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Biomedical subjects

Philippe Gevaert

Publications and source records attributed to Philippe Gevaert.

17 recordsLinked to original sources
PubMed2006

Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps is characterized by an eosinophilic inflammation and high IL-5 levels. OBJECTIVES: Antagonizing the effect of IL-5 is a potential new treatment strategy in patients with nasal polyps. METHODS: In a double-blind, placebo-controlled, randomized, 2-center safety and pharmacokinetic study, 24 subjects with bilateral nasal polyps were randomized to receive a single intravenous infusion of reslizumab, a humanized anti-human IL-5 mAb, at 3 mg/kg or 1 mg/kg or placebo. We evaluated the safety and pharmacokinetics of reslizumab, and biologic activity was assessed by means of endoscopic evaluation of polyp size, symptoms, peripheral eosinophil counts, peripheral and local IL-5 levels, eotaxin levels, and eosinophil cationic protein levels. RESULTS: We demonstrated that a single injection of reslizumab up to 3 mg/kg is safe and well tolerated. Blood eosinophil numbers and concentrations of eosinophil cationic protein were reduced up to 8 weeks after treatment in serum and nasal secretions. Individual nasal polyp scores improved only in half of the treated patients for 4 weeks. Responders had increased IL-5 concentrations in nasal secretions at baseline compared with nonresponders, and logistic regression analysis revealed that increased nasal IL-5 levels (>40 pg/mL) predict the response to anti-IL-5 treatment. CONCLUSION: A single injection of anti-IL-5 reduces the size of nasal polyps for 4 weeks in half of the patients, and nasal IL-5 levels predict the response to anti-IL-5 treatment. CLINICAL IMPLICATIONS: Intravenous administration of a humanized anti-human IL-5 mAb is safe and reduces the size of nasal polyps in half of the patients.

Adolescent↗
PubMed2005

Pharmacological management of nasal polyposis.

Nasal polyposis affects nearly 4% of the total population in Western countries, and presents a real challenge to the physician because of its severity, chronicity and recurrence rate. Characteristic histomorphological features of polyps are an eosinophilic inflammation and the destruction of connective tissue; recent research has focused on cytokines, chemokines, growth factors and metalloproteinases to explain these features, as the aetiology of nasal polyposis remains largely unclear. Currently, topical and systemic corticosteroids are first-choice drug therapy approaches, and good evidence from controlled trials is available for topical, but not for systemic, corticosteroid therapy. Surgery is indicated if adequate drug treatment fails, which often needs to be maintained after surgery. There is limited experience for other drugs, such as antihistamines, leukotriene antagonists and frusemide (furosemide), which may be added to corticosteroid therapy in selected patients. Aspirin (acetylsalicylic acid) desensitisation may be a therapeutic option for patients who do not respond to corticosteroids or surgery. Recently, antibiotics such as macrolides have been suggested to have therapeutic activity based on their anti-inflammatory properties but large-scale controlled trials are lacking. New approaches are currently evolving, specifically targeting eosinophilic recruitment (chemokine receptor 3, eotaxin) and inflammation (interleukin-4, -5, -13), immunoglobulin-E, or tissue remodeling by reducing the activity of metalloproteinases. This review summarises current knowledge on pathogenesis as well as established and future approaches in the pharmacological management of bilateral eosinophilic nasal polyposis.

Administration, Topical↗
PubMed2004

Soluble interleukin-5 receptor alpha is increased in acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: During chronic obstructive pulmonary disease (COPD) exacerbations (AE-COPD), an influx of eosinophils into the bronchial mucosa has been described. Eosinophilic cationic protein (ECP) and soluble interleukin-5 receptor alpha (sIL5Ralpha) are secreted by eosinophils and increased in eosinophilic airway diseases. METHODS: We studied ECP and sIL5Ralpha expression in patients with COPD compared to healthy controls and smokers and investigated a possible association to viral exacerbations of COPD. Expression of sIL5Ralpha in serum was analyzed by ELISA and ECP by the Uni-Cap system. Induced sputum from patients with COPD was analyzed for six different respiratory viruses by nested PCR. RESULTS: ECP and sIL5Ralpha were significantly elevated in AE-COPD subjects (n = 54) compared to healthy controls (n = 11, p = 0.018). Furthermore, there was a significant increase in sIL5Ralpha, but not in ECP, in 30 patients with virus-associated AE-COPD compared to smokers without COPD (n = 16) and healthy controls. The increase in FEV(1) after resolution of the AE-COPD correlated with the decrease in sIL5Ralpha (r = 0.269, p = 0.034). CONCLUSIONS: sIL5Ralpha is increased in AE-COPD and not affected by smoking like ECP. sIL5Ralpha is increased in patients with virus-associated AE-COPD compared to smokers and controls. Concentrations of sIL5Ralpha mirror changes in the clinical status and lung function. These data support the involvement of eosinophils in acute exacerbations of COPD.

Blood Proteins↗
PubMed2004

Aspirin sensitivity and IgE antibodies to Staphylococcus aureus enterotoxins in nasal polyposis: studies on the relationship.

BACKGROUND: Nasal polyposis is a multifactorial disease characterized by a chronic eosinophilic inflammation of the sinus mucosa, often associated with asthma and aspirin sensitivity. We have recently shown that the presence of IgE antibodies to Staphylococcus aureus enterotoxins (SAEs) was related to the severity of eosinophilic inflammation in nasal polyp tissue. In this study, we therefore aimed to determine, whether aspirin sensitivity was related to an immune response to SAEs, and how both criteria would be related to eosinophilic inflammation. METHODS: 40 subjects with nasal polyposis (NP) were classified as aspirin-sensitive (n=13, ASNP) or aspirin-tolerant (n=27, ATNP) based on a bronchial aspirin challenge test. Homogenates prepared from nasal polyp tissue and inferior nasal turbinates from healthy subjects (n=12) were analyzed for concentrations of IL-5 by enzyme immunoassay and for ECP, total and IgE to a mix of SAEs (A, C, TSST-1) using the ImmunoCAP system. RESULTS: Concentrations of IL-5, ECP, total IgE, and IgE to an SAE mix were significantly increased in ASNP compared with ATNP patients and controls. In addition, a subgroup analysis showed an increase in eosinophilic markers in ATNP-SAE(+) compared to ATNP-SAE(-). This relationship, however, was not found in ATNP-SAE(+) and ATNP-SAE(-) subjects, indicating that SAE immune response is overlapped or not relevant in this condition. CONCLUSIONS: Aspirin sensitivity was associated with increased concentrations of eosinophil-related mediators, as well as IgE antibodies to SAEs in nasal polyp tissue. However, a direct impact of S. aureus could not be established. It seems that aspirin sensitivity and immune reactions to SAEs are independently related to eosinophilic inflammation.

Adult↗
PubMed2004

Increased IgE-antibodies to Staphylococcus aureus enterotoxins in patients with COPD.

Recent evidence suggests that Staphylococcus aureus enterotoxins (SAEs) could modify airway disease by acting as superantigens, an immune response that can be monitored by detection of IgE antibodies to SAEs. We studied the expression of total IgE and specific IgE to SAEs using the Uni-CAP system in healthy controls, smokers without COPD and COPD patients. Only 1/10 controls (10%) and 1/16 smokers (6.3%) had IgE to SAEs compared to 7/18 patients with stable COPD (38.9%) and 21/54 patients with exacerbated COPD (38.9%). The IgE levels to SAEs of the patients with stable COPD (0.18 [0.05-26.2]kUA/l) and the patients with exacerbated COPD (0.09 [0.05-18.6]kUA/l) were significantly higher than those of smokers (n = 16; 0.05 [0.05-0.82]kUA/l) and controls (n = 11; 0.05 [0.05 0.9]kUA/l, P<0.05). IgE to SAEs decreased significantly in the exacerbated patients during hospitalization (0.13 [0.05-18.3] vs. 0.05 [0.05-11]kUA/l, P<0.001) going along with a significant increase in FEV1 (38.1 [16.9-79.5] vs. 51.6 [15-80]%predicted, P<0.001). Similarly to severe asthma, we found significantly elevated IgE to SAE in COPD patients. Our data for the first time suggest differences between healthy subjects, smokers and patients with established COPD regarding the role of bacterial products and point to a possible disease modifying role of SAEs.

Adult↗
PubMed2003

Collection of nasal secretions for immunological analysis.

The biochemical analysis of nasal secretions has become essential in the study of nasal or sinus diseases and the monitoring of medical and surgical treatment. The nasal fluid greatly reflects the inflammatory activity within the nasal mucosa. This paper discusses techniques for nasal fluid collection described before and proposes a new approach for the collection and calculation of nasal secretions based on sinus packs. The method is non-invasive, well standardized and reproducible and therefore may serve as a valid tool for future investigations.

Adolescent↗
PubMed2003

Quantitative real time polymerase chain reaction for measurement of human interleukin-5 receptor alpha spliced isoforms mRNA.

BACKGROUND: Expression of human Interleukin-5 receptor alpha (hIL-5Ralpha) is controlled by alternative splicing, which generates two different transcripts encoding a membrane-anchored and a soluble form of the receptor, respectively. Although the study of the expression and regulation of hIL-5Ralpha is of crucial importance in the field of immunological processing, methods and techniques until now described lack sufficient sensitivity for detection of small differences in the expression of these isoforms. The aim of this study was to develop a reliable and sensitive real-time quantitative PCR assay to analyse the expression level of each isoform. METHODS: For the quantitative real-time PCR assay, two standard curves specific for each splice variant were constructed. PCR amplifications were performed on CDNA from peripheral blood, eosinophilic chronic rhinosinusitis and normal nasal tissue using a common forward and two specific reverse primers, in combination with SYBR Green I as the detection format. RESULTS AND CONCLUSION: We have developed an accurate and reliable assay for quantification of interleukin-5 receptor alpha mRNA isoforms over a broad dynamic range of input molecules. Importantly, excess of one isoform did not influence accurate quantification of the other isoform. Quantification of hIL-5Ralpha variants in human samples demonstrated an overexpression of both membrane-anchored and soluble encoding variants in eosinophilic chronic rhinosinusitis tissue and peripheral blood in patients with eosinophilic chronic rhinosinusitis compared to healthy subjects. The implementation of this assay will allow a better understanding of the regulatory mechanisms of the hIL-5Ralpha gene and hence its role in the pathogenesis of chronic inflammatory diseases.

Alternative Splicing↗
PubMed2003

Superantigens and nasal polyps.

Nasal polyps represent an often severe T-cell-orchestrated eosinophilic upper airway disease with currently unknown pathogenesis, often associated with lower airway disease, such as asthma. Superantigens, predominantly derived from Staphylococcus aureus, are potent activators of T cells, induce the synthesis of IgE in B cells, and have direct effects on pro-inflammatory cells, such as eosinophils. IgE antibodies to S. aureus enterotoxins have been described in polyp tissue, linked to a local polyclonal IgE production and an aggravation of eosinophilic inflammation. Furthermore, such IgE antibodies have also been described in the sera of patients with asthma, and linked to severity of disease and steroid insensitivity. This review summarizes our current understanding of the possible role of S. aureus enterotoxins in chronic severe airway disease, such as nasal polyposis.

B-Lymphocytes↗
PubMed2003

Interleukin-5, eosinophilic diseases and therapeutic intervention.

Interleukin 5 (IL-5) is the key cytokine in an eosinophil's life span: it supports eosinophilopoiesis and eosinophil differentiation, contributes to eosinophil migration, tissue localisation and function, and prevents eosinophil apoptosis. Given the likely role of eosinophils in chronic inflammatory diseases, a lot of research over the past decade was aimed at antagonising IL-5 function. It appears from recent studies that, although this can easily be achieved in vitro, blocking IL-5 function in vivo is much more difficult than originally anticipated. Here, we review the current status of IL-5 and IL-5 receptor research, with emphasis on strategies to interfere with IL-5 function.

Animals↗
PubMed2002

Secretion of TGF-betal, TGF-beta2, EGF and PDGF into nasal fluid after sinus surgery.

Wound healing is a highly coordinated process involving clot formation, inflammatory reaction, immune response and tissue remodeling. The transforming growth factor beta (TGF-beta), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) are known to be active during different phases of wound repair. The authors postulated that changes in the spontaneous secretion of these growth factors could be detected in nasal fluid after sinus surgery and propose a standardized technique to follow the healing process. The study was designed as a single-center prospective pilot study. Nasal secretions were obtained from eight patients at 1, 2 and 3 weeks after functional endoscopic sinus surgery (FESS) and compared to 13 controls. Nasal fluid was collected by sinus packing and was analyzed by ELISA for TGF-betal, TGF-beta2, EGF and PDGF. Comparing patients at 1 week after surgery with control subjects, a significant increase in the concentrations of TGF-betal, TGF-beta2 and PDGF in nasal secretions could be demonstrated ( P<0.001). At 2 and 3 weeks after surgery, decreasing amounts of these growth factors were found, nearly reaching normal conditions again. This decrease was not significant between visits. In contrast, EGF concentrations in nasal fluids tended to have decreased in patients 1 week after FESS compared to controls, with this level persisting during 3 weeks of mucosal healing. This is the first study proposing a follow-up method for nasal and sinus mucosal healing after surgery in order to determine cytokine secretion profiles.

Adult↗
PubMed2002

Staphylococcus aureus superantigens and airway disease.

Twenty-five percent of the population are permanent carriers of Staphylococcus aureus, possibly producing a variety of toxins with superantigenic properties. Staphylococcal superantigens are a group of high- molecular-weight pyrogenic proteins that have in common an extremely potent stimulatory activity for T-lymphocytes, macrophages, mast cells, eosinophils, and epithelial cells. The role of staphylococcal superantigens in atopic dermatitis has recently been recognized, and new evidence suggests that similar mechanisms may also be relevant in airway disease. This circumstantial evidence is currently limited to rhinitis, sinusitis, and possibly asthma, but may, if supported, open a new understanding of pathomechanisms and therapeutic targets.

Allergens↗
PubMed2002

Mediators in nasal polyposis.

Nasal polyposis (NP) is a chronic inflammatory disease of the sinuses often associated with asthma. Although we have not yet achieved a full understanding of the precise mechanisms underlying the pathogenesis of NP, recent insights have been acquired into the regulation of eosinophil chemotaxis, activation, and survival, in addition to their possible link to gross histopathologic changes such as pseudocyst formation. Interleukin (IL)-5, transforming growth factor-beta(1), and eotaxin seem to be crucial players in the regulation of eosinophilic inflammation and extracellular matrix breakdown. The cytokine pattern in NP assumes neither a T helper 1 (Th1) nor Th2 type predominance, because IL-4, IL-5, IL-12, and interferon-gamma have all been shown to be upregulated in NP tissue, without influence of the atopic status. However, recent studies have demonstrated a strong local upregulation of the immunoglobulin E (IgE) synthesis with the formation of specific IgE to Staphylococcus aureus enterotoxins, suggesting a possible role of superantigens in these pathologic processes.

Cell Adhesion Molecules↗
PubMedDate not supplied

Wound healing of the nasal and paranasal mucosa: a review.

BACKGROUND: Wound healing is a highly coordinated process involving clot formation, inflammatory reaction, immune response, and, finally, tissue remodeling and maturation. Only few data regarding the specific healing of the nasal or sinusal mucosa are available. METHODS: After a short summary of the general principles of wound healing, the most important data regarding in vitro or in vivo models of wound healing of the nasal and paranasal mucosa are discussed. Attention is paid to clinical application. MAIN FINDINGS: First observations regarding the specific regulation of epithelial regeneration by growth factors have underlined the complex relationship between extracellular matrix and epithelium during the repair process. However, only poor and aspecific correlations can be described between endoscopically and histomorphologically defined postoperative phases.

Animals↗
PubMedDate not supplied

Transforming growth factor beta1 in nasal remodeling: differences between chronic rhinosinusitis and nasal polyposis.

BACKGROUND: Chronic rhinosinusitis (CRS) and nasal polyposis (NP) are histopathologically characterized by different gross morphological aspects. Transforming growth factor (TGF) beta1 plays an important role in tissue remodeling, which is poorly understood in chronic diseases of the sinuses. METHODS: The expression of TGF-beta1 was analyzed by enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction, and immunohistochemistry in nasal tissue from controls (n = 6), CRS (n = 19), or NP (n = 19). RESULTS: CRS presented significantly higher concentrations of TGF-beta1 at protein (p = 0.0008) and mRNA levels (p = 0.025) when compared with NP samples. In CRS, TGF-beta1+ staining of the extracellular matrix was found abundantly and related to fibrosis. In contrast, no TGF-beta1 staining was found in the pseudocyst areas in NP. CONCLUSION: CRS was histologically characterized by fibrosis, which was reflected by a significantly higher expression of TGF-beta1 at RNA and protein levels when compared with NP. We show that TGF-beta1 expression is related to fibrosis, differentiating CRS without polyps from NP.

Chronic Disease↗