François Lavigne

Evidence for Local Eosinophil Differentiation Within Allergic Nasal Mucosa: Inhibition with Soluble IL-5 Receptor

Eosinophil differentiation occurs within the bone marrow in response to eosinopoietic cytokines, particularly IL-5. Recently, however, eosinophil precursors (CD34/IL-5Rα+ cells) and IL-5 mRNA+ cells have been identified within the lungs of asthmatics, indicating that a population of eosinophils may differentiate in situ. In this report, we examined the presence of eosinophil precursors within allergic nasal mucosa and examined whether they undergo local differentiation following ex vivo stimulation. We cultured human nasal mucosa obtained from individuals with seasonal allergic rhinitis with either specific allergen, recombinant human IL-5 (rhIL-5), or allergen + soluble IL-5Rα (sIL-5Rα), shown to antagonize IL-5 function. Simultaneous immunocytochemistry and in situ hybridization demonstrated that there were fewer cells coexpressing CD34 immunoreactivity and IL-5Rα mRNA following culture with allergen or rhIL-5, compared with medium alone. Immunostaining revealed that the number of major basic protein (MBP) immunoreactive cells (eosinophils) was higher within tissue stimulated with allergen or rhIL-5, compared with unstimulated tissue. In situ hybridization detected an increase in IL-5 mRNA+ cells in sections from tissue cultured with allergen, compared with medium alone. These effects were not observed in tissue cultured with a combination of allergen and sIL-5Rα. Colocalization analysis indicated this expression to be mainly, but not exclusively, T cell (44%) and eosinophil (10%) derived. Our findings suggest that a subset of eosinophils may differentiate locally within allergic nasal mucosa, in what appears to be a highly IL-5-dependent fashion, and imply that this process might be regulated in vivo by endogenous production of sIL-5Rα.

Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults.

BACKGROUND Exposure to bacterial products in early life could protect against development of atopy. We examined the effect of bacterial lipopolysaccharide on allergic inflammation and expression of cytokines and lipopolysaccharide receptor (toll-like receptor 4 TLR4) in nasal mucosa of 15 atopic children and ten atopic adults. METHODS Explanted mucosa was cultured with allergen with or without lipopolysaccharide (0.1 mg/L) for 24 h. Immunocytochemistry and in-situ hybridisation were used to phenotype the cells and cytokines. FINDINGS In explants from atopic children, lipopolysaccharide prevented allergen-induced T-helper type 2 (Th2) inflammation and upregulated Th1 cytokine reactivity and expression. These effects were blocked by antibody to interleukin 10. In children but not in adults, lipopolysaccharide caused increases of three times in T-cell reactivity, five times in T-cell proliferation, and four times in expression of interleukin 10 compared with mucosa stimulated with allergen alone. This difference in response was mirrored by lipopolysaccharide-induced increases in TLR4 reactivity in children but not adults. TLR4 receptor was expressed by CD3-positive T cells, and TLR4-positive cells contained interleukin 10. Lipopolysaccharide increased expression of cells positive for both CD3 and TLR4; both TLR4 and interleukin 10; and both CD4 and CD25. INTERPRETATION Lipopolysaccharide inhibits allergic inflammation in nasal mucosa of atopic children by skewing local immune responses from Th2 to Th1 and upregulating production of interleukin 10. These effects are mediated by TLR4. Our results emphasise an important difference between adults and children in their ability to respond to bacterial products. These differences could have a role in normal maturation of the immune system.

Interleukin-6 expression in chronic sinusitis: Colocalization of gene transcripts to eosinophils, macrophages, T lymphocytes, and mast cells

Chronic sinusitis in allergic (ACS) and nonallergic (NCS) patients is characterized by persistent inflammation and subepithelial fibrosis of the sinus mucosa. The inflammatory infiltrate is rich in T lymphocytes, monocyte/macrophages, plasma cells, and eosinophils. Th2-type cytokines are thought to regulate inflammatory cell recruitment, activation, survival, and the release of tissue-damaging mediators. Interleukin-6 is a proinflammatory Th2-type cytokine that stimulates fibroblast proliferation and collagen synthesis. Expression of interleukin-6 has been reported in pulmonary fibrosis and a number of other conditions associated with fibrotic tissue changes. In vitro studies have indicated that interleukin-6 is produced by macrophages, T cells, eosinophils, mast cells, and other cell types. Here we examined interleukin-6 messenger RNA and immunoreactivity in the sinus epithelium and subepithelium of subjects with ACS and NCS by in situ hybridization and immunocytochemistry, performed on sinus biopsy and polyp sections obtained from patients. Nasal turbinate biopsy specimens from normal volunteers were used as controls. Interleukin-6 messenger RNA and immunoreactivity were expressed by a significantly greater proportion of epithelial and subepithelial cells in ACS and NCS subjects than in normal controls. There was no difference in epithelial or subepithelial interleukin-6 expression between ACS and NCS patients. Colocalization studies revealed that macrophages, T cells, eosinophils, and mast cells are sources of interleukin-6 messenger RNA in ACS and NCS. The numbers of interleukin-6 messenger RNA-positive cells coexpressing immunoreactivity for the mast-cell marker were significantly greater in ACS than in NCS subjects. The results of this study suggest a role for interleukin-6 in the inflammatory response of chronic sinusitis.

Comparison of inflammatory cell profile and Th2 cytokine expression in the ethmoid sinuses, maxillary sinuses, and turbinates of atopic subjects with chronic sinusitis

Chronic sinusitis is a common disease characterized by persistent inflammation of the sinus mucosa. This study was undertaken to investigate immunopathologic findings in biopsy specimens from the ethmoid sinuses, maxillary sinuses, and inferior nasal turbinates of 14 allergic subjects with chronic sinusitis. The composition of the inflammatory infiltrate in the three tissue sites was examined by immunocytochemistry with anti-CD3 (total T cells), anti-CD4 (helper T cells), anti-CD8 (suppressor T cells), anti-MBP (eosinophils), antitryptase (mast cells), and antichymase (mast cells) antibodies. These revealed a significant increase in the T-cell helper/suppressor ratio and eosinophils in the ethmoid sinus mucosa compared with those in the maxillary sinus mucosa and the inferior turbinate. Eosinophil numbers were also higher in the maxillary sinus than in the inferior turbinate. Mast cells were present in significantly higher numbers in the ethmoid sinus and inferior turbinate biopsy sections than in the maxillary sinus. With antisense, radiolabeled riboprobes, we used in situ hybridization to examine the expression of interleukin-4 and interleukin-5 transcripts. The density of cells expressing interleukin-4 transcripts was significantly higher in the inferior turbinate biopsy sections than in those from the ethmoid and maxillary sinuses. In addition, the number of interleukin-4 mRNA—positive cells was higher in the ethmoid than in the maxillary sinus mucosa. The density of interleukin-5 mRNA—positive cells was significantly higher in the ethmoid and maxillary sinuses than in the inferior turbinate. The results of this study indicate (1) a more intense inflammatory response in the ethmoid sinus than in the maxillary sinus and inferior turbinate in allergic chronic sinusitis and (2) different inflammatory responses in the upper airways that are dependent on the anatomic site. These findings have potential implications in the design of new therapeutic interventions for allergic chronic sinusitis. (Otolaryngol Head Neck Surg 1998;118:804–9.)

Acute Bacterial Sinusitis in Adults: Management in the Primary Care Setting

Sinus disease is inherently associated with viral upper respiratory tract infections and occurs in 90% of individuals with the common cold. Acute bacterial sinusitis occurs in 0.5 to 2% of these individuals. Although the diagnosis of acute bacterial sinusitis is usually based on physical findings, no one sign or symptom is either sensitive or specific for sinusitis. The predictive power can be significantly improved when all signs and symptoms are combined into a clinical impression. Imaging studies have not been shown to be cost effective in the initial assessment and treatment of patients in the primary care setting. Simple plain films may be indicated to resolve the diagnosis in patients with an equivocal history or to follow patients admitted to hospital with severe sinus disease. The initial management of acute sinusitis should be directed toward the relief of symptoms with a 7-day course of decongestants and mucoevacuents. For patients who fail to improve with symptomatic treatment, a 10-day course of amoxicillin is recommended. Second line antibiotics should be initiated if improvement is not seen within 72 to 96 hours.

Intratympanic corticosteroids injections: a systematic review of literature

The objective of the study was to determine the evidence of intratympanic steroids injections (ITSI) for efficacy in the management of the following inner ear diseases: Ménière’s disease, tinnitus, noise-induced hearing loss (NIHL) and idiopathic sudden sensorineural hearing loss (ISSNHL). The data sources were literature review from 1946 to December 2014, PubMed and Medline. A systematic review of the existing literature was performed. Databases were searched for all human prospective randomized clinical trials using ITSI in at least one treatment group. The authors identified 29 prospective randomized clinical trials investigating the benefits of an intratympanic delivery of steroids. Six articles on Ménière’s disease were identified, of which one favored ITSI over placebo in vertigo control. Of the five randomized clinical trials on tinnitus therapy, one study found better tinnitus control with ITSI. The only available trial on NIHL showed significant hearing recovery with combination therapy (ITSI and oral steroids therapy). Seventeen studies were identified on ISSNHL, of which 10 investigated ITSI as a first-line therapy and 7 as a salvage therapy. Studies analysis found benefits in hearing recovery in both settings. Due to heterogeneity in treatment protocols and follow-up, a meta-analysis was not performed. Given the low adverse effects rates of ITSI therapy and good patient tolerability, local delivery should be considered as an interesting adjunct to the therapy of the ISSNHL and NIHL. Only one article over six where ITSI therapy offers potential benefits to patients with Ménière’s disease in the control of tinnitus and vertigo was found. ITSI does not seem to be effective in the treatment of tinnitus.

Selective irrigation of the sinuses in the management of chronic rhinosinusitis refractory to medical therapy: a promising start.

BACKGROUND Although endoscopic sinus surgery has been widely used for the treatment of chronic rhinosinusitis, some patients fail to derive clinical benefit from this procedure. We evaluated the efficacy of a treatment regimen consisting of selective irrigation of diseased sinus mucosa with topical antibiotics and steroids in conjunction with oral antibiotics and steroids. METHODS Twenty patients suffering from chronic rhinosinusitis and resistant to medical treatment (mean duration 3.4 years) underwent intubations of the affected maxillary and/or ethmoid sinuses for irrigation for a duration of 21 to 30 days. A computed tomographic (CT) scan of the paranasal sinus was taken both pre- and post-treatment and staged according to the Lund-MacKay system. Clinical symptoms were scored for rhinorrhea, facial pain, nasal congestion, and smell at least 2 months prior to treatment and approximately 18 months after the follow-up. RESULTS The clinical experience with the technique of intubation and irrigation was well tolerated by all patients. We found an improvement in all symptom scores, including rhinorrhea, nasal congestion, smell (n = 20; p < .001), and facial pain (n = 20; p < .01). Similar improvements were seen on the CT scans, with reduced staging from 14.6 +/- 1.1 to 5.6 +/- 1.1 (p < .001). Only three patients did not respond to selective irrigation of the sinuses and needed further surgery. CONCLUSION These results suggest that sinus irrigation could provide a reasonable and effective alternative to ethmoidectomy with drainage procedures and offer promise for the treatment of patients with chronic rhinosinusitis who are resistant to medical treatment.

Steroid-eluting sinus implant for in-office treatment of recurrent nasal polyposis: a prospective, multicenter study.

Treatment options for chronic rhinosinusitis with recurrent polyposis (CRSwNP) after endoscopic sinus surgery (ESS) are limited, and include frequent use of systemic steroids and revision surgery. A bioabsorbable, steroid‐eluting implant was studied for its ability to dilate sinuses obstructed by polyps and provide localized, controlled steroid delivery to reestablish sinus patency. This study assessed the initial feasibility, safety, and efficacy of steroid‐eluting implants placed in the office setting in patients who were candidates for revision ESS.

Amb a 1-immunostimulatory Oligodeoxynucleotide Conjugate Immunotherapy Increases CD4 + CD25 + T Cells in the Nasal Mucosa of Subjects with Allergic Rhinitis

BACKGROUND We have previously shown that short-course treatment with Amb a 1-immunostimulatory phosphorothioate oligonucleotide conjugate (AIC) before the ragweed season modifies the response of the nasal mucosa to allergen challenge in ragweed-sensitive patients by increasing Th1 cytokines and decreasing both Th2 cytokines and eosinophilia after the ragweed season. The effect of AIC immunotherapy on CD4+CD25+ T cell expression in the nasal mucosa is unknown. OBJECTIVE To determine the in vivo effect of short-course AIC immunotherapy on CD4+CD25+ regulatory T cells in the nasal mucosa of ragweed-sensitive subjects. METHODS 19 ragweed-sensitive patients with allergic rhinitis were randomly assigned to receive either 6 escalating doses of AIC (0.06-12microg; n = 12) or placebo (n = 7) at weekly intervals immediately before the 2001 ragweed season. Nasal biopsies were taken at baseline prior to immunization and again post immunization 24 hours after ragweed allergen challenge at the start and end of the ragweed season. The expression of T regulatory cells, IL-10 and TGF-beta was assessed at each time point by immunohistochemistry. RESULTS The numbers of allergen-induced CD4+-, CD4+CD25+-, IL-10- and TGF-beta-positive cells in the nasal mucosa after AIC immunization before the ragweed season did not differ between the two groups. Repeat challenge after the ragweed season led to a significant increase in CD4+CD25+ cells in AIC-compared with placebo-treated subjects. A trend toward an increase in IL-10-positive cells in the AIC-treated group did not reach statistical significance. CONCLUSIONS Short-course AIC immunotherapy increases CD4+CD25+ regulatory T cell infiltration in the nasal mucosa following allergen challenge after seasonal ragweed-pollen exposure.

Facial artery musculomucosal flap for reconstruction of skull base defects: A cadaveric study

Failure in skull base defects reconstruction following tumor resection can have serious consequences such as ascending meningitis and pneumocephaly. The nasoseptal flap showed a very low incidence of cerebrospinal fluid leak but is not always available. The superiorly pedicled facial artery musculomucosal (FAMM) flap has been successfully used for reconstruction of head and neck defects. Our objective is to show that the FAMM flap can be used as a new alternative in skull base reconstruction.