Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms.

Macrolide antibiotics are well known for their antibacterial and anti-inflammatory properties. This article provides an overview of the biological mechanisms through which macrolides exert this 'double effect'. Their antibacterial effect consists of the inhibition of bacterial protein synthesis, impaired bacterial biofilm synthesis, and the attenuation of other bacterial virulence factors. Apart from these direct antimicrobial effects, macrolides are known for their modulating effect on many components of the human immune system. By influencing the production of cytokines, they have a dampening effect on the proinflammatory response. Furthermore, the majority of cells involved in the immune response are, in one way or another, influenced when macrolide antibiotics are administered. Having such an obvious effect on the various aspects of the immune system, macrolides seem to be exceptionally suited for the treatment of chronic inflammatory diseases.

Immunomodulatory effects of macrolide antibiotics - part 2: advantages and disadvantages of long-term, low-dose macrolide therapy.

The available evidence for long-term, low-dose treatment with 14- and 15-membered ring macrolides in non-cystic fibrosis (CF) bronchiectasis, COPD, chronic sinusitis, and asthma is reviewed with special attention to possible adverse effects and the emergence of resistance during long-term macrolide treatment. Macrolide maintenance therapy has been proven to be of benefit in diffuse panbronchiolitis and CF, presumably due to an anti-inflammatory mechanism of action in addition to its direct antimicrobial effect. Solid evidence to justify this treatment regimen for non-CF bronchiectasis, asthma, or sinusitis is still lacking, although a beneficial effect of long-term macrolide therapy has been found in small clinical trials on these subjects. Data from randomized trials of long-term macrolide treatment in COPD are conflicting. A sufficiently long duration of treatment and the careful selection of patients appears to be crucial. Aside from its beneficial effects, possible side effects of macrolide treatment should be taken into account, the most important of these being gastrointestinal upset and cardiac arrhythmias. Development of macrolide resistance among respiratory pathogens is very common during long-term macrolide treatment. Whether this finding is clinically significant is a matter of debate.

Sputum colour reported by patients is not a reliable marker of the presence of bacteria in acute exacerbations of chronic obstructive pulmonary disease.

Sputum colour is regarded as a good marker of bacterial involvement in acute exacerbations of chronic obstructive pulmonary disease (COPD) and guides many physicians in deciding on antibiotic treatment. Although most doctors rely on the sputum colour that is reported by patients, it can also be assessed using a validated colour chart. In this study, reported sputum colour and assessed sputum colour were compared as markers of the presence of bacteria, bacterial load, and systemic inflammation. Data on 257 exacerbations in 216 patients hospitalized with an acute exacerbation were analysed (mean age, 72 years; mean forced expiratory volume in 1 s, 44.8% + or - 17.8% (+ or - standard deviation)). Sputum colour was reported by the patients and assessed at the laboratory with a colour chart. Subsequently, quantitative sputum cultures were performed. C-reactive protein was measured as a marker of systemic inflammation. A sputum sample was obtained in 216 exacerbations (84%), of which 177 (82%) were representative. A pathogen was identified in 155 patients (60%). Assessed sputum colour was a better marker of the presence of bacteria (OR 9.8; 95% CI 4.7-20.4; p <0.001) than reported sputum colour (OR 1.7; 95% CI 1.0-3.0; p 0.041). The sensitivity and specificity were 73% and 39% for reported sputum colour, and 90% and 52% for assessed sputum colour. Assessed sputum colour was clearly related to sputum bacterial load and C-reactive protein levels, whereas reported sputum colour was not. It is concluded that sputum colour reported by patients is an unreliable marker of the presence of bacteria in acute exacerbations of COPD. Assessed sputum colour is clearly superior and is also related to bacterial load and systemic inflammation.

[Pharyngitis with necrotising pneumonia caused by Arcanobacterium haemolyticum]. / Faryngitis met een holtevormende pneumonie veroorzaakt door Arcanobacterium haemolyticum.

A 20-year-old woman developed symptoms of pharyngitis followed by generalised skin rash and pulmonary infiltrates with cavitation. Arcanobacterium haemolyticum was identified in blood culture, which was susceptible to the antibiotics given. After initiating pathogen-directed therapy, the patient recovered completely. A. haemolyticum is a Gram-positive rod that can grow under aerobic and anaerobic conditions. The pathogen causes a characteristic haemolysis when cultured on human blood agar. A. haemolyticum causes pharyngitis and skin rash, particularly in adolescents. If the infection is not treated adequately, progression to more severe infections such as pneumonia, meningitis and sepsis can occur. The treatment of choice is a macrolide antibiotic.

Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study.

BACKGROUND: There is much controversy about the ideal approach to the management of community acquired pneumonia (CAP). Recommendations differ from a pathogen directed approach to an empirical strategy with broad spectrum antibiotics. METHODS: In a prospective randomised open study performed between 1998 and 2000, a pathogen directed treatment (PDT) approach was compared with an empirical broad spectrum antibiotic treatment (EAT) strategy according to the ATS guidelines of 1993 in 262 hospitalised patients with CAP. Clinical efficacy was primarily determined by the length of hospital stay (LOS). Secondary outcome parameters for clinical efficacy were assessment of therapeutic failure on antibiotics, 30 day mortality, duration of antibiotic treatment, resolution of fever, side effects, and quality of life. RESULTS: Three hundred and three patients were enrolled in the study; 41 were excluded, leaving 262 with results available for analysis. No significant differences were found between the two treatment groups in LOS, 30 day mortality, clinical failure, or resolution of fever. Side effects, although they did not have a significant influence on the outcome parameters, occurred more frequently in patients in the EAT group than in those in the PDT group (60% v 17%, 95% CI -0.5 to -0.3; p<0.001). CONCLUSIONS: An EAT strategy with broad spectrum antibiotics for the management of hospitalised patients with CAP has comparable clinical efficacy to a PDT approach.

Value of intensive diagnostic microbiological investigation in low- and high-risk patients with community-acquired pneumonia.

In a prospective study to evaluate the diagnostic yield of different microbiological tests in hospitalised patients with community-acquired pneumonia, material for microbiological investigation was obtained from 262 patients. Clinical samples consisted of the following: sputum for Gram staining, culture, and detection of pneumococcal antigen; blood for culture and serological tests; urine for detection of Legionella pneumophila serogroup 1 antigen and pneumococcal antigen; and specimens obtained by fiberoptic bronchoscopy. A pathogen was identified in 158 (60%) patients, with Streptococcus pneumoniae (n=97) being the most common causative agent of community-acquired pneumonia. In 82% of the 44 patients with an adequate sputum specimen, a positive Gram stain was confirmed by positive sputum culture. S. pneumoniae infections were detected principally when adequate sputum specimens were examined by Gram stain and culture and when adequate and inadequate sputum specimens were tested for the presence of pneumococcal antigen (n=58; 60%). The urinary pneumococcal antigen test was the most valuable single test for detection of S. pneumoniae infections (n=52; 54%) when sputum pneumococcal antigen determination was not performed. Fiberoptic bronchoscopy was of additive diagnostic value in 49% of the patients who did not expectorate sputum and in 52% of those in whom treatment failed. Investigation of sputum by a combination of Gram stain, culture, and detection of pneumococcal antigen was the most useful means of establishing an aetiological diagnosis of community-acquired pneumonia, followed by testing of urine for pneumococcal antigen. Fiberoptic bronchoscopy may be of additional value when treatment failure occurs.

[Migrating pulmonary infiltrates due to a foreign body]. / Verspringende longinfiltraten door een corpus alienum.

A 67-year-old man was admitted with a postobstructive pneumonia of the right upper lobe of the lung. Initially neoplasm was considered, but eventually the obstruction proved to be a foreign body, more specifically, a tooth. Two years before, after an episode of pneumonia caused by anaerobic bacteria, he had been advised to have his remaining teeth extracted because of poor dentition. Hereafter the patient experienced several episodes of pneumonia in different lobes, both right and left sided which were due to the migrating foreign body in the bronchial tract. He recovered after bronchoscopic removal.

Prospective evaluation of pneumonia severity index in hospitalised patients with community-acquired pneumonia.

The aim of the present study was to investigate whether the pneumonia severity index (PSI) could adequately predict the severity of community-acquired pneumonia (CAP) and could be used as a severity of illness classification system. Furthermore, reasons that may influence the decision to admit low risk patients were analysed. In a prospective study 260 patients with CAP were included. Stratification in five risk classes according to the PSI was compared with parameters that are closely related to severity of CAR A significant difference in severity parameters, such as length of stay (P < 0.001) and simplified acute physiologic score and acute physiologic and chronic health evaluation II score (P < 0.001) was found between the five risk classes. Furthermore, a positive British Thoracic Society (BTS) rule and modified BTS rule score was significantly more prevalent in the higher risk classes (P < 0.001). The patient population had an average 30-day mortality of 10% and a mean Intensive Care Unit (ICU) admission rate of 8%. The mortality rate and ICU admission rate significantly differed between the five risk classes (P < 0.001), in which the highest ICU admission rate (40.9%) and the highest mortality percentage (40.9%) were both found in risk class V. Several clinical factors (n = 64), such as an exacerbation of chronic obstructive pulmonary disease in 17 patients and clinical appearance of being ill in 16 patients, lack of improvement on outpatient antibiotic therapy (n = 15) and social circumstances (n = 3) were reasons that influenced the decision to hospitalise low risk patients (n = 82). The results show that the PSI adequately predicted the severity of CAP and can be used as a severity of illness classification in CAP. Clinical and social factors other than those mentioned in the PSI have to be considered when making the decision to hospitalise patients with CAP.

[Community-acquired pneumonia: pathogens and course in patients admitted to a general hospital]. / Buiten het ziekenhuis opgelopen pneumonie: verwekkers en beloop bij patiënten opgenomen in een algemeen ziekenhuis.

OBJECTIVE: To determine prognostic factors and the significance of (non-invasive) microbiological tests for the clinical course of patients admitted to one general hospital with community-acquired pneumonia (CAP). DESIGN: Prospective observational study. METHOD: Patients admitted to one location of a general hospital with symptoms of CAP during the period January 1998-December 1999 were included. Data from the anamnesis, physical examination and laboratory tests were recorded and samples were taken for diagnosis of the possible pathogens. Cultures were made of sputum and blood, serum and sputum were examined for infection with viral and atypical microorganisms, and the urine was screened for Streptococcus pneumoniae and Legionella antigens. RESULTS: Of the 157 patients studied, 28 (18%) died as a direct result of CAP. In a stepwise multivariate analysis, age > or = 65 years, increased serum-creatinine levels and hypercapnia were independent predictors of mortality. Streptococcus pneumoniae and Haemophilus influenzae were detected 53 and 19 times, respectively, and were the bacterial pathogens most frequently found. Among the nonbacterial pathogens, Mycoplasma pneumoniae was found 37 times and serologic tests for influenza A or B virus were positive in 34 cases. In 62 patients (39%), extensive microbiological tests revealed signs of a combined infection and in 20 patients (13%) no microorganism could be detected. An elevated serum-procalcitonin level was associated with bacterial infections. As a consequence of their retrospective nature, the results of the extensive serological tests did not contribute to reaching a diagnosis in daily clinical practice. In comparison with the literature, there was a markedly high number of subclinical or atypical infections with Legionella (8%) and Bordetella (18%) and a high incidence of viral and atypical microorganisms as the cause of CAP.

[Bronchocentric granulomatosis and mycoplasmal pneumonia]. / Bronchocentrische granulomatose en Mycoplasma-pneumonie.

A 61-year-old man presented with dyspnoea, chest pain, high fever and rigour. Chest X-ray revealed a combination of alveolar consolidations and abnormal nodular and interstitial markings. His clinical condition deteriorated despite treatment with antibiotics prescribed on a working diagnosis of pneumonia with an atypical pathogen. Finally, an open-lung biopsy specimen showed the characteristic picture of bronchocentric granulomatosis. Serological testing supported a primary infection with Mycoplasma pneumoniae. The patient responded well to treatment with prednisolone and erythromycin and five months after discharge, no radiological abnormalities were found. The combination of bronchocentric granulomatosis and mycoplasmal pneumonia has never been described in the literature and a causal relation can only be suggested. This case-report illustrates the importance of invasive diagnostic procedures if a patient with a clinical pneumonia fails to respond to adequate treatment.

[Pleural effusion and empyema as complications of pneumonia]. / Pleuravocht en empyeem als complicatie van pneumonie.

Parapneumonic effusion is observed radiologically in approximately 40% of the patients with a bacterial pneumonia. In most cases the course of the disease is uncomplicated, and the parapneumonic effusion (PPE) resolves with antibiotic therapy. However, in 5-10% of the patients, PPE becomes more complicated (loculation) and the effusion eventually leads to the formation of an empyema if no drainage has been performed. In view of negative impact on morbidity and mortality, it is important to recognise and evaluate a PPE as soon as possible. Intrapleural pus is the only absolute indication for drainage. In all other cases, the risk of a complicated PPE has to be established in the early phase of the illness, based on radiological, biochemical and microbiological parameters of the effusion. Based on these findings one or more of the following therapeutic strategies can be chosen: tube installation with drainage, fibrinolytical therapy, video-assisted thoracoscopic surgery, thoracotomy with or without decortication, or open drainage. Although every PPE needs to be evaluated on an individual basis, an attempt has been made to formulate a strategy that can be used in clinical practice, based on recent literature and expert opinions.

Unusual association of Hodgkin's disease and sarcoidosis.

We report a 51-year-old patient who developed abdominal lymphadenopathy following Hodgkin's disease seven years after she was diagnosed as having sarcoidosis. The patient had been treated with steroids, methotrexate and azathioprine. After three cycles of chemotherapy for Hodgkin's disease, the patient again developed sarcoidosis in the mediastinal lymph nodes. A greater awareness of the co-existence of sarcoidosis and Hodgkin's disease could circumvent the diagnostic difficulties.

The degree of branching of the glycans of alpha(1)-acid glycoprotein in asthma. A correlation with lung function and inflammatory parameters.

Alpha(1)-acid glycoprotein (AGP) is a plasma protein belonging to the group of acute-phase proteins. It contains five N-linked glycans which, depending on pathophysiologic state, differ in their degree of branching (i.e., in the relative proportions of di-, tri-, and tetraantennary glycans). Changes in the degree of branching of these glycans have been shown to affect various immunomodulatory properties of AGP. We wanted to investigate whether changes occur in the branching of AGP glycans in plasma and in bronchoalveolar lavage fluid (BALF) in asthma. For this purpose, we selected three groups of patients for study: patients with atopic asthma (AA), atopic nonasthmatic patients, and a group of patients with various interstitial lung diseases (ILDs). The plasma AGP concentration was normal in both atopic study groups, but was increased in ILD patients. In contrast, the branching of glycans of AGP was altered in subjects with AA, whereas it was normal in the other study groups. The presence of asthma symptoms correlated with the increased glycan branching of AGP in both plasma and BALF. Additionally, the degree of branching of AGP in BALF was related to FEV(1), to the provocative dose of histamine causing a 20% decrease in FEV (PD(20)), and to the number of eosinophils. In conclusion, asthma is accompanied by changes in the branching of AGP glycans that indicate an inflammatory reaction that differs markedly from a normal acute-phase response, in which decreased branching of AGP occurs.

[Acute abdomen: consider also the thorax]. / Acute buik: denk ook aan de thorax.

Three patients, 2 men aged 22 and 62 years en 1 woman aged 49, presented with symptoms of an acute abdomen. While infiltrative signs were described on radiodiagnostic images two patients underwent laparotomies. In all three subsequently the diagnosis of pneumonia was established and the patients made full recovery after antibiotic therapy. When a patient presents with symptoms of an acute abdomen, the possibility of an existing pneumonia should always be borne in mind. It is therefore recommended to make a chest radiograph with frontal and lateral view. In the presence of infiltrative signs the existence of pneumonia as the cause of abdominal symptoms should be considered in order to avoid unnecessary laparotomy.

Clinical and immunological evaluation of patients with mild IgG1 deficiency.

Serum IgG subclass concentrations were determined in patients visiting, the pulmonology out-patient clinic with chronic respiratory tract problems. A total of 24 patients with a serum IgG1 concentration < 4.9 g/l (i.e. below the reference range) and normal values for IgG2, IgM and IgA were included. Patients with a selective IgG1 deficiency were vaccinated with a 23-valent pneumococcal polysaccharide vaccine. There were nine patients with a poor antibody response to pneumococcal capsular polysaccharide antigens. Responsiveness to protein antigens was intact in all patients. Patients with pneumonia showed a significantly lower anti-polysaccharide response in the IgG2 subclass than patients without pneumonia. Patients with recurrent sinusitis showed a significantly lower response in the IgA isotype after vaccination with pneumococcal polysaccharide vaccine compared with non-sinusitis patients. It can be concluded that patients with recurrent sinopulmonary infections and a mild IgG1 subclass deficiency have an impaired IgG1 anti-polysaccharide response, which can extend to decreased IgG2 and IgA anti-polysaccharide responses.

Effects of theophylline on tolerance to the bronchoprotective actions of salmeterol in asthmatics in vivo.

Long-term treatment with salmeterol produces tolerance for its protective effects against bronchoconstrictor stimuli in patients with asthma. There is human in vitro evidence that theophylline may prevent beta2-adrenoceptor downregulation. Therefore, we investigated the effect of theophylline on the tolerance to the protective effect of salmeterol against histamine challenge in asthma in vivo. In a parallel 6-wk study, 25 asthmatics were treated with theophylline (mean serum level +/- SEM: 9.9 +/- 1.1 mg/L, Days 1 to 40) or placebo, combined with inhaled salmeterol (50 microgram twice daily, Days 8 to 36). Histamine challenges were carried out by tidal breathing method at entry, and at Days 4, 8, 22, 36, and 40. The response was measured by PC20. There was no significant change in PC20 after 4 d monotherapy with theophylline or placebo (mean difference +/- SEM: 0.54 +/- 0.39 and -0.02 +/- 0.41 doubling dose [DD], respectively; p > 0.15). One hour after the first dose, salmeterol afforded significant protection against histamine, as shown by an increase in PC20 in both the theophylline and placebo group (by 3.49 +/- 0.28 and 3.36 +/- 0.32 DD, respectively; p < 0. 001). However, after 2 and 4 wk salmeterol treatment, the improvements in PC20 by salmeterol were significantly reduced to 1. 80 +/- 0.35 and 1.69 +/- 0.36 DD, respectively, in the theophylline group (p < 0.001), and to 1.55 +/- 0.47 and 1.52 +/- 0.56 DD, respectively, in the placebo group (p < 0.002). These changes were not significantly different between the groups (p > 0.80). After cessation of salmeterol treatment, PC20 was not significantly different from the values at entry in either group (p > 0.90). We conclude that regular theophylline treatment neither prevents, nor worsens, the development of tolerance to the bronchoprotective effect of salmeterol in asthmatics in vivo.

Quality of life during formoterol treatment: comparison between asthma-specific and generic questionnaires. Canadian and the Dutch Formoterol Investigators.

This study aimed to investigate the effect of treating patients with moderate asthma with formoterol on quality of life (QoL) and to compare several questionnaires in their ability to detect changes in QoL. In an eight month multicentre, randomized, placebo-controlled trial, patients with asthma using daily inhaled corticosteroids and beta2-agonists (> or = 5 inhalations x week(-1)) were randomized to 6 months treatment with formoterol 24 microg b.i.d. (by Turbuhaler) or a matching placebo. Patients recorded symptoms (maximal score 21) and peak expiratory flow (PEF) twice daily. QoL was measured with two asthma-specific questionnaires, the Asthma Quality of Life Questionnaire (AQLQ) and the Living with Asthma Questionnaire (LWAQ), and with two generic QoL forms, i.e. the Short Form 36 (SF36) and the Psychological and General Well-Being scale (PGWB) at randomization and after 6 months of treatment. Out of 110 patients studied, 56 received formoterol and 54 placebo. Mean baseline forced expiratory volume in one second was 65% predicted. Mean morning PEF was 369 L x min(-1). Mean total symptom score was 3.6. Morning PEF increased (26.8 L x min(-1), p=0.0001) and symptoms decreased (-1.23, p=0.012) in the formoterol group in contrast to placebo. QoL improvements were measured in the LWAQ total score (baseline 0.61, change -0.05, p=0.048) and the physical construct of the LWAQ (baseline 0.71, change 0.07, p=0.044). The AQLQ and the generic QoL instruments showed no significant changes. In conclusion, the improvement in quality of life reported after 6 months was very small and only reflected by the Living with Asthma Questionnaire.

Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators.

BACKGROUND: The long acting beta 2 agonist formoterol has proved to be an effective bronchodilator with a prolonged action of 12-14 hours. However, the precise role of formoterol in the maintenance treatment of asthma is still under debate. A study was performed to investigate the efficacy and safety of treatment with formoterol for six months in subjects with asthma. METHODS: In a multicentre double blind, placebo controlled, parallel group study 239 subjects with mild to moderate asthma were randomly assigned to treatment with either inhaled formoterol 24 micrograms twice daily (n = 125) or placebo (n = 114) during eight months. The study consisted of a four week run in period, a 24 week treatment period, and a four week washout period. All subjects were using regular inhaled corticosteroids (100-3200 micrograms daily) but were still needing at least five inhalations of short acting beta 2 agonist per week for symptom relief. The study was performed in 10 outpatient clinics in Canada, and five outpatient clinics and one coordinating centre for 44 Dutch general practitioners in The Netherlands. Twice daily self-reported peak expiratory flow (PEF) measurements, symptom scores, and rescue beta 2 agonist use during the last 28 treatment days compared with baseline values were used as main outcome measures. Spirometric values were measured at entry, at the start of treatment, after four, 12 and 24 weeks of treatment, and after four weeks washout. RESULTS: One hundred and twenty five subjects received formoterol 24 micrograms twice daily via Turbohaler and 114 received placebo. Baseline FEV1 was 67.1% predicted and mean bronchodilator reversibility was 26%. The mean total asthma symptom score was 3.6 (maximum possible 21). A significant decrease in symptoms in favour of formoterol (difference from placebo -0.64, 95% CI -0.04 to -1.23, p = 0.04) was observed. Compared with placebo, morning PEF increased (difference from placebo 28 l/min, 95% CI 18.3 to 37.7, p = 0.0001) and the use of short acting beta 1 agonists decreased (daytime difference from placebo -1.1 inhalation, 95% CI -1.4 to -0.7, p = 0.0001) in the formoterol group. PEF returned to baseline following discontinuation of formoterol, as did asthma symptom scores. Thirty three patients treated with formoterol and 32 treated with placebo required treatment with prednisolone during the study (58 and 55 courses, respectively). CONCLUSIONS: Adding formoterol 24 micrograms twice daily by Turbohaler to inhaled corticosteroids was effective in improving symptom scores and morning PEF, and decreasing the use of rescue beta 2 agonists. There was no apparent loss of asthma control during 24 weeks of treatment with formoterol.