Chronic Bronchial Sepsis Research Articles

Effect of long‐term nebulized colistin on lung function and quality of life in patients with chronic bronchial sepsis

Recurrent Gram-negative bacterial infection is a significant cause of death in patients with bronchiectasis and severe chronic obstructive pulmonary disease (COPD). Nebulized colistin in cystic fibrosis has shown maintenance of pulmonary function and improved symptom scores. We prospectively followed 18 patients with chronic bronchial sepsis treated with nebulized colistin 30 mg daily. Mean decline in forced expiratory volume in 1 s was significantly slower following commencement of inhaled colistin (44 mL/year vs 104 mL/year, P = 0.035). Mean decline in forced vital capacity was also significantly slower following commencement of colistin (48 mL/year vs 110 mL/year, P = 0.033). Patient-reported quality of life improved following commencement of colistin (3.6 vs 6.2, P = 0.001). No patient had isolates resistant to colistin. No side-effects were reported by patients in the cohort. Use of inhaled colistin in the treatment of bronchiectasis and severe (COPD) in patients with recurrent Gram-negative infections is safe. Inhaled colistin may improve quality of life and slow decline in forced expiratory volume in 1 s and forced vital capacity.

Pulmonary transplantation for cystic fibrosis: pre-transplant recipient characteristics in patients dying of peri-operative sepsis

Background: Pulmonary transplantation has emerged as a successful treatment for end-stage cystic fibrosis. Despite the chronic bronchial sepsis and often multi-resistant organisms seen in this group of recipients, death due to post-operative sepsis is relatively scarce. Identifying potential recipient risk factors for poor outcome may further improve the utilization of a scarce donor pool. Methods: We assessed the role of pre-operative clinical measures of sepsis, microbial characteristics and recipient characteristics on post-transplant outcome in 85 cystic fibrosis patients who underwent pulmonary transplantation. Ten percent of patients died in the early post-operative period due to sepsis. The prognostic role of recipient factors including markers of sepsis, such as white cells and C-reactive protein (CRP), and the influence of multi-resistant organisms, in particular organisms from the Burkholderia cepacia complex, on outcomes were investigated. Results: We found no prognostic effect of gender, pre-transplant CRP, forced expiratory volume in 1 second (FEV 1), weight, diabetic status or infection with multi-resistant Pseudomonas organisms. A raised white cell count or temperature or a pre-transplant infection with B cepacia was, however, associated with a significantly poorer prognosis at p = 0.03, 0.03 and 0.001, respectively. Conclusions: Pre-operative B cepacia complex infection, leukocytosis and pyrexia, but not CRP, weight, diabetes or lung function, were found to be associated with poorer post-transplant outcome. The most clinically relevant of these to the subsequent risk of post-operative death from sepsis appear to be B cepacia infection and pyrexia.

Influenza virus inhibits lysozyme secretion by sputum neutrophils in subjects with chronic bronchial sepsis.

Neutrophils are central to the control of infection within the bronchial mucosa. To determine whether the link between bacterial and viral infection in the respiratory tract can be partly explained by acute reduction of neutrophil function, we examined the influence of influenza virus on lysozyme secretion by sputum neutrophils obtained from patients with bronchiectasis. Sputum neutrophils infected with influenza A virus had a significantly reduced capacity to secrete lysozyme but not myeloperoxidase. Influenza virus A strains were more effective in inhibiting lysozyme secretion than were influenza B virus strains. Reduction of bactericidal activity was similarly reduced by different strains of influenza A virus, but an influenza virus B strain had no effect. Our results show that downregulation of sputum neutrophil function characterized by lysozyme secretion and bactericidal activity could contribute to reduction in the capacity to control bacterial colonization in the respiratory tract following influenza virus infection.

Autocrine modulation of IL-8 production by sputum neutrophils in chronic bronchial sepsis.

We examined the activity of neutrophils isolated from sputum and blood of subjects with chronic bronchial sepsis in terms of interleukin-8 (IL-8), IL-1beta, and tumor necrosis factor-alpha (TNF alpha) production. In sputum, the numbers of neutrophils correlated with the concentrations of these cytokines. Sputum neutrophils constitutively secreted large amounts of IL-8, IL-1beta, and TNF alpha. The patterns of secretion, however, differed from those of blood neutrophils stimulated with bacterial lipopolysaccharide (LPS). Cytokine secretion was time-dependent and was inhibited by cycloheximide and dexamethasone. IL-10 inhibition of IL-8 production by sputum neutrophils was significantly less than that noted with activated neutrophils. Antibody to IL-1beta but not to TNF alpha, inhibited IL-8 secretion by sputum neutrophils, contrasting with results found using blood neutrophils. Incubation of blood neutrophils in sputum sol induced a similar cytokine secretion profile to that following exposure to LPS. The inhibitory effects on IL-8 protein production correlated with messenger RNA (mRNA) gene expression. These observations indicate that neutrophils are a significant source of IL-8 in purulent sputum, and that an autocrine loop involving IL-1beta maintains secretion within the bronchus lumen.

Management of Chronic Bronchial Sepsis Due to Bronchiectasis

Although saccular bronchiectasis is becoming rare, cylindrical bronchiectasis is increasingly recognized now that thin section computed tomography (CT) scanning is more commonly performed. Patients present with regular sputum production, which may be chronically infected, and frequently with rhinosinusitis. There is often an associated history of wheezy bronchitis in childhood, resolution of symptoms in teenage years, and relapse as an adult, often following a viral illness. The disease may progress insidiously, and undue tiredness is a common symptom. Pathogenesis of established disease involves bacteria-provoked host-mediated inflammatory lung damage. Investigation should include establishing the diagnosis of bronchiectasis and the microbiology of the infection, elucidating the cause if known (in about 40% of cases with the rest being idiopathic), assessing lung structure (by CT) and function, and measuring disease activity. Management might involve prevention, surgery, treatment of specific conditions such as antibody deficiency, as well as treatment of airflow obstruction and sinusitis. Physiotherapy should be taught and practiced regularly to drain the affected lobes. At one extreme antibiotics should be used to eliminate bacteria during an exacerbation, and at the other extreme may be used continuously when lung damage is severe to suppress bacterial numbers and thus control inflammation. If deterioration in lung function occurs despite optimal medical treatment, then lung transplantation might be considered. Improved mucus clearance or control of inflammation seems to be the most likely way future therapy might be improved.

Fertility in men with primary ciliary dyskinesia presenting with respiratory infection.

Primary ciliary dyskinesia is characterised by chronic rhinosinusitis, chronic bronchial sepsis (usually with bronchiectasis), dextrocardia in approximately 50% of cases, and male infertility. The latter, described in patients attending infertility clinics, results from immotile but viable spermatozoa. Experience in a respiratory clinic suggests that infertility in men is not invariable. The seminal fluid of 12 men with primary ciliary dyskinesia, six with dextrocardia, who presented consecutively with upper and lower respiratory tract sepsis was examined. Nasal ciliary beating was dyskinetic or absent in all cases, and nasal ciliary ultrastructure was abnormal in those 11 patients examined. Viable but immotile spermatozoa with abnormal tail ultrastructure were found in the ejaculate of only two patients. Two other patients had apparently fathered children; seminology in both these cases showed a normal spermatozoa count, one with normal spermatozoal motility and normal ultrastructure, the other with moderately reduced spermatozoal motility and abnormal ultrastructure (dynein arm deficiency on the peripheral microtubule doublets). A further two patients had normal spermatozoa counts, normal spermatozoa tail ultrastructure, and normal or only moderately reduced motility of spermatozoa. The spermatozoa of one patient were normally motile but there was severe oligozoospermia, and five patients were azoospermic. Not all men with primary ciliary dyskinesia have immotile spermatozoa. Seminal analysis is recommended in men with primary ciliary dyskinesia so that accurate counselling about reproductive capability may be given.

Sputum and serum pharmacokinetics of loracarbef (LY163892) in patients with chronic bronchial sepsis

Sputum and serum pharmacokinetics of loracarbef (LY163892) were performed in 19 patients with purulent bronchiectasis. Nine of the patients received 200 mg twice daily and ten patients, 400 mg twice daily, for a total of 14 days. beta-Lactamase activity was measurable in the lung secretions of all 19 patients at the start of therapy. Mean peak serum concentrations of 11.7 mg/L (S.E.M. 1.7) were recorded at 1 h after administration of 200 mg doses on day 2 of therapy and were 18.5 mg/L (S.E.M. 1.9) at 1.5 h in the 400 mg group. Loracarbef was shown to penetrate lung secretions even in the presence of beta-lactamase activity. Mean peak sputum concentrations were achieved between 2 and 4 h following dosing and were 0.2 mg/L (S.E.M. 0.05) in the 200 mg group and 0.4 mg/L (S.E.M. 0.08) in the 400 mg group. On days 7 and 14 of therapy, sputum loracarbef concentrations were similar 4 h after the morning dose (0.23 mg/L following 200 mg; 0.35 mg/L after 400 mg). These concentrations were approximately 2% of the peak serum concentration and penetration into lung secretions is similar to other beta-lactams.

The effect of erythromycin on Pseudomonas aeruginosa and neutrophil mediated epithelial damage.

Erythromycin therapy for long periods may benefit patients with chronic bronchial sepsis colonized by Pseudomonas aeruginosa despite the lack of antibacterial activity. We have investigated the effect of filtrates of 24 h P. aeruginosa cultures (CF) with or without erythromycin 0.5, 5, 20 mg/L on human nasal epithelium in the absence or presence of polymorphonuclear leucocytes (PMN). Ciliary beat frequency (CBF) and epithelium integrity were examined for 4 h. Erythromycin (20 mg/L) alone did not affect epithelium. CF without erythromycin slowed CBF by 63.5% of control at 4 h, and caused disruption of surface integrity in 80% of the epithelium. Addition of erythromycin to CF did not inhibit these effects. Erythromycin did not affect growth of P. aeruginosa. Filtrates of P. aeruginosa cultured with erythromycin (5 and 20 mg/L) caused less CBF slowing (37.2% and 19.2% of control, respectively) and epithelial disruption (4.2% and 6.7%, respectively). Unstimulated PMN (10(7)/mL) slowed CBF by 13% of control at 4 h but did not cause epithelial disruption. PMN and CF together slowed CBF (95.4% of control) and damaged epithelium (93.3% of epithelium disrupted) synergically. Pre-incubation of PMN with erythromycin did not inhibit these effects. PMN and filtrates of P. aeruginosa cultured with erythromycin (5 and 20 mg/L) caused less CBF slowing (58.0% and 33.6% of control, respectively) and epithelial disruption (40.0% and 13.3%, respectively). Erythromycin may benefit patients by reducing P. aeruginosa production of factors which damage epithelium and stimulate neutrophil mediated cytotoxicity.

Tumour necrosis factor-alpha, resting energy expenditure and cachexia in cystic fibrosis.

1. We investigated the relationship between circulating tumour necrosis factor-alpha concentrations, resting energy expenditure, cachexia and altered intermediary metabolism in patients with cystic fibrosis and chronic pulmonary infection. 2. Twenty adult patients with cystic fibrosis and chronic bronchial sepsis covering a spectrum of severity of lung disease (forced expiratory volume in 1 s 30-100% of predicted) were compared with 10 age matched, healthy, non-cystic fibrosis subjects. 3. Circulating tumour necrosis factor-alpha, C-reactive protein and neutrophil elastase-alpha 1-antiproteinase complex concentrations were determined simultaneously with glycerol, non-esterified fatty acids, catecholamines, anthropometric indices and resting energy expenditure (ventilated hood method). 4. Weight, body mass index and arm muscle mass were reduced in patients with cystic fibrosis compared with healthy control subjects (P < 0.01), whereas mean resting energy expenditure was increased [121 versus 101% predicted, mean difference 19.2% (95% confidence interval 11.0-27.4%), P < 0.001]. Circulating concentrations of glycerol (P < 0.01), non-esterified fatty acids (P < 0.01), adrenaline (P < 0.05), tumour necrosis factor-alpha, C-reactive protein and neutrophil elastase-alpha 1-antiproteinase complex (P < 0.01) were increased in patients compared with control subjects [tumour necrosis factor-alpha 96.9 versus 24.7 pg/ml, mean difference 72.2 pg/ml [95% confidence interval 27.7-116.7 pg/ml), P < 0.001]. Resting energy expenditure was significantly related to tumour necrosis factor-alpha levels and forced expiratory volume in 1 s. 5. In patients with cystic fibrosis and chronic pulmonary sepsis changes in resting energy expenditure, body composition and intermediary metabolism are consistent with the systemic effects of the host inflammatory response, which may be responsible for cachexia in adult patients. In particular these changes are consistent with the action of tumour necrosis factor-alpha, which was detected in the circulation during a period of apparent clinical stability.

Indium-111 labelled granulocyte scanning to detect inflammation in the lungs of patients with chronic sputum expectoration.

Thirty eight patients with chronic sputum expectoration underwent indium-111 labelled granulocyte lung scanning and measurement of whole body loss of indium-111 labelled granulocytes. Twenty four patients had radiologically proved bronchiectasis and 14 had mucus hypersecretion without radiological evidence of bronchiectasis. None was having an acute exacerbation at the time of the scan. The median 24 hour volume of sputum expectorated was 17 (range 2-175) ml. The 24 hour volume of purulent sputum was 5 (0-142) ml; six patients expectorated mucoid sputum only. Twenty one of the 38 patients had a positive granulocyte lung scan. All nine patients expectorating more than 20 ml purulent sputum in 24 hours had positive lung scans and all had lost more than 19% of the indium-111 from the body after five to seven days. Of the six patients with mucoid sputum, only one had a positive scan and these subjects lost only 6-11% of the indium-111 in five to seven days. The percentage loss of indium-111 from the body correlated with 24 hour purulent sputum volume (r = 0.41, n = 38, p less than 0.001) and total elastolytic activity in 24 hour sputum (r = 0.54, n = 14, p less than 0.01). The loss of indium-111 was not related to the extent of bronchiectasis when purulent sputum volume was allowed for. Indium-111 labelled granulocyte scanning provides a sensitive and objective method for detecting inflammation in the lungs and should help to improve understanding of chronic bronchial sepsis and possibly treatment in selected cases.

Host-microbe relationships in chronic respiratory infection.

Infection of the upper and lower respiratory tracts accounts for 85% of the respiratory disease seen by primary-care physicians. Acute infection is usually attributable to microbial virulence but may occur on a background of immune deficiency. Recurrent acute bronchial and pneumonic infection is associated with considerable immunological abnormality (up to 75%) for which a high index of suspicion must be maintained. Chronic bronchial sepsis, on the other hand, has a paradoxically low prevalence of immune deficiency (less than 10%) and the pathogenesis depends on initially compromised mucociliary clearance (by exogenous agents or underlying genetic disease) allowing certain microbes to be selected for airway colonisation according to their ability to release cilio-inhibitory factors and factors damaging ciliated epithelium. Once microbial colonisation is established, the host responds exuberantly with non-specific and immune inflammatory responses which fail to clear the microbial flora but damage the 'innocent bystander' lung. This further compromises bronchial clearance mechanisms in a 'vicious circle' of events whose end result is progressive lung damage and cardio-respiratory failure.

The effect of bacterial products on ciliary function.

Mucociliary clearance protects the respiratory epithelium against inhaled particles. There is in vitro evidence that some bacteria produce factors that cause ciliary slowing, dyskinesia, and stasis. These changes may predominantly affect ciliary function alone or be associated with epithelial disruption and cell death. Some factors act immediately, while others can take up to a number of days to achieve effect. It is postulated that rapidly acting factors may be involved during bacterial colonization, allowing the bacterium time (by slowing clearance) to penetrate the mucociliary barrier and reach putative receptors on the epithelial surface. The compounds might similarly facilitate contiguous spread through the bronchial tree and augment the tissue damage caused by the host inflammatory response during chronic bronchial sepsis. Future work should define more clearly the in vivo significance of the largely in vitro observations made to date.

A Comparison of Postural Drainage and Positive Expiratory Pressure in the Domiciliary Management of Patients with Chronic Bronchial Sepsis

Summary We report a study comparing the effects of postural drainage and the administration of positive expiratory pressure as techniques of physiotherapy in the domiciliary management of patients with chronic bronchial sepsis. The comparison is in the form of an open study on 12 patients over a period of six weeks. After two weeks run-in, analysis was performed on the subsequent four weeks, with conventional techniques of postural drainage being administered on one day alternating with the use of positive expiratory pressure on the next. Measurements have been made of sputum production during physiotherapy, total daily sputum production, total time spent on physiotherapy, mean daily peak expiratory flow rates derived from morning and evening measurements, and an assessment of overall well-being derived from a visual analogue scale. At the end of the study the subjects were also asked to score the two techniques with regard to ease of use, convenience of use, effect on clearing secretions and overall performance. Contrary to some earlier studies we find that positive expiratory pressure does not produce an overall improvement in the management of patients with chronic bronchial sepsis. A minority of patients benefit from the technique, but for those who can demonstrate a good independent treatment with postural drainage and the use of the forced expiration technique (FET). the positive expiratory pressure (PEP) mask does not provide added advantages. The technique may serve as a useful adjunct to treatment in some cases, but is not regarded as a method of priority in chest clearance.

Impaired mucus clearance in patients with chronic bronchial sepsis, sinusitis and dextrocardia.

Published reports have indicated that patients with Kartagener's syndrome (dextrocardia, sinusitis and bronchiectasis) have no significant lung mucociliary clearance. With a radioaerosol technique we measured over a 6-hour observation period the tracheobronchial clearance of 8 patients with dextrocardia, chronic bronchial sepsis and chronic sinusitis (DC). The tracheobronchial clearance of these patients was significantly reduced (p less than 0.02) compared with that of 29 healthy subjects of similar age. However, even when allowance was made for productive coughing during the observation period, the reduced clearance was much better than anticipated from published reports in patients with Kartagener's syndrome, which confined their observations to a 2-hour period. The tracheobronchial clearance of the DC patients, adjusted for productive coughing, was as bad as that found in an older group of patients with chronic obstructive airways disease who refrained from expectorating during the equivalent test period. Our study implies one or more of the following possibilities: (a) a spectrum of mucociliary impairment in patients with DC; (b) an effective cough clearance deeper in the lung than hitherto believed, and (c) two-phase flow of mucus cephalad as an effective clearance mechanism in patients with DC.

Deleterious effects of purulent sputum sol on human ciliary function in vitro: at least two factors identified.

Patients with chronic bronchial sepsis have impaired mucociliary clearance. A study was carried out on the effect of sputum sol (obtained by rapid centrifugation of purulent sputum) from 20 patients with chronic bronchial sepsis on the beating of human nasal cilia in vitro by a photometric technique. Thirteen sols caused significant (p less than 0.001) ciliary slowing. Two patterns of slowing were observed: firstly, a gradual onset associated with epithelial disruption (inhibited by alpha 1 antiprotease) and, secondly, an immediate onset associated with ciliary dyskinesia and ciliostasis (inhibited by chloroform extraction). The ciliary slowing activity of sputum sols was associated with the isolation of Pseudomonas aeruginosa (p less than 0.01). It is concluded that purulent sputum contains at least two factors that impair ciliary beating--one a serine protease, which is probably a product released by the host's phagocytic defences, and the other, which is chloroform extractable and probably a bacterial product.

Effect of short and long term antibiotic response on lung function in bronchiectasis.

In a study designed to show whether purulent bronchial secretions damage the lung reversibly or irreversibly, 18 patients with bronchiectasis underwent lung function tests before and after two weeks' antibiotic treatment to convert their sputum from purulent to mucoid, and 10 of them also after four months' treatment. After two weeks FEV1, forced vital capacity, vital capacity, functional residual capacity, and total lung capacity showed small but statistically significant (though not clinically useful) improvements. In the 10 patients studied after four months only FVC (of the four indices with significant improvements at two weeks in this group) was still higher than before treatment. These results contrast with those of an earlier study, in which large acute changes were found, perhaps because of differences in the patients studied. It is concluded that the absence of major changes in lung function points to physiological abnormality that is largely irreversible in these patients with chronic bronchial sepsis.

Isolation of spheroplastic forms of Haemophilus influenzae from sputum in conventionally treated chronic bronchial sepsis using selective medium supplemented with N-acetyl-D-glucosamine: possible reservoir for re-emergence of infection.

The isolation rate of Haemophilus influenzae from patients with persistent production of purulent sputum has been increased by the routine use of a selective medium. Nevertheless, some purulent sputum still fails to yield a pathogen. The selective medium was supplemented with N-acetyl-D-glucosamine to encourage primary isolation of colony forming, spheroplastic H influenzae, which reverted to normal forms on subculture. On the basis of in vitro experiments it is postulated that these spheroplastic forms of H influenzae may be induced by inadequate antimicrobial chemotherapy and may be responsible for re-emergence of symptoms in these patients during or shortly after stopping chemotherapy.

A simple oral antimicrobial regimen effective in severe chronic bronchial suppuration associated with culturable Haemophilus influenzae.

Three grams of amoxycillin administered twice daily for seven days, as an oral powder (Amoxil 3G sachets, Bencard) dispersed in water, to 17 patients with bronchiectasis resulted in striking clinical, spirometric and bacteriological improvement in 11 of 12 patients who were producing purulent sputum from which Haemophilus influenzae was cultured by a selective bacteriological technique (Roberts & Cole, 1980). In the five patients from whose sputum this organism could not be cultured, and in one from whom it could, there was no improvement. Untoward effects were limited to nausea in one patient and acceptability of the regimen by the remaining patients was unanimous. There was no evidence of accumulation of the drug in serum or sputum. The rapidity of effect and oral form of the treatment suggest that it may provide a simple out-patient regimen for chronic bronchial sepsis and severe purulent exacerbations of chronic bronchitis from which H. influenzae can be cultured.