*Specialist Registrar in Dermatology, Ninewells Hospital, Dundee, U.K. 
(Previously Senior House Officer in Medicine, Manor Hospital, Walsall)
**Specialist Registrar in Endocrinology, Princess Royal Hospital, Telford, U.K.
(Previously Senior House Officer in Medicine, Manor Hospital, Walsall)
***General Practice Registrar, Leicester Vocational Training Scheme, U.K.
(Previously Senior House Officer in Medicine, Manor Hospital, Walsall)
****Specialist Registrar in Respiratory Medicine, Walsgrave Hospital, Coventry, U.K.
*****Staff Grade Physician in Respiratory Medicine, Manor Hospital, Walsall, U.K.
******Retired Consultant Physician in Respiratory Medicine, Manor Hospital, Walsall, U.K.
*******Consultant Physician in Respiratory Medicine, Manor Hospital, Walsall, U.K.

Address for correspondence and requests for reprints:
Dr. U. Nandy, 35-Lister Place, Ninewells Hospital, Dundee DD2 1UX 
Telephone: 01382 669998
Mobile: 07766003307 
Fax: 01922 656449
E-mail: utpalnandy@hotmail.com

Abstract

Bronchiectasis is often associated with increased microbial load. This results in persistent inflammatory host response thereby causing progressive lung damage and deterioration in lung functions. Antibiotic therapy is given for infective exacerbation or on regular pulsed basis to reduce microbial load. Daily nebulised antibiotic therapy in cystic fibrosis has shown to, improve lung functions, reduce the density of microflora in the sputum and hospital admissions. We retrospectively analysed the effects of daily nebulised antibiotic therapy in 20 adults with bronchiectasis not associated with cystic fibrosis. Conclusion: Regular nebulised antibiotic therapy in patients with bronchiectasis requiring frequent courses of systemic antibiotics is well tolerated. It reduces infection and hence inflammation thereby improving symptoms and preserving pulmonary functions, with minimal side effects.
Key Words: Bronchiectasis, ESR (Erythrocyte Sedimentation Rate), CRP (C-Reactive Protein), Nebuliser, Antibiotics.



Short Introduction

Bronchiectasis is defined as permanent abnormal dilation and destruction of segmental or subsegmental bronchi or bronchioles. Generally accompanied by suppurative inflammations, the end result of a various group of pathologies. First described by Laennec in 1819 and later detailed by Sir William Osler in the Late 1800s.The incidence has dramatically decreased over the last 60 years in developed countries because of the remarkable advance in our ability to prevent or treat many infectious respiratory diseases that caused bronchiectasis. This is due to vaccinations for measles, pertussis and influenza, treatment for tuberculosis and antibiotics effective against the usual bacterial causes of pneumonia and acute bronchitis. Now, this primary form is becoming increasingly rare. (Table 1)

Bronchiectasis is often associated with increased microbial load. This results in persistent inflammatory host response thereby causing progressive lung damage and deterioration in lung functions. Antibiotic therapy is given for infective exacerbation or on regular pulsed basis to reduce microbial load. Daily nebulised antibiotic therapy in cystic fibrosis has shown to, improve lung functions, reduce the density of microflora in the sputum and hospital admissions. We retrospectively analysed the effects of daily nebulised antibiotic therapy in 20 adults with bronchiectasis not associated with cystic fibrosis. They had a history of at least one exacerbation a month requiring systemic antibiotic therapy. Lung function tests, inflammatory markers, number of acute exacerbations, hospital admissions and symptoms before and while on regular nebulised antibiotics were analysed. Mean duration of follow up was 3.7 years and median 3.2 years. There was a mean reduction in acute exacerbation by 41% and hospital admissions by 38%. FEV1 improved or remained stable in 65%, FVC in 45% and PEFR in 75%. Mean reduction in ESR was 45% and in CRP 20%. Symptoms improved in 60% of patients. Colour and quantity of sputum improved in 45%. None of the patients had antibiotic related side effects. We conclude that regular nebulised antibiotic therapy in bronchiectasis is well tolerated, improves symptoms and preserves lung functions.


Materials and Methods 

Case notes of 60 patients who were attending the Bronchiectasis outpatient clinic were retrospectively audited. The diagnosis of Bronchiectasis was based on history, clinical examination and chest x-ray. It had been confirmed with High Resolution CT or conventional CT scan of the chest. The main criteria being the internal diameter of the bronchus greater than the diameter of the accompanying pulmonary artery with or without morphological criteria, e.g. cylindrical, varicose and cystic types. The patients who had purulent sputum requiring treatment with systemic antibiotic on at least one occasion in a month were those found to have been treated with nebulised antibiotics. Three sputa specimens had been obtained during an acute exacerbation, for microbiological examination prior to the commencement of the nebulised antibiotic. Selection of an antibiotic for nebulisation was based on the results of sputum culture and sensitivity. Side effects profiles of the antibiotics had been explained to the patients and verbal consent had been obtained. Intravenous preparation of the antibiotics Amoxycillin 500mg, Cefuroxime 750mg, Gentamycin 80mg and Colistin 1 million units were used. Gentamycin and Colomycin were avoided in those patients with obvious renal failure. Nebulised antibiotics were administered twice daily. Total volume of nebulised solution varied between 3-5ml. Patients had been encouraged to continue self-administered postural drainage once or twice daily and to continue their regular drug therapy. Patients were reviewed at about every three months. On each visit patients had clinical assessment, haematological and biochemical profiles and pulmonary function tests. 

Results

20 out of 60 patients had long-term nebulised antibiotic therapy. A retrospective audit of these patients' medical records in assessing age, sex, height, weight, smoking, respiratory symptoms, colour and volume of the sputum, type of organism, inflammatory markers, pulmonary function tests and number of hospital admissions were carried out. Self-administered questionnaires had been used in assessing colour and volume of the sputum and respiratory symptoms. A patient was considered to have persistent infection with a bacterial pathogen if that organism was grown on three consecutive sputum cultures. Similarly the patient was assumed to be free of bacterial pathogens when three consecutive specimens of sputum were negative on culture. Respiratory symptoms, mean inflammatory markers, the best set of values of pulmonary function tests, number of acute exacerbations, number of hospital admissions and colour and volume of sputum in the pre antibiotic and antibiotic phase were compared. Statistical significance was calculated by using Paired student's-Test (p <0.05) and confidence interval. Colour of the sputum was analysed by using scoring system, mucoid-1, mucopurulent-2, purulent-3 and the significance was estimated by the Wilcoxon Matched Test. Acute exacerbation was defined as increased sputum production with change in colour and worsening respiratory symptoms. Mean duration of follow up on nebulised antibiotics were 3.7 years (Median 3.2 years; Range 1.1 - 8.8 years). The objective of treatment with nebulised antibiotics in patients with bronchiectasis is to reduce the colonising microbial load in the lungs, improve symptoms and prevent deterioration of lung function, without the side effects associated with prolonged antibiotic therapy. Only 20 out of 60 patients with bronchiectasis had satisfied the criterion for nebulised antibiotic therapy, i.e. at least one exacerbation in a month requiring a systemic antibiotic. Median age of these patients was 65 years and 55% of patients were female. None of the patients were smokers during the period of study. [Table 3]

Common respiratory pathogens [Table 4] were Haemophilus influenzae (12 patients) and Pseudomonas aeruginosa (6 patients). Resistance to Amoxycillin occurred in 3 patients with H. Influenzae and to Gentamicin in one patient with P. aeruginosa, necessitating a change of administered antibiotic. 

Haemophilus Influenzae was eradicated in 10 out of 12 patients; four of these patients, however, were subsequently colonised with other organisms; P. aeruginosa in two and mixed coliforms in two. Pseudomonas aeruginosa tends to colonise patients with severe disease, associated with poor lung functions[1]. This pathogen is difficult to eradicate even with antibiotics effective against the organism2. It can reduce the density of P. aeruginosa in sputum. It was, however, possible to eradicate it in two of the 8 patients colonised with P. aeruginosa. In patients with cystic fibrosis introduction of antibiotic therapy (nebulised or combined nebulised and oral) at the time of initial colonisation may delay or prevent the establishment of chronic infection[2,3,4] and improve lung functions[2]. 

Mean CRP and ESR were elevated and mean white cell count was at the upper limit of normal prior to nebulised antibiotic therapy. Inflammatory markers such as CRP, ESR and white cell counts correlate with severity of the disease and impairment of lung functions5. With nebulised antibiotic therapy the reduction in mean values of ESR, CRP and white cell count were 45%, 20% and 11% respectively. Only the reduction in ESR was statistically significant [Table 5].

All the patients had cough, sputum production and breathlessness on exertion. Twelve patients (60%) achieved subjective improvement in respiratory symptoms and feeling of well being with antibiotic therapy. Daily purulent sputum production, indicative of significant host inflammatory response, is likely to be an important risk factor for progression of the disease[6]. Nebulised antibiotic therapy reduced the volume and purulence of sputum in 45% of our patients. The reduction in purulence is statistically significant; the reduction in volume could not be statistically analysed. Stockley7 has shown reduction in sputum volume and purulence with prolonged nebulised Amoxycillin in six patients who did not respond to oral high dose Amoxycillin. Prolonged administration of oral Amoxycillin in very high doses (3 g twice daily) has been shown to reduce the sputum volume8. We were able to achieve the same objective without the side effects inherent with prolonged high dose oral antibiotic therapy. Some studies have shown that nebulised Gentamicin is effective in improving airway hypersecretion and inflammation.

Pulmonary function tests [Table 7] showed obstructive ventilatory defect in 18 patients; of these mixed obstructive and restrictive pattern was seen in 13 patients and exclusively obstructive defect in 5 patients. Only 2 patients showed restrictive ventilatory defect. Seven patients with obstructive or mixed ventilatory disorder had Kco less than 80% of predicted. a1 anti-protease level was checked in 11 patients, including the 7 patients with low Kco, and was found to be in the normal range. 

Patients with bronchiectasis are at risk of disease progression and worsening of pulmonary functions9. Currie et al8 observed no deterioration of pulmonary functions in patients with bronchiectasis on prolonged oral Amoxycillin in very high doses (3 grams twice daily). Stockley et al7 showed an improvement in PEFR on prolonged treatment with nebulised Amoxycillin in six patients who failed to improve with oral high dose Amoxycillin. In our patients on nebulised antibiotics there was no deterioration in pulmonary functions over a mean follow up period of 3.7 years.

There was statistically significant reduction of 41% in number of acute exacerbation per year in our patients while on nebulised antibiotic therapy. Hospital admissions per year declined by 38%. Number of hospital admissions, however, was too small to be of statistical significance. [Table 6]

The average annual cost per person of nebulised antibiotic therapy was £1388.00. The only side effect encountered was occasional development of oral thrush, only in those patients who were also on high dose inhaled cortico-steroids.

Discussion

In 1950 Reid classified Bronchiectasis based on bronchographic and autopsy findings. Nowadays it is based on non-invasive technique by HRCT. The diameter of the normal bronchus is approximately the same as its accompanying pulmonary artery. The bronchial dilatation and destruction that characterises bronchiectasis is classified morphologically as cylindrical, varicose (fusiform) or saccular. Cyclindral changes are common in basal segments. Varicose or fusiform bronchiectasis is characterised by a greater and irregular widening of the bronchi. Saccular bronchiectasis is characterised by enlarged rounded terminal sacs. Different morphologies can occur in the same patient. 

The lumen usually contains purulent mucous. Microscopically there are varying degrees of submucosal infiltration with neutrophils, macrophages, dendritic cells and plasma cells, lymphocyte and there may be lymphoid follicles. The mucosa is very oedematous. With more advanced disease, there may be areas of fibrosis; destruction of small air ways; mucosal erosion, ulceration and abscess formation; bronchomalacia and airway muscle hypertrophy. There may be neovascularisation of bronchial arteries with bronchopulmonary artery anastomoses. The extent and character of the pathologic changes determine the functional and haemodynamic abnormalities, which often include reduced airflow rates and increased or reduced lung volumes, ventilation/perfusion defects and hypoxia. 

In the past several structural theories have been proposed to explain the development of bronchiectasis. Traction which is associated peribronchial scarring and over distended alveoli produced increased elastic recoil on the bronchial wall; with lobar collapse the bronchial wall is pulled out by increased intrapleural pressure; middle lobe syndrome where predisposition to obstruction due to long narrow middle lobe bronchus, acute angulation and surrounding lymph nodes, impacted very viscous mucous expands, distends the bronchi which do not return to normal once the impaction clears. However bronchial health and defence rests dominantly on the normal action of the mucociliary escalator, though other elements including immunoglobulin function, make important contribution. Mucociliary clearance may be impaired by local obstruction; ciliary abnormality, unusual or excessive mucus production and all of them predispose to secondary infection. It is believed that initial insult to mucociliary escalator either by infection or toxic agent results in impaired mucociliary clearance. This permits micro-organisms to colonise and persist in the airway produces further reduction in ciliary beating. Persistent inflammatory host response causing progressive lung damage and recurrent infective exacerbation in primary bronchiectasis and secondary bronchiectasis. Microbiological studies may show a variety of organisms, some commensals others pathogenic. 

The characteristic presentation is that of recurrent or persistent cough with production of large amounts of sputum, usually purulent. The sputum may be mucoid or mucopurulent or have blood streaking. In contrast, bronchiectasis involving the upper lobes, as a complication of pulmonary tuberculosis or fungal infection does not produce purulent sputum, leads to dry Bronchiectasis. The patient may also complain of dyspnoea. Without appropriate treatment, progressive destruction of lung tissue leads to respiratory failure, corpulmonale, inanition and death by the fourth or fifth decade, if not sooner. Massive haemoptysis, empyema, clubbing, pulmonary osteoarthropathy, amyloidosis and metastatic brain abscess are frequent.

Diagnosis is made based on the clinical picture with compatible chest radiography and confirmed with a High Resolution Computed Tomography (HRCT) scan. Therapy of Bronchiectasis is directed at airway obstruction, including chest physiotherapy and bronchodilators, at infections and at complications. If the disease is confined to localised areas of lung, surgical resection of the affected segments is often performed. There is no, surgery versus conservative management randomised controlled studies. High dose fluticasone is effective in reducing the sputum inflammatory indices, in daily sputum production, improve the cough and may improve the lung function. There is not enough evidence for the routine use of mucolytics.

Antibiotics are commonly administered orally or intravenously as a short term or intermittent cyclical course. Regular nebulised antibiotic therapy has been shown to improve pulmonary functions, reduce the density of microflora in the sputum and hospital admissions in cystic fibrosis. The principle of regular long-term nebulised antibiotic therapy is to reduce the colonising microbial load thus improving the balance between colonising bacteria and host defence.

Conclusions
In our experience regular nebulised antibiotic therapy in patients with bronchiectasis requiring frequent courses of systemic antibiotics is well tolerated. It reduces infection and hence inflammation thereby improving symptoms and preserving pulmonary functions, with minimal or no side effects.

Acknowledgements

We would like to appreciate the help given by Mr. Richard Johnson of the Medical Audit Department, all the staff in the Respiratory Physiology Laboratory, outpatient nursing staff and Dr. M. Thuse, Consultant Radiologist in enabling us to conduct this audit project. 


TABLES