3rd ed. Oxford: Blackwell Scientific Publications:417-30.
10 Currie DC, Cooke JC, Morgan AD, Kerr IH et al. Interpretation of bronchograms and chest radiographs in patients with chronic sputum production. Thorax 1987; 42: 278-84.
11 O'Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000; 55: 635-42.
12 Ellis DA, Thornley PE, Wightman AJ, Walker M et al. Present outlook of bronchiectasis: Clinical and social study and review of factors affecting prognosis. Thorax 1981; 36: 659-64.
13 Cole P. Bronchiectasis. Chapter 39 in Respiratory Medicine Textbook 2nd edition eds. Brewis RAL, Corrin B, Geddes DM, Gibson GJ. publ. WB Saunders Co Ltd. 1995: 1286-1316.
14 Greenstone M & Cole PJ. Br.J.Dis.Chest 1985; 79: 9-26.
15 Shin MS, Ho KJ. Bronchiectasis in patients with alpha 1-antitrypsin deficency. A rare occurrence? Chest 1993; 104: 1384-6.
16 Annobil SH, Morad NA, Kameswaran M, el Tahir MI, Adzaku F. Bronchiectasis due to lipid aspiration in childhood: clinical and pathological correlates. Ann.Trop.Paed. 1996;16: 19-25.
17 McCarthy DS, Simon G, Hargreave FE. The radiological appearances in allergic bronchopulmonary aspergillosis. Clin.Radiol. 1970; 21: 366-75.
18 Holmes AH, Trotman-Dickenson B, Edwards A, Peto T, Luzzi GA. Bronchiectasis in HIV disease. Q.J.Med. 1992; 85: 875-82.
19 Dukes RJ, Rosenow EC III, Herman PE. Pulmonary manifestations of hypogammaglobulinaemia. Thorax 1978; 33: 603-7.
20 Hendry WF, Knight RK, Whitfield HN, Stansfield AG et al. Obstructive azoospermia: respiratory function tests, electron microscopy and results of surgery. Br.J.Urol. 1978; 50: 598-604.
21 Hendry WF, A'Hern RP, Cole PJ. Was Young's syndrome caused by exposure to mercury in childhood? BMJ. 1993; 307: 1579-82.
22 Butland RJA, Cole P, Citron KM, Turner-Warwick M. Chronic bronchial suppuration and inflammatory bowel disease. Q.J.Med. 1981; 50: 63-75.
23 Walker WC.Pulmonary infections & rheumatoid arthritis.QJMed 1967; 36: 239-51
24 Hiller E, Rosenow EC III, Olsen AM. Pulmonary manifestations of yellow nail syndrome. Chest 1972; 61: 452-7.
25 Dhillon SS, Watanakunakorn C. Lady Windermere syndrome: middle lobe bronchiectasis and Mycobacterium avium intracellulare due to voluntary cough suppression. Clin Infect. Dis. 2000; 30:572-5.
26 Evans SH, Davis R, Cooke J, Anderson W. A comparison of radiation doses to the breast in computed tomographic chest examinations for two scanning protocols. Clin. Radiol. 1989; 40: 45-6.
27 Thomas RD, Blaquiere RM. Reactive mediastinal lymphadenopathy in bronchiectasis assessed by CT. Acta Radiol. 1993; 34: 489-91.
28 Currie DC, Garbett ND, Chan KL, Higgs E et al. Double-blind randomised study of higher-dose amoxycillin in purulent bronchiectasis. Q.J.Med. 1990; 76: 799-816.
29 Stockley RA, Bayley D, Hill SL, Hill AT et al. Assessment of airway neutrophils by sputum colour: correlation with airways inflammation. Thorax 2001; 56: 366-72.
30 May JR. Pathogenic bacteria in chronic bronchitis. Lancet 1954; 2: 839-42.
31 Fujita J, Nakamura H, Yamagishi Y, Yamaji Y et al. Elevation of plasma truncated elastase alpha 1-proteinase inhibitor complexes in patients with inflammatory lung diseases. Chest 1992; 102: 129-34.
32 Shah PL, Mawdsley S, Nash K, Cullinan P et al. Determinants of chronic infection with Staphlococcus aureus in patients with bronchiectasis. Eur.Respir.J. 1999; 14: 1340-4.
33 Currie DC, Saverymuttu SH, Peters AM, Needham SG et al. 111Indium-labelled granulocyte accumulation in the respiratory tract in bronchiectasis. Lancet 1987; 1: 1335-9.
34 Bahous J, Cartier A, Pineau L, Bernard C et al. Pulmonary function tests and airway responsiveness to metacholine in chronic bronchiectasis of the adult. Bull.Europ.Physiopath.Respir. 1984; 20: 375-80.
35 Cherniack N, Vosti KL, Saxton GA, Lepper MH et al. Pulmonary function tests in fifty patients with bronchiectasis. J.Lab.Clin.Med. 1959; 52: 693-707.
36 Pande JN Jain BP, Gupta RG, Guleria JS. Pulmonary ventilation and gas exchange in bronchiectasis. Thorax 1971; 26: 727-33.
37 Munro NC, Currie DC, Lindsay KS, Ryder TA et al. Fertility in men with primary ciliary dyskinesia presenting with respiratory infection. Thorax 1994; 49: 684-7.
38 Rutland J, Cole PJ. Non-invasive sampling of nasal cilia for measurement of beat frequency and study of ultrastructure. Lancet 1980; 2: 564-5.
39 Karadag B, James AJ, Gultekin E, Wilson NM, Bush A. Nasal and lower airway level of nitric oxide in children with primary ciliary dyskinesia. Eur.Respir.J. 1999; 13: 1402-5.
40 Hill SL, Mitchell JL, Burnett D, Stockley RA. IgG subclasses in the serum & sputum from patients with bronchiectasis. Thorax 1998; 53: 463-8.
41 Ward S, Heyneman L, Lee MJ, Leung AN et al. Accuracy of CT in the diagnosis of ABPA in asthmatic patients. AJR. 1999; 173: 937-42.
42 Hodson ME, Beldon I, Power R et al. Sweat test to diagnose cystic fibrosis in adults. BMJ. 1983; 286: 1381-3.
43 Cole PJ. Inflammation: a two-edged sword - the model of bronchiectasis. Eur.J.Respir.Dis. 1986; 69 suppl 147: 6-15.
44 Munro NC, Han LY, Currie DC, Strickland B, Cole PJ. Radiological evidence of progression of bronchiectasis. Respir.Med. 1992; 86: 397-401.
45 Cotes JE. Lung function: principles and application in medicine. 1979 4th ed. Oxford: Blackwell Scientific Publications.
46 Agasthian T, Deschamps C, Trastek VF, Allen MS, Pairolero PC. Surgical management of bronchiectasis. Ann.Thor.Surg. 1996; 62: 976-80.
47 Au J, Scott C, Hasan A, Colquhoun I et al. Bilateral sequential lung transplant for septic lung disease: surgical and physiological advantages over heart-lung transplant. Transplant Proc. 1992; 24: 2652-5.
48 Department of Health et al. Ed Salisbury DM, Begg NT. Immunisation against infectious disease (in the UK) 1996.
49 Currie DC, Higgs E, Metcalfe S, Roberts DE, Cole PJ. A simple method of monitoring the colonising microbial load in chronic bronchial sepsis: pilot comparison of the reduction in colonising microbial load with intermittent and continuous antibiotics. J.Clin.Path.1987; 40: 830-6.
50 Medical Research Council (subcommittee of the antibiotics clinical trials[non-tuberculous] committee). Prolonged antibiotic therapy in severe bronchiectasis. BMJ. 1957; 2: 255-9.
51 Barker AF, Couch L, Fiel SB, Gotfried MH et al. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis. Am.J.Respir.Crit.Care Med. 2000; 162: 481-5.
52 Welsh Drug Information Centre. Questions and Answers for junior doctors. August 2000
53 Hill SL, Morrison HM, Burnett D, Stockley RA. Short-term response of patients with bronchiectasis to treatment with amoxycillin given in standard or high doses or by inhalation. Thorax 1986; 41: 559-65.
54 Allen MB, Fitzpatrick RW, Barratt A, Cole RB. The use of probenecid to increase the serum amoxycillin levels in patients with bronchiectasis. Respir. Med. 1990; 84: 143-6.
55 Currie DC. Cambridge University MD Thesis: The progression of lung damage in bronchiectasis - testing a hypothesis. 1988; 49-58.
56 Ambrose NS, Johnson M, Burdon DW, Keighley MRB. The influence of single dose intravenous antibiotics on faecal flora and emergence of Clostridium difficile. J.Antimicrob.Chemother. 1985; 15: 319-26.
57 Harris MS, Gomell L, Shore C, Lovitz H. Chloramphenicol in the control of bronchopulmonary suppuration. Dis.Chest 1952; 21: 450-4.
58 Franklin AW, Garrod LP. Chloramphenicol treatment of bronchiectasis in children. BMJ. 1953; 2: 1066-9.
59 Pines A, Raafat H, Plucinski K, Greenfield JSB, Linsell WD. Cephaloridine compared with penicillin and streptomycin in chronic purulent bronchitis. Br.J.Dis.Chest 1967; 61: 101-10.
60 Munro NC et al. Cefaclor. Eur.J.Respir.Dis. circa 1990
61 Cherniack N, Vosti KL, Dowling HF, Lepper MH, Jackson GG. Long-term treatment of bronchiectasis & chronic bronchitis. Arch.Intern.Med 1959; 103: 345-53.
62 Tsang KW, Ho PI, Chan KN, Ip MS et al. A pilot study of low-dose erythromycin in bronchiectasis. Eur.Respir.J. 1999; 13: 361-4.
63 Koh YY, Lee MH, SunYH, Sung KW, Chae JH. Effect of roxithromycin on airway responsiveness in children with bronchiectasis: a double blind, placebo-controlled study. Eur.Respir.J. 1997; 10: 994-9.
64 Rayner CF, Tillotson G, Cole PJ, Wilson R. Efficacy and safety of long-term ciprofloxacin in the management of severe bronchiectasis. J.Antimicrob.Chemother. 1994; 34:149-56.
65 Lin H-C, Cheng H-F, Wang C-H, Liu C-Y et al. Inhaled gentamicin reduces airway neutrophil activity and mucus secretion in bronchiectasis. Am.J.Respir.Crit.Care Med. 1997; 155: 2024-9.
66 Currie DC. Nebulised gentamicin in ten patients with bronchiectasis. Presentation to Yorkshire & Northern UK Thoracic Societies 9th March 1997 (unpublished).
67 Melani AS, Di Gregorio A. Acute respiratory failure due to gentamicin aerosolisation. Monaldi Arch. Chest. Dis. 1998; 53: 274-6.
68 Orriols R, Roig J, Ferrer J, Sampol G et al. Inhaled antibiotic therapy in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Respir. Med. 1999; 93: 476-80.
69 O'Donnell A, Tully H, Kylstra JW, Wells C et al. Tobramycin solution (TOBI) as maintenance treatment for bronchiectasis patients with Pseudomonas aeruginosa. Thorax 1999; 54 suppl. 3: 200 (A68).
70 Rose HD, Pendharker MB, Snider GL, Kory RC. Evaluation of sodium colistimethate in Gram-negative infections of the respiratory tract. J.Clin.Pharm. 1970; 10: 274-81.
71 Currie DC, Munro C, Gaskell D, Cole PJ. Practice, problems and compliance with postural drainage: a survey of chronic sputum producers. Br.J.Dis.Chest 1986; 80:249-53.
72 Pryor JA, Webber B, Hodson ME, Batten JC. Evaluation of the forced expiration technique as an adjunct to postural drainage in the treatment of cystic fibrosis. BMJ. 1979; 2:417.
73 Benhamou D, Muer JF, Raspaid C, Cuvelier A et al. Longterm efficency of home mask ventilation in patients with diffuse bronchiectasis.and severe chronic respiratory failure: a case control study. Chest 1997; 112: 1259-66.
74 Elborn JS, Johnston B, Allen F, Clarke J et al. Inhaled steroids in patients with bronchiectasis. Respir. Med. 1992; 86: 121-4.
75 Tsang KW, Ho PL, Lam WK, Ip MS et al. Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis. Am.J.Respir.Crit.Care Med. 1998; 158: 723-7.
76 Eaton TE,Lambie N, Well AU. Bronchiectasis following colectomy for Crohn's disease. Thorax 1988; 53: 526-7.
77 Auerbach HS, Williams M, Kirkpatrick JA, Colten HR. Alternate-day prednisolone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 1985; 2: 686-8.
78 Pantin CFA, Stead RJ, Hodson ME, Batten JC. Prednisolone in the treatment of airflow obstruction in adults with cystic fibrosis. Thorax 1986; 41: 34-8.
79 Burge PS, Calverley PMA, Jones PW, Spencer S et al on the behalf of the ISOLDE study investigators. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320: 1297-303.
80 Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking (Euroscop). N.Engl.J.Med. 1999; 340: 1948-53.