Azithromycin reduces pulmonary fibrosis in a bleomycin mouse model.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease without proper treatment. Despite intensive research, the exact underlying pathogenesis remains elusive. It is regarded as a continuous injury, resulting in inflammation, infiltration, and proliferation of fibroblasts and extracellular matrix deposition, leading to an irreversible restrictive lung function deterioration and death. In this study the effect of azithromycin, a macrolide antibiotic on bleomycin-induced pulmonary fibrosis was investigated. C57BL/6 mice were intratracheally instilled with bleomycin (0.5 mg/kg) or saline. In the bleomycin group, half of the animals received azithromycin every other day from day 1 on. Bronchoalveolar lavage and histology were performed at days 7 and 35, and pulmonary function tests on day 35. At day 35, fibrotic lesions (spindle cell proliferation/collagen I deposition) were paralleled by a restrictive lung function pattern. Alterations were found in neutrophils and macrophages (innate immunity) and in T(H)2, T(H)17, and Treg cytokines (adaptive immunity). Azithromycin significantly reduced both fibrosis and the restrictive lung function pattern. This study demonstrated a beneficial effect of azithromycin on bleomycin-induced pulmonary fibrosis. A possible mechanism could be a modulation of both innate immunity and adaptive immunity. These findings might suggest a potential role for azithromycin in the treatment of IPF.

Multidisciplinary interobserver agreement in the diagnosis of idiopathic pulmonary fibrosis.

The purpose of the present study was to evaluate the accuracy of the diagnosis of idiopathic pulmonary fibrosis (IPF) by respiratory physicians in six European countries, and to calculate the interobserver agreement between high-resolution computed tomography reviewers and histology reviewers in IPF diagnosis. The diagnosis of usual interstitial pneumonia (UIP) was assessed by a local investigator, following the American Thoracic Society/European Respiratory Society consensus statement, and confirmed when a minimum of two out of three expert reviewers from each expert panel agreed with the diagnosis. The level of agreement between readers within each expert panel was calculated by weighted kappa. The diagnosis of UIP was confirmed by the expert panels in 87.2% of cases. A total of 179 thoracic high-resolution computed tomography scans were independently reviewed, and an interobserver agreement of 0.40 was found. Open or thoracoscopic lung biopsy was performed in 97 patients, 82 of whom could be reviewed by the expert committee. The weighted kappa between histology readers was 0.30. It is concluded that, although the level of agreement between the readers within each panel was only fair to moderate, the overall accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis in expert centres is good (87.2%).

Necrotising sarcoid granulomatosis: clinical, functional, endoscopical and radiographical evaluations.

Necrotising sarcoid granulomatosis (NSG) is a rare disease diagnosed on the basis of pathological features. The present study reports the characteristics of 14 cases of NSG. The mean age at the appearance of first symptoms was 37 yrs and the mean delay between first symptoms and diagnosis was 1 yr. Extrarespiratory symptoms were more common (12 out of 14) than respiratory symptoms (eight out of 14). Seven patients had inflammatory syndrome. Bronchoalveolar lavage was performed in eight patients and found to be normal in three cases. Respiratory function was normal in 13 patients, but carbon monoxide diffusing capacity was slightly decreased in eight of the 11 patients tested. A computed tomography scan showed a solitary nodule in four out of 14 cases, bilateral nodules in three and infiltrates in seven. One patient died from neurological complications despite treatment with corticosteroids and immunosuppressive drugs. Two cases of relapse were observed in patients initially treated with corticosteroids, and there were two cases of relapse after surgery. No relapse occurred in the five untreated patients. During the follow-up, lung cancer was detected at 26 months and 8 yrs, respectively, after NSG diagnosis in two patients. In conclusion, no one treatment is associated with a better outcome than the others, although lung biopsy might be necessary in case of isolated nodule or cavitation. Greater vigilance is required during the follow-up.

Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status.

BACKGROUND: Skeletal muscle weakness is assumed to be present in patients with sarcoidosis but has never been reported in a consecutive group of patients. Moreover, its relationship with previously observed exercise intolerance and reduced health status has never been studied in these patients. METHODS: Pulmonary function, skeletal and respiratory muscle forces, peak and functional exercise capacity, health status, and the circulating levels of inflammatory and anabolic markers were determined in 25 patients with sarcoidosis who complained of fatigue (15 men) and in 21 healthy subjects (13 men). RESULTS: Patients with sarcoidosis had lower respiratory and skeletal muscle forces, reduced exercise capacity and health status, higher anxiety and depression scores, and higher circulating levels of tumour necrosis factor-alpha than healthy subjects (all p< or =0.01). Its soluble receptor p75 tended to be higher (p=0.04). Circulating levels of interleukin (IL)-6, IL-8, insulin-like growth factor I and its binding protein 3 were not significantly different between the two groups. Skeletal muscle weakness was related to exercise intolerance, depression, and reduced health status in patients with sarcoidosis, irrespective of age, sex, body weight and height (p< or =0.05). Quadriceps peak torque was inversely related to fatigue but not to the circulating levels of inflammatory or anabolic markers. The mean daily dose of corticosteroids received in the 6 month period before testing was related to quadriceps peak torque only in patients who received oral corticosteroids. CONCLUSION: Skeletal muscle weakness occurs in patients with sarcoidosis who complain of fatigue and is associated with reduced health status and exercise intolerance.

Treatment of chronic respiratory failure in kyphoscoliosis: oxygen or ventilation?

Patients with kyposcoliosis and chronic respiratory insufficiency are treated either with home oxygen therapy or ventilation. Kyphoscoliotic patients demonstrate impaired ventilatory mechanics, consequently ventilation seems to be the treatment of choice. Yet, no randomised controlled trials (CRT) exist to prove it. Most investigators find it difficult to ethically justify a CRT. Therefore, the current authors performed the following retrospective study: survival and pulmonary function were analysed in all consecutive kyphoscoliotic patients who started long-term oxygen therapy (LTO group; n=15, aged 62+/-11 yrs (mean+/-SD)) or LTO plus nocturnal nasal intermittent positive pressure ventilation (nNIPPV group; n=18, aged 61+/-7 yrs) in the Dept of Pulmonology (University Hospital Gasthuisberg, Leuven) between 1990-2002. Prior to treatment partial pressure of oxygen (PO2) was lower, partial pressure of carbon dioxide (PCO2) tended to be higher and vital capacity (VC) tended to be lower in the nNIPPV group than in the LTO group (PO2 5.9+/-1 versus 6.7+/-0.9 kPa (44+/-8 versus 50+/-7 mmHg), PCO2 8+/-1 versus 7.3+/-0.9 kPa (60+/-8 versus 55+/-7 mmHg), VC 32+/-12 versus 40+/-16% predicted, or 645+/-244 versus 970+/-387 mL). In the nNIPPV group the 1-yr survival was higher (100% versus 66%). nNIPPV patients demonstrated an improvement in PO2 (breathing air) +54%, PCO2 (breathing air) -21%, VC +47% and maximal static inspiratory mouth pressure +33%; these improvements were absent in the LTO group. In conclusion, nocturnal nasal intermittent positive pressure ventilation, plus long-term oxygen therapy results in more favourable survival and changes in blood gases and respiratory function than long-term oxygen therapy alone.

Primary pulmonary hypertension after amfepramone (diethylpropion) with BMPR2 mutation.

Primary pulmonary hypertension (PPH) is characterised by sustained elevations of pulmonary arterial pressure without a demonstrable cause, leading to right ventricular failure and death. Hereditary mutations in the bone morphogenetic protein receptor type II (BMPR2) gene result in familial PPH transmitted as an autosomal dominant trait, albeit with low penetrance. The causes in cases without a BMPR2 mutation are unknown, but a syndrome of pulmonary arterial hypertension (PAH) similar to hereditary PPH is associated with systemic connective tissue disease, congenital heart disease, portal hypertension, and human immunodeficiency virus infection, or with the use of appetite-suppressant drugs. The authors identified a BMPR2 gene mutation in a 27-yr-old female who developed PAH after a short course of the appetite-suppressant drug amfepramone (diethylpropion). This allowed molecular genetic counselling and prevention of potentially harmful drug exposure in the patient's son treated for attention deficit disorder with methylphenidate, an amphetamine-related drug. No BMPR2 mutation was found in four additional, unrelated patients with appetite suppressant-related PPH. The findings provide strong evidence that amfepramone can trigger primary pulmonary hypertension in a bone morphogenetic protein receptor type II gene mutation carrier, and indicate that other genes are probably implicated in genetic susceptibility to appetite suppressants.

Modulation by cAMP of IL-1beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells.

Inflammatory cells, such as eosinophils, seem to be key players in the inflammatory process of asthma. These cells are attracted by chemokines, for example eotaxin and monocyte chemotactic protein (MCP-1). In this study, the authors investigated whether eotaxin and MCP-1 expression and release in human airway smooth muscle cells could be modulated by an increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. The possible involvement of cAMP-dependent protein kinase A (PKA) was also studied. Forskolin, a direct stimulator of adenylyl cyclase, decreased the interleukin (IL)-1beta-induced eotaxin and MCP-1 release by 73+/-8 and 65+/-6%, respectively. 8Bromo-cAMP, a cAMP analogue, similarly decreased the chemokine production by 58+/-9 and 63+/-8% for eotaxin and MCP-1, respectively. Prostaglandin E2, known as an activator of the prostanoid receptors EP2 and EP4, which are positively coupled to adenylyl cyclase, also decreased the IL-1beta-induced eotaxin and MCP-1 production by 57+/-17 and 53+/-4%, respectively. H-89, an inhibitor of PKA, was able to inhibit the decrease in eotaxin and MCP-1 protein release induced by forskolin. Using Western-blot analysis, no effect of cAMP was found on the IL-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. This study shows that an increase in intracellular cyclic adenosine monophosphate concentration may decrease the interleukin-1beta-induced eotaxin and monocyte chemotactic protein-1 expression and production. This can be inhibited by addition of H-89, an inhibitor of cyclic adenosine monophosphate-dependent protein kinase. No decrease was observed in interleukin-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. These findings may be important for the further development of new anti-inflammatory drugs.

N-acetylcysteine reduces chemokine release via inhibition of p38 MAPK in human airway smooth muscle cells.

Reactive oxygen species are involved in the activation of several mitogen-activated protein kinases (MAPKs), key-players in the production of several cytokines. Therefore the current study investigated whether N-acetylcysteine (NAC), an antioxidative agent, inhibits the interleukin (IL)-1beta-induced expression and production of eotaxin and monocyte chemotactic protein (MCP)-1 in human airway smooth muscle cells (HASMC). NAC (10 mM) decreased the expression of eotaxin and MCP-1, by 46 +/- 11% (n=7) and 87 +/- 4% (n=6), respectively; the eotaxin release was inhibited by 75 +/- 5% (n=7), whereas the MCP-1 release was decreased by 69 +/- 41% (n=10). NAC (1 mM) also decreased the IL-1beta-induced activation of p38 MAPK. Compared with unstimulated cells, a four-fold increase in 8-isoprostane production in IL-1beta-stimulated HASMC was observed, which could be inhibited by NAC in a concentration-dependent way, with a maximum inhibition of 39 +/- 12%, with 1 mM NAC. The present study demonstrated that N-acetylcysteine inhibits the interleukin-1beta-induced eotaxin and monocyte chemotactic protein 1 expression and production due to a decreased activation of p38 mitogen-activated protein kinase. This study has also shown that N-acetylcysteine decreases the interleukin-1beta-induced production of reactive oxygen species, as suggested by a reduction in the 8-isoprostane production.

[Minocycline-induced pulmonary infiltration and eosinophilia]. / Minocycline-geassocieerde pulmonale infiltraten en eosinofilie.

A 90-year old woman with pulmonary infiltrates and eosinophilia caused by minocycline is described. Until now, in the English, French and Dutch literature only some 35 cases are known. The prognosis is good, especially after treatment with corticosteroids. This doesn't legitimate, however, the use of minocycline without a clear indication. This case again stresses the need for a careful history taking, especially regarding the intake of medications (like minocycline), when one is confronted with a diagnostic problem of pulmonary infiltrates and eosinophilia.

Exhaled nitric oxide after lung transplantation: impact of the native lung.

It has already been demonstrated that exhaled nitric oxide (eNO) is increased in lung transplant patients with chronic rejection, although it is not known whether the diseased native lung after single lung transplantation (SLTx) contributes to the increased eNO values. This study aimed to compare the eNO values in stable lung transplant patients (SLTx versus sequential (S)SLTx and heart (H)LTx) and in patients with established chronic rejection. Altogether, 42 LTx patients (25 females, 13 SLTx, 18 SSLTx, 11 HLTx), with a mean follow-up of 1149 days and a mean age of 44.6 yrs at transplantation, were included. Twenty-six patients had no signs of chronic rejection (five SLTx and 21 SSLTx/HLTx). There was no difference in their eNO values (10.2 in SLTx versus 12.2 (parts per billion) ppb in SSLTx/HLTx). Sixteen patients (eight SLTx and eight SSLTx/HLTx) had a chronic rejection (eight bronchiolitis obliterans syndrome (BOS) potential stage, four BOS stage 1, three BOS stage 2 and one BOS stage 3). Their eNOs were 18.1 (SLTx) and 17.0 (SSLTx/HLTx) ppb, respectively, which were significantly different to the stable LTx patients and showed a trend towards significance for SSLTx/HLTx. There was no significant difference in eNO between the patients with chronic rejection who underwent SLTx and those who underwent SSLTx/HLTx. The diseased native lung after single lung transplantation probably does not contribute much to the exhaled nitric oxide values, either in stable lung transplant patients or in lung transplant patients with chronic rejection.

Evaluation of an individualised asthma programme directed at behavioural change.

An individualised asthma programme directed at behavioural change was evaluated in asthmatic subjects who reported complaints and impairment, despite adequate medical treatment. Mild-to-moderate asthma patients (n=23) were randomly assigned to a programme or waiting list condition. Outcome measures were: McMaster Asthma Quality of Life Questionnaire, Asthma Symptom Checklist, Negative Emotionality Scale, Knowledge, Attitude and Self-Efficacy Asthma Questionnaire, Adherence Scale, and peak flow measurements. Both groups were evaluated at three consecutive moments, each separated by 3 months; the programme was delivered between the first two evaluations. At onset the patient received a workbook containing information, exercises and homework assignments. Psycho-education, behavioural and cognitive techniques were introduced during six 1-h individual sessions. Compared with controls the programme group reported less symptoms (obstruction, fatigue), better quality of life (activity, symptoms, emotions), decreased negative affectivity, and increased adherence, immediately after finishing the programme and at 3 months follow-up. All three cognitive variables (knowledge, attitude towards asthma, self-efficacy) and day and night peak flow ratings improved in the programme group but not in the waiting list group. Participation in an individualised programme resulted in improvement of asthma morbidity, and asthma-related behaviour and cognitions, in subjects reporting symptoms and impairment despite adequate medical therapy.

New classifications and concepts of pathogenesis and management of diffuse interstitial lung diseases.

The diffuse interstitial lung diseases (ILD) are a very complex group of disorders, of which more than 200 specific disease entities are known. All ILD are characterized by a homogenous or heterogenous affection of the lung parenchyma. In recent years there was a renewed interest in the ILD because new concepts have been developed on aetiologic influences, on pathogenetic mechanisms (of inflammation versus active fibrosis) and on genetic susceptibility and consequently on the diagnostic-therapeutic management. Yet, there remain many questions still, e.g. concerning the exact incidence and prevalence of the majority of these diseases and concerning the genetic aspects. More specifically much research has been carried out on the important group of "idiopathic interstitial pneumonias" (IIP) and in particular on "idiopathic pulmonary fibrosis" (IPF). Recently several international consensus reports have been published with guidelines on the histologic and clinical definitions and on the classification and the diagnostic-therapeutic management.

Impact of age and radiographic presentation on the presumptive diagnosis of pulmonary tuberculosis.

We compared delay in presumptive diagnosing pulmonary tuberculosis (PTB) in elderly and younger patents, yield of diagnosis and whether the yield is influenced by the radiographic presentation, even when PTB was suspected. Time from first complaints to first consideration of PTB was determined as suspicion interval (SI) and from first consideration to diagnosis as recognition interval (RI). Presumptive diagnosis was defined as positive staining for acid-fast bacilli or presence of granulomatous lesions in pulmonary specimens. Inthe elderly and in the younger patients, the mean SI was 111.1 and 878 days respectively (P = NS), and the mean RI was 5.9 and 8.3 days, respectively (P = NS). The mean RI was longer in uncharacteristic than in characteristic radiographic findings in both elderly (8.2 and 4.6 days; P = 0.007) and younger patients (10.6 and 3.9 days; P=0.0001). A diagnosis was obtained in 89/113 elderly (79%) and in 109/138 younger (79%) patients (P=NS) and also in 59/80 (73%) patients with uncharacteristic findings and in 139/170 (82%) patients with characteristic findings (P = NS). In the latter, sputum contributed for 66% ofdiagnosis, whereas it was only 31% in patients with uncharacteristic findings (P < 0.005). In elderly patients with uncharacteristic radiographic findings, diagnosis was obtained from sputum in 41% and from other specimens in 35% (P = NS); in the younger group diagnosis was obtained from sputum in 23% and from other specimens in 48% (P < 0.05). In conclusion, there was no difference in SI and RI in elderly patients in comparison with younger patients. Uncharacteristic radiographic findings increased RI in both age groups. Age or radiographic presentation did not influence diagnosing PTB. In patients with characteristic radiographic findings, diagnosis was especially made from examination of sputum, whereas in those with uncharacteristic findings, diagnosis was more often obtained from the complementary investigation of other specimens.

Pertechnegas lung clearance in different forms of interstitial lung disease.

Interstitial lung diseases (ILD) are characterized by an acute or chronic inflammation of the alveolar capillary membrane, which affects the permeability of this membrane. A possible way to measure the permeability of the membrane is by radionuclide aerosol imaging. Pertechnegas, a gas composed of technetium-labelled carbon particles, has recently been proposed as a new ventilation agent to measure this lung clearance. The clearance by pertechnegas in the four most common forms of ILD (eight patients with connective tissue disease, 10 with hypersensitivity pneumonitis, nine with idiopathic interstitial pneumonia and 10 with sarcoidosis) was measured and compared with 10 nonactive smoking controls. Because forced vital capacity (FVC), total lung capacity (TLC) and carbon monoxide diffusing capacity of the lung (DL,CO) are used in the assessment of functional severity of the ILD, the pertechnegas clearance was correlated with these lung-function indices. It was found that the time to half clearance of pertechnegas of the lung is significantly decreased in idiopathic interstitial pneumonia (p<0.0001), hypersensitivity pneumonitis (p=0.0005) and connective tissue disease (p=0.002) but not in sarcoidosis when compared with 10 nonsmoking controls. A significant correlation is also found between time to half clearance and FVC (r=0.76; p<0.0001), TLC (r=0.63; p<0.0001) and DL,CO (r=0.75; p<0.0001) for all groups together. For all subjects as a group, the time to half clearance is shorter in the upper lung zones than in the lower zones (p<0.0001) and the ratio between both zones is not significantly different between the different types of disease. These results indicate that pertechnegas clearance is increased in idiopathic interstitial pneumonia, hypersensitivity pneumonitis and connective tissue disease, but not in sarcoidosis and is related to the functional severity of the disease.

The effect of age on cell-mediated immunity to tuberculin: a study on in vivo and in vitro tuberculin reactivity.

We investigated reactivity to tuberculin in a group of 91 elderly subjects (65 years old and more) and in a control group of 53 younger subjects between 18 and 59 years old, by means of the tuberculin skin test (TST) and by an in vitro lymphocyte stimulation test (LST). The LST had been validated in preliminary tests to accurately reflect T cell reactivity towards tuberculin. We defined a LST with a stimulation index (SI) (ratio of the tuberculin stimulated cultures to the non-stimulated cultures) of 10 or more at a concentration of 0.4 microgram/ml as indicative for sensitisation to tuberculin. The correlation between TST and LST was r = 0.58 (p = 0.0001) in the elderly subjects and r = 0.64 (p = 0.0001) in the younger age group; age did not affect those correlations (p = 0.39). Of the subjects with initially negative TST, 44.4% (16 LST-positive and 16 LST-negative) reacted positive on TST as well as on LST after repeated testing. We conclude that (a) there is a statistically significant but rather weak correlation between in vivo and in vitro assays of cell-mediated immune response to tuberculin, (b) age did not influence this correlation, (c) the in vivo and in vitro tests give complementary information but cannot substitute for each other and (d) repeated TST can induce an immunological boosting phenomenon on TST as well as on LST.

Evaluation of impulse oscillation system: comparison with forced oscillation technique and body plethysmography.

The impulse oscillation system (IOS) has been developed recently to measure respiratory system resistance (Rrs) and reactance (Xrs) at different frequencies up to > or = 25 Hz. IOS has, however, not been validated against established techniques. This study compared IOS with the classical pseudorandom noise forced oscillation technique (FOT) and body plethysmographic airway resistance (Raw) in 49 subjects with a variety of lung disorders and a wide range of Raw (0.10-1.28 kPa x L(-1) x s). Rrs,IOS was slightly greater than Rrs,FOT, especially at lower frequencies, with a mean +/- SD difference at 5-6 Hz of 0.14 +/- 0.09 kPa x L(-1) x s. Comparisons with the wave-tube technique applied on two analogues indicated an overestimation by IOS. Xrs,IOS and Xrs,FOT were very similar, with a slightly higher resonant frequency with IOS than with FOT (mean difference +/- SD 1.35 +/- 3.40 Hz). Raw was only moderately correlated with Rrn,FOT and Rrs-IOS; although the mean differences were small (0.04 +/- 0.14 kPa x L(-1)s for Rrs6,FOT and -0.10 +/- 0.14 kPa x L(-1) x s for Rrs5,IOS), IOS and FOT markedly underestimated high resistance values. In conclusion, the impulse oscillation system yields respiratory system resistance and reactance values similar, but not identical to those provided by the forced oscillation technique.

Practical approach to patients presenting with multiple synchronous suspect lung lesions: a reflection on the current TNM classification based on 54 cases with complete follow-up.

OBJECTIVES: To examine the survival after surgical treatment of patients presenting with two synchronous suspect lung lesions, and to reflect on the recent TNM classification, which has upgraded patients with two malignant lung lesions of the same histology into the T4 (both lesions in the same ipsilateral lobe) or M1 (different lobes or lungs) category. METHODS: Retrieval of all consecutive patients with a diagnosis of two synchronous suspect lung lesions in the prospective database of the Leuven Lung Cancer Group in the interval between 1990 and 1994. Analysis of characteristics and survival of all patients, who underwent surgical resection with intention to cure for both lesions. RESULTS: Forty-eight of 54 patients had surgical resection with curative intent. Thirty-five of these proved to have two malignant lesions, in 13 the second lesion was benign. The 5-year survival rate in the patients with two malignant lesions was 33% (95% CI: 17-49). The median survival time was 28 months. Although the number of patients in the subgroups was small, there were no obvious differences between patients with two lesions in the same or in different lobes, if a complete resection could be achieved. CONCLUSIONS: An aggressive surgical approach in carefully selected patients presenting with two suspect pulmonary lesions can be rewarding. Although some degree of upstaging is appropriate in patients with two malignant lung tumours of the same histology, their current stage IIIB or IV classification probably underestimates their prospects for long-term survival after radical resection.