B. Wallaert

Airway remodeling is correlated with obstruction in children with severe asthma.

Background:  Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern.

Cytokine mRNA gene expression in active and nonactive pulmonary sarcoidosis

Sarcoidosis is a multisystem granulomatous disease associated with the expansion and activation of CD4+ T-lymphocytes and macrophages. To investigate the immunopathology of active and nonactive pulmonary sarcoidosis, we have examined the expression of cytokine gene transcripts in bronchoalveolar lavage cells from 15 patients with active pulmonary sarcoidosis, eight patients with non-active pulmonary sarcoidosis, and nine normal controls. Using in situ hybridization, the percentage of cells expressing messenger ribonucleic acid (mRNA) for interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 and interferon-gamma (IFN-gamma) were compared in the groups studied. In individuals with active sarcoidosis, there were significantly greater proportions of cells expressing mRNA for IL-2, IL-10, IL-12 and IFN-gamma than in subjects with nonactive disease and normal controls (p < 0.01). There was no significant difference in the percentage of positive cells expressing IL-10 and IL-12 mRNA in the nonactive group compared to the normal controls (p > 0.05). No significant differences in the percentages of IL-3, IL-4 and IL-5 mRNA positive cells were observed between active and nonactive sarcoidosis patients and normal controls (p > 0.05). These results demonstrate that there is a preferential expression of T-helper type 1 cytokines in pulmonary sarcoidosis, and that cytokines related to macrophage activation are the most prominent. In addition, these data implicate an elevated expression of interleukin-2, -10 and -12 and interferon-gamma in active compared to nonactive sarcoidosis.

VENOM IMMUNOTHERAPY MODULATES INTERLEUKIN-4 AND INTERFERON-GAMMA MESSENGER RNA EXPRESSION OF PERIPHERAL T LYMPHOCYTES

The mechanism by which specific immunotherapy exerts its beneficial effect remains unclear. In order to evaluate the influence of venom immunotherapy on the T‐cell cytokine pattern of allergic reactions, we studied interleukin‐4 (IL‐4) and interferon‐γ (IFN‐γ) mRNA expression of peripheral T lymphocytes from 12 patients undergoing rush venom desensitization, before treatment at Day 0 (D0), at Day 15 (D15) and Day 90 (D90) after treatment, and from seven controls. Antigen‐specific T‐cell proliferation was also determined. Cytokine mRNA expression was evaluated using in situ hybridization, 24 hr after culture of peripheral T cells with medium, venom, or an unrelated allergen. Allergen‐induced T‐cell proliferation decreased at D15 and D90 of rush immunotherapy (P ≤ 0.02). In venom‐stimulated cultures of the patient group, there was a decrease in IL‐4 mRNA‐positive cells at D15 and D90 (P ≤ 0.001). Before desensitization, IFN‐γ mRNA expression was lower in patients than in controls and did not increase after in vitro allergen stimulation. In contrast, after immunotherapy, spontaneous IFN‐γ mRNA expression increased, but only at D90 (P ≤ 0.001). The cytokine pattern observed at D90 after immunotherapy was similar to that observed in control subjects. In conclusion, venom immunotherapy induced an altered cytokine mRNA pattern in allergen‐stimulated T cells which was dissociated from the early changes of allergen‐induced T‐cell responsiveness.

Involvement of CCL18 in Allergic Asthma

Allergic asthma is associated with a pulmonary recruitment of Th type 2 cells, basophils, and eosinophils, mainly linked to chemokine production. CCL18 is a chemokine preferentially expressed in the lung, secreted by APCs, induced by Th2-type cytokines, and only present in humans. Therefore, CCL18 may be involved in allergic asthma. PBMC from asthmatics allergic to house dust mite cultured in the presence of Dermatophagoides pteronyssinus 1 (Der p 1) allergen secreted CCL18, 48 and 72 h after stimulation, whereas those from healthy donors did not. Part of CCL18 was directly derived from Der p 1-stimulated plasmacytoid dendritic cells, whereas the other part was linked to monocyte activation by IL-4 and IL-13 produced by Der p 1-stimulated T cells. In bronchoalveolar lavages from untreated asthmatic allergic patients, CCL18 was highly increased compared with controls. Functionally, CCL18 preferentially attracted in vitro-polarized Th2 cells and basophils, but not eosinophils and Th1 cells, and induced basophil histamine and intracellular calcium release. These data show a new function for CCL18, i.e., the recruitment of Th2 cells and basophils, and suggest that CCL18 may play a predominant role in allergic asthma.

Interleukin-5 immunoreactivity and mRNA expression in gut mucosa from patients with food allergy

Eosinophils, mast cells and T lymphocytes are important cells in the allergic inflammatory process. These cells produce and are regulated by cytokines such as interleukin‐3 (IL‐3), interleukin‐5 (IL‐5) and granulocyte macrophage‐colony stimulating factor (GM‐CSF). We initiated this study to evaluate pathological abnormalities and to detect IL‐5 in the duodenal mucosa from patients with food allergy.

Long-term follow-up of pulmonary function in chronic eosinophilic pneumonia. Groupe d'Etude en Pathologie Interstitielle de la Societe de Pathologie Thoracique du Nord

The prognosis of chronic eosinophilic pneumonia (CEP) is usually good under corticosteroid therapy (CST). The main complications are relapses when treatment is tapered or discontinued. The aim of this retrospective, multicentre study was to evaluate the long-term consequences of CEP on pulmonary function tests. Nineteen patients (mean +/- SEM age 51 +/- 16 yrs) with CEP were studied. Lung function tests were performed at the time of diagnosis and at follow-up, and included flow-volume curve. The results of the first pulmonary function test were normal in six patients, restrictive in nine, and obstructive in four. Relapses (recurrence of initial signs) occurred in nine patients. The last evaluation (mean +/- SEM follow-up of 49 +/- 44 months, range 12-142 months) showed a complete recovery in 8 of the 19 patients. One patient developed bilateral apical fibrosis. The remaining 10 patients, exhibited obstructive pulmonary function without relapse of CEP at this time. Bronchoalveolar lavage (BAL) eosinophilia at the time of the initial evaluation tended to be higher (p = 0.05) in these 10 patients than in those with normal pulmonary function findings at follow-up. This study demonstrates: firstly, that the development of an obstructive ventilatory defect is a common finding during the course of chronic eosinophilic pneumonia (CEP); secondly, that bronchial obstruction might appear despite the absence of clinical and radiological signs of relapse; and, thirdly, that a markedly increased bronchoalveolar lavage eosinophilia at the initial evaluation is associated with a higher risk of development of bronchial obstruction. These results suggest that pulmonary function tests should be included in the management of chronic eosinophilic pneumonia.

Transforming growth factor-β 1 in sarcoidosis

Transforming growth factor-β (TGF-β) is a cytokine that promotes extracellular matrix accumulation and inhibits matrix degradation. Although the natural course of sarcoidosis is usually favourable, granuloma healing in the lung may result in pulmonary fibrosis and respiratory impairment in some patients. In this study TGF-β1 was evaluated in bronchoalveolar lavage (BAL) fluid and cul- ture supernatants of alveolar macrophages (AM) from 73 patients with biopsy- proven sarcoidosis. Disease activity was defined when patients recently developed or increased symptoms (cough, dyspnoea, systemic symptoms) and/or demonstrated increasing opacities on chest radiography. Pulmonary function tests were performed in all patients including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and the diffusing capacity of the lung for carbon monoxide (DL,CO). Fourteen patients with idiopathic pulmonary fibrosis (IPF) and 14 healthy subjects were investigated as a control group. Immunohistochemistry was used to evaluate the cell distribution of TGF-β1 on lung specimens. TGF-β1 levels in BAL and in AM supernatants were not different between sar- coidosis and healthy subjects, whereas they were markedly increased in IPF. How- ever, the TGF-β1 level was significantly increased in BAL fluid but not in AM supernatants from sarcoidosis with altered lung function, compared with patients with normal lung function. The TGF-β1 level in BAL was increased in active sarcoido- sis but this increased level was mainly related to the higher level observed in patients with altered lung function. TGF-β1 levels in BAL correlated significantly with the lymphocyte percentage. TGF-β1 staining assessed by immunohistochemistry was intense in epithelioid histiocytes comprising non-necrotizing granuloma and in bron- chiolar epithelial cells, in hyperplastic type II pneumocytes and occasionally in AM. This study supports the hypothesis that overproduction of transforming growth factor-β1 is associated with functional impairment in patients with pulmonary sar- coidosis. Eur Respir J 1998; 12: 913-919.

Diesel Exposure Favors Th2 Cell Recruitment by Mononuclear Cells and Alveolar Macrophages from Allergic Patients by Differentially Regulating Macrophage-Derived Chemokine and IFN-γ-Induced Protein-10 Production

Diesel exhausts and their associated organic compounds may be involved in the recent increase in the prevalence of allergic disorders, through their ability to favor a type 2 immune response. Type 2 T cells have been shown to be preferentially recruited by the chemokines eotaxin (CCL11), macrophage-derived chemokine (MDC, CCL22), and thymus activation-regulated chemokine (CCL17) through their interaction with CCR3 and CCR4, respectively, whereas type 1 T cells are mainly recruited by IFN-γ-induced protein-10 (CXCL10) through CXCR3 binding. The aim of the study was to evaluate the effect of diesel exposure on the expression of chemokines involved in type 1 and 2 T cell recruitment. PBMC and alveolar macrophages from house dust mite allergic patients were incubated with combinations of diesel extracts and Der p 1 allergen, and chemokine production was analyzed. Diesel exposure alone decreased the constitutive IP-10 production, while it further augmented allergen-induced MDC production, resulting in a significantly increased capacity to chemoattract human Th2, but not Th1 clones. Inhibition experiments with anti-type 1 or type 2 cytokine Abs as well as cytokine mRNA kinetic evaluation showed that the chemokine variations were not dependent upon IL-4, IL-13, or IFN-γ expression. In contrast, inhibition of the B7:CD28 pathway using a CTLA-4-Ig fusion protein completely inhibited diesel-dependent increase of allergen-induced MDC production. This inhibition was mainly dependent upon the CD86 pathway and to a lesser extent upon the CD80 pathway. These results suggest that the exposure to diesel exhausts and allergen may likely amplify a deleterious type 2 immune response via a differential regulation of chemokine production through the CD28 pathway.

High-dose and low-dose systemic corticosteroids are equally efficient in acute severe asthma

The optimal amount of systemic corticosteroids to be used in acute severe asthma remains an unresolved issue. In this double-blind, randomized study we compared two doses of methylprednisolone (1 vs 6 mg.kg-1 q.d.) in asthmatics presenting with an acute severe asthma attack, unresponsive to an intensive beta 2-agonist regimen administered during a run-in period. Concurrent therapy, including oxygen, inhaled and intravenous salbutamol, and aminophylline was strictly standardized. The response was assessed by serial bedside spirometry. The primary outcome measurement was forced expiratory volume in one second (FEV1) (expressed as percentage of predicted values) at 24 and 44 h. The trial was designed in order to achieve a statistical power of 90%. Twenty three patients were included in the low-dose group and 24 in the high-dose group. Both groups were comparable in terms of demographic profiles, history of asthma, and severity of the current attack. Improvement in pulmonary function was similar in both groups. At 44 h, the mean (+/- SD) FEV1 values were 53 +/- 22 and 45 +/- 14% in the low and in the high-dose group respectively (NS). We conclude that high dose systemic corticosteroids offer no further benefit over low-doses in the treatment of severe acute asthma.

Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses

To the Editors: Acute exacerbations (AEs) are now recognised as a frequent and severe complication of idiopathic pulmonary fibrosis (IPF). In a large series, 1- and 3-yr incidences were 14.2% and 20.7%, respectively [1]. New diagnostic criteria were published in 2007 [2]. The pathogenesis of these episodes remains unknown, although invasive procedures have been described as possible triggers. Prognosis is poor, with a short-term mortality rate of 45–85%. There is no consensus regarding treatment, as no published study has compared the efficiency of different treatment regimens, and treatment often differs between patients within a given study [1–4]. Since 2005, exacerbations of IPF identified in our referral centre (Centre Hospitalier Regional de Lille, Lille, France) have been treated with pulses of methylprednisolone followed by pulses of cyclophosphamide [5]. The main goal of the present retrospective study was to evaluate the mortality of exacerbations of IPF treated with this regimen. Following admission for aggravation of dyspnoea, a series of tests were run to determine diagnosis and functional impairment. When an exacerbation of IPF was diagnosed, patients were treated with a methylprednisolone pulse (1,000 mg) at days 1–3 and on day 4 placed on an escalating regimen of cyclophosphamide with an initial dose of 500 mg intravenously [5]. The dose of cyclophosphamide was increased by 200 mg every 2 weeks, provided the total white blood cell count remained at >3,000 cells·mm−3. The maximum single administered dose was 1,500 mg of cyclophosphamide. The diagnosis of IPF was reassessed for the purpose of this study …