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Background: Allergy to heat stable potato proteins can cause severe allergic disease in children. Objective: To study diagnostic criteria for allergy to cooked potatoes and to describe its clinical characteristics and natural history. Methods: Thirty-six children, aged 4–36 months, with atopic symptoms and having a positive potato-CAP and/or skin prick test (SPT) were included. Potato allergy was documented by means of provocation, or elimination and reintroduction or an unequivocal clinical history. Potato-CAP and SPT with a commercial extract were evaluated for diagnostic performance. Results: Presenting symptoms in children with proven potato allergy ( n = 17) were eczema (16 of 17), gastrointestinal complaints (eight of 17), urticaria and/or angioedema (five of 17), wheezing/rhinitis (three of 17) and anaphylaxis (two of 17). Fifteen children had previously diagnosed cow's milk protein allergy and were egg-sensitized. Potato-CAP at cut-off >2 kU/l provided a 100% sensitivity and a 62.5% specificity for diagnosis of potato allergy, while a SPT score ≥ 3 had a 100% sensitivity and a score ≥ 4 had a 100% specificity. Tolerance to cooked potato was achieved in 80% of subjects at age 16–102 months. Of 12 subjects having reached the age of 3 years during the study, 10 were re-evaluated at age 3–6 years: seven of 10 subjects had developed clinical pollen allergy, compared with four of 18 atopic controls ( P < 0.05). Conclusions: Potato-CAP and SPT at specific cut-off are valuable tools in the diagnosis of allergy to cooked potato. Most children with potato allergy develop tolerance at mean age of 4 years. Allergy to cooked potatoes is a risk factor for the development of pollen allergy. [ABSTRACT FROM AUTHOR]

Background: There is an increasing interest in targeted application of probiotic bacteria for prevention and treatment of airway diseases, including allergies. Here, we investigated the beneficial effects of preventive intranasal treatment with probiotics Lactobacillus rhamnosus GG and L. rhamnosus GR‐1 in a mouse model of allergic asthma. Methods: Lactobacillus rhamnosus was administered intranasally eight times on days 1‐4 and 8‐11 at 5 × 108 CFU/dose, followed by a 2‐week asthma induction protocol with birch pollen extract on alternating days. Effects of preventive treatment were analyzed based on serum antibody levels, bronchoalveolar lavage cell counts, lung histology, lung cytokine levels, and airway hyperreactivity. Colonization and translocation of L. rhamnosus were assessed by bacterial cell counts in nasal mucosa, fecal samples, cervical lymph nodes, and blood. Binding of fluorescent L. rhamnosus to fixed murine nasal mucosal cells and airway macrophages was visualized by fluorescence microscopy. Results: Transient colonization of the murine upper airways by L. rhamnosus GG was demonstrated and was approximately ten times higher compared to L. rhamnosus GR‐1. Marked binding of fluorescent L. rhamnosus GG to murine nasal mucosal cells and airway macrophages was visualized. Preventive treatment with L. rhamnosus GG (but not L. rhamnosus GR‐1) resulted in a significant decrease in bronchoalveolar lavage eosinophil counts, lung interleukin‐13 and interleukin‐5 levels, and airway hyperreactivity. A tendency toward a decrease in serum Bet v 1‐specific immunoglobulin G1 was likewise observed. Conclusion: Intranasally administered L. rhamnosus GG prevents the development of cardinal features of birch pollen‐induced allergic asthma in a strain‐specific manner. Intranasal Lactobacillus rhamnosus GG (but not L. rhamnosus GR‐1) pretreatment prevents the development of airway inflammation and hyperreactivity in a mouse model of birch pollen‐induced asthma, without observable side effects. Effects of intranasally administered L. rhamnosus GG are linked to a significant decrease in lung eosinophilia and lung IL‐13 and IL‐5 levels. L. rhamnosus GG adheres well to isolated murine nasal mucosa cells and airway macrophages, and can transiently colonize the murine upper airways. This is less pronounced for L. rhamnosus GR‐1. [ABSTRACT FROM AUTHOR]

Abstract: Background: Nasal hyperreactivity (NHR) is an important clinical feature of allergic rhinitis (AR). The efficacy of MP29‐02 (azelastine hydrochloride (AZE) and fluticasone propionate [FP]) nasal spray on local inflammatory mediators and NHR in AR is unknown. We tested if MP29‐02 decreases inflammatory mediators and NHR in AR and if this effect is due to restoration of nasal epithelial barrier function. Methods: A 4‐week double‐blinded placebo‐controlled trial with MP29‐02 treatment was conducted in 28 patients with house dust mite (HDM) AR. The presence of NHR was evaluated by measuring reduction in nasal flow upon cold dry air exposure. The effects of AZE ± FP on barrier integrity and airway inflammation were studied in a murine model of HDM‐induced NHR and on reduced activation of murine sensory neurons and human mast cells. Results: MP29‐02 but not placebo reduced NHR (P < .0001 vs P = .21), levels of substance P (P = .026 vs P = .941), and β‐hexosaminidase (P = .036 vs P = .632) in human nasal secretions. In wild‐type C57BL6 mice, the reduction in β‐hexosaminidase levels (P < .0001) by AZE + FP treatment upon HDM challenge was found in parallel with a decreased transmucosal passage (P = .0012) and completely reversed eosinophilic inflammation (P = .0013). In vitro, repeated applications of AZE + FP desensitized sensory neurons expressing the transient receptor potential channels TRPA1 and TRPV1. AZE + FP reduced MC degranulation to the same extent as AZE alone. Conclusion: MP29‐02 treatment reduces inflammatory mediators and NHR in AR. The effects of AZE + FP on MC degranulation, nasal epithelial barrier integrity, and TRP channels provide novel insights into the pathophysiology of allergic rhinitis. [ABSTRACT FROM AUTHOR]

Background Programmed cell death-1 (PD-1) is a negative regulator of T-cell responses. Expression of PD-1 and its ligands PD-L1 and PD-L2 in chronic rhinosinusitis with nasal polyps (CRSwNP) is poorly studied. Methods Expression of PD-1, PD-L1, PD-L2, TGF-β, IL-5, and IL-10 mRNA was measured by real-time quantitative PCR on tissue homogenates of patients with CRSwNP ( n = 21) and healthy controls ( n = 21) and on primary epithelial cells. Disease severity was scored using the Lund-Mackay scores of maxillofacial computed tomography (CT) scans. Expression of PD-1 and PD-L1/L2 was evaluated at the cellular and tissue levels ( n = 6) by flow cytometry and immunohistochemistry. Results Programmed cell death-1 mRNA expression was increased in tissue homogenates from patients with CRSwNP compared with controls, irrespective of the atopy status. Importantly, expression of PD-1 correlated with the total CT scan scores ( r = 0.5, P = 0.02). Additionally, a significant association was found between PD-1 mRNA and expression of IL-5 mRNA in control nasal tissue ( r = 0.95, P < 0.0001) and in CRSwNP ( r = 0.63, P = 0.002). PD-1 was expressed on different subsets of T cells and CD11b− dendritic cells. Both PD-1 and its ligands were expressed on primary epithelial cells from control nasal tissue and nasal polyp tissue. Conclusions Higher PD-1 expression was found in CRSwNP than in nasal tissue from controls. This was associated with disease severity and tissue IL-5 expression but unrelated to the patients' atopy status. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "A new framework for the interpretation of IgE sensitization" that was published in the 2016 issue.

The upper and lower airways are closely linked from an anatomical, histological and immunological point of view, with inflammation in one part of the airways influencing the other part. Despite the concept of global airway disease, the upper airways tend to be overlooked by respiratory physicians. We provide a clinical overview of the most important and recent insights in rhinitis and rhinosinusitis in relation to lower airway disease. We focus on the various exogenous and endogenous factors that play a role in the development and aggravation of chronic upper airway inflammation. In addition to the classical inhaled allergens or microorganisms with welldefined pathophysiological mechanisms in upper airway disease, environmental substances such as cigarette smoke, diesel exhaust particles and occupational agents affecting lower airway homeostasis have recently gained attention in upper airway research. We are only at the beginning of understanding the complex interplay between exogenous and endogenous factors like genetic, immunological and hormonal influences on chronic upper airway inflammation. From a clinical perspective, the involvement of upper and lower airway disease in one patient can only be fully appreciated by doctors capable of understanding the interplay between upper and lower airway inflammation. [ABSTRACT FROM AUTHOR]

Background Daily intensive exercise by elite athletes can result in exercise-induced asthma especially in elite swimmers and this may be linked to epithelial damage. Objective To study airway epithelial damage and release of damage-associated molecular patterns ( DAMPs) after intensive exercise in elite athletes and controls. Methods We recruited competitive swimmers ( n = 26), competitive indoor athletes ( n = 13) and controls ( n = 15) without any history of asthma. Lung function was measured before, immediately after and 24 h after a 90-min intensive exercise protocol. Sputum induction was performed at baseline and 24 h after exercise. Exercise-induced bronchoconstriction ( EIB) was assessed by the eucapnic voluntary hyperventilation test. Results Baseline sputum uric acid, high mobility group box-1, CXCL8 mRNA, sputum neutrophils and serum Clara cell protein-16 (CC-16) were significantly higher in competitive swimmers compared with controls. Intensive swimming for 90 min resulted in an increase of sputum IL-1β, IL-6 and TNF mRNA in competitive swimmers, and of sputum IL-6 mRNA and sputum neutrophils in controls. Although all participants were asymptomatic, seven competitive swimmers, one indoor athlete and one control met the criteria for EIB. Conclusion Our findings show that the intensive training combined with exposure to by-products of chlorination induces airway epithelial damage in competitive swimmers. This is associated with increased damage-associated molecular patterns, innate cytokine release and neutrophilic airway inflammation. [ABSTRACT FROM AUTHOR]

Background Data from birth cohort studies suggest that increased cord blood total IgE and reduced cord blood regulatory T cells increase the risk of developing allergic sensitization and atopic dermatitis. Objective We here addressed whether serum total IgE and hen's egg-specific IgE levels at birth and at age 1 year differed between healthy and allergic children in a Belgian birth cohort (FONIA). We furthermore studied whether these parameters as well as cord blood Foxp3/CD3γ mRNA levels might predict the allergic outcome. Methods and results Children ( n = 84) were clinically assessed at the ages of 6, 12, 18, and 24 months and at 6 years. Cord blood total IgE levels above 0.35 kU/L predicted early (i.e. before or at the age of 2 years) allergy development. Presence of serum IgE antibodies to hen's egg (cut-off 0.05 Ua/ mL) at the age of 1 year was associated with early as well as late (i.e. between the age of 2 and 6 years) allergy development. Cord blood Foxp3/CD3γ mRNA ratios were significantly lower in early allergic children and levels below 0.32 predicted the allergic outcome. Conclusions and clinical Relevance Low cord blood Foxp3/CD3γ mRNA ratios are highly predictive for early allergy development, whereas specific IgE levels to hen's egg white above 0.05 Ua/ mL at age 1 year predict allergy development in general. [ABSTRACT FROM AUTHOR]

Background Edema represents a key feature of nasal polyp ( NP) disease. Members of the vascular endothelial growth factor ( VEGF) family may be involved, but the precise role of VEGF-A, VEGF-B, placental growth factor (Pl GF), and their receptors VEGFR1 and VEGFR2 in NP edema formation remains elusive. Objective Exploring the expression of VEGF family members and their receptors and their correlation with clinical, radiological, and edema markers in NP. Methods The expression of VEGF- A, VEGF- B, Pl GF, VEGFR1, and VEGFR2 was measured in NP ( n = 23) and control tissue ( n = 22) at mRNA and protein level. Edema was evaluated by measuring albumin levels and wet/dry ratios. Computed tomography ( CT) scans were scored using the Lund-Mackay scoring system. IL-5 mRNA expression was determined by real-time RT- PCR. Cell suspensions from NP ( n = 10) and control tissue ( n = 12) were stimulated in vitro with IL-1β or TNFα. Results mRNA expression of VEGFR1 and VEGF- B was significantly higher in NP compared with control tissue. Expression levels of VEGF- B and VEGFR1 significantly correlated with NP albumin content ( VEGF- B: P = 0.0208; VEGFR1: P = 0.0293), CT scan scores ( VEGF- B: P = 0.0075; VEGFR1: P = 0.0068), and IL-5 mRNA ( VEGF- B: P = 0.0027; VEGFR1: P = 0.0001). In vitro stimulation of control and NP tissue cell suspensions with IL-1β or TNFα significantly reduced the expression of VEGFR2 in control tissue, without altering VEGFR1 and VEGF- B expression. hVEGF- B induced nitric oxide production in NP macrophages ( P < 0.05). Conclusion Expression levels of VEGFR1 and VEGF- B correlate with edema and clinical markers of NP disease and therefore represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Highlights: [•] Si cap passivation on Ge shows low border trap response. [•] The Si cap passivation is also suitable for Ge nMOS applications. [•] Low D it at E c can be achieved by tuning the amount of Si at the interface. [•] A dry O3 process can be used to control the amount of Si that is oxidized. [Copyright &y& Elsevier]

Background and objective Asthma is a heterogeneous disease with various clinical, inflammatory and molecular phenotypes. We studied sputum cytokine mRNA expression patterns in an unselected group of adult asthma patients to characterize the underlying inflammatory process. Methods Differential cell counts and cytokine mRNA (quantified by real-time PCR) were analysed on sputum from 40 controls and 66 asthmatic adults. A 'cytokine-high' profile was defined if mRNA levels for that particular cytokine exceeded the 90th percentile value in the control population. Radar graphs were used to visualize cytokine profiles. Results Sputum mRNA analysis confirmed heterogeneity of cytokine patterns among patients. Thirty-six patients (55%) had a Th2 cytokine pattern: 'IL-5-high' ( n = 13), 'IL-4-high' ( n = 17) or 'IL-4- and IL-5-high' ( n = 6). The 'IL-5-high' asthma profile ( n = 13) coincided with the 'IL-25-high' (10/13) and surprisingly also with the 'IL-17A-high' (11/13) profile. The 'IL-5-/IL-25-/IL-17A-high profile was different from the 'IL-4-high' pattern. Patients with the 'IL-5, IL-17A, IL-25-high' pattern had significantly worse lung function parameters. Uncontrolled asthmatics [Asthma Control Test (ACT) < 20] had higher sputum IL-5, IL-17A and IL-25 mRNA levels compared to controlled asthmatics ( P = 0.002; P = 0.002; P = 0.066) and uncontrolled asthma is more common among 'IL-5- and IL-17A-high' asthmatics compared to 'IL-5-, IL-17A-low' asthmatics (χ2 = 3.7, P = 0.027; relative risk (RR): 1.8, 95% CI = 1.1-3.1). Conclusions and Clinical Relevance Patients with the ' IL-5, IL-17A, IL-25-high' airway inflammatory pattern are often uncontrolled asthmatics, despite daily treatment. It seems worthwhile to evaluate whether measuring sputum cytokine levels might be used to assess the response to increased doses of steroids in patients with asthma. [ABSTRACT FROM AUTHOR]

While some probiotic strains might have adjuvant effects in the therapy for inflammatory bowel diseases (IBD), these effects remain controversial and cannot be generalized. In this study, a dltD mutant of the model probiotic Lactobacillus rhamnosus GG (LGG), having a drastic modification in its lipoteichoic acid (LTA) molecules, was analysed for its effects in an experimental colitis model. Dextran sulphate sodium (DSS) was used to induce either moderate to severe or mild chronic colitis in mice. Mice received either phosphate-buffered saline (PBS), LGG wild-type or the dltD mutant via the drinking water. Macroscopic parameters, histological abnormalities, cytokine and Toll-like receptor (TLR) expression were analysed to assess disease activity. LGG wild-type did not show efficacy in the different experimental colitis set-ups. This wild-type strain even seemed to exacerbate the severity of colitic parameters in the moderate to severe colitis model compared to untreated mice. In contrast, mice treated with the dltD mutant showed an improvement of some colitic parameters compared to LGG wild-type-treated mice in both experimental models. In addition, treatment with the dltD mutant correlated with a significant down-regulation of Toll-like receptor-2 expression and of downstream proinflammatory cytokine expression in the colitic mice. These results show that molecular cell surface characteristics of probiotics are crucial when probiotics are considered for use as supporting therapy in IBD. [ABSTRACT FROM AUTHOR]

To cite this article: Callebaut I, Spielberg L, Hox V, Bobic S, Jorissen M, Stalmans I, Scadding G, Ceuppens JL, Hellings PW. Conjunctival effects of a selective nasal pollen provocation. Allergy 2010; 65: 1173–1181. Background: Several clinical and experimental observations suggest that allergen deposition in the nose may partially be responsible for the induction of conjunctival symptoms in allergic rhinitis. The aims of this study were to evaluate the induction of conjunctival symptoms by selective nasal allergen provocation and to assess the feasibility of the different tools for evaluation of conjunctival allergic inflammation. Methods: Grass pollen allergic subjects with rhinoconjunctivitis symptoms during the pollen season ( n = 12) underwent a nasal sham and grass pollen provocation extra-seasonally. Nasal and conjunctival symptoms were scored using the Visual Analogue Scale (VAS) system at baseline, 15 min, 1 h and 24 h after provocation. In addition to Peak Nasal Inspiratory flow (PNIF) measurements, conjunctival inflammation and vascular congestion were evaluated and histamine and substance P levels in tear fluid were measured. Results: Selective nasal grass pollen provocation induced ocular pruritus, lacrimation and conjunctival vascular congestion. PNIF values correlated inversely with lacrimation ( r = −0.71, P < 0.001) and ocular pruritus ( r = −0.41, P < 0.05). Four out of 11 patients showed a conjunctival eosinophilic inflammation and levels of histamine ( r = 0.73, P < 0.05) and substance P ( r = 0.67, P = 0.05) in tear fluid correlated with conjunctival symptoms. Conclusion: Selective nasal grass pollen provocation induced conjunctival inflammation, ocular pruritus and lacrimation, which correlated with histamine and substance P levels in tear fluid and inversely with the PNIF values. These data show a naso-ocular interaction in allergic rhinitis and offer objective tools for evaluation of conjunctival inflammation in allergic rhinoconjunctivitis. [ABSTRACT FROM AUTHOR]

To cite this article: Huvenne W, Callebaut I, Reekmans K, Hens G, Bobic S, Jorissen M, Bullens DMA, Ceuppens JL, Bachert C, Hellings PW. Staphylococcus aureus enterotoxin B augments granulocyte migration and survival via airway epithelial cell activation. Allergy 2010; 65: 1013–1020. Background: Staphylococcus aureus enterotoxin B (SEB) has recently been postulated to be involved in the pathology of granulocyte-dominated disease. Studying the immunologic interaction between SEB and airway epithelial cells in immortalized cell lines or long-term epithelial cell cultures has obvious disadvantages. Methods: We used a novel technique of freshly isolated and purified human nasal epithelial cells (HNEC) from healthy, nonallergic individuals, which were incubated for 24 h without/with SEB at different concentrations. Chemokine production was evaluated in the supernatant using Cytometric Bead Array. The chemotactic activity of the supernatant was studied in vitro using a Boyden chamber. Survival was evaluated with flow cytometry, using propidium iodide to identify dead cells. Results: Staphylococcus aureus enterotoxin B showed a dose-dependent induction of interferon-inducible protein-10, monokine induced by interferon-γ, regulated upon activation normal T cell expressed and secreted, monocyte chemoattractant protein 1 (MCP-1) and granulocyte colony stimulating factor production by epithelial cells in vitro. The supernatant of epithelial cells had chemotactic activity for granulocytes in vitro, which was enhanced in the supernatant of SEB-stimulated epithelial cells. Reduced number of propidium iodide positive granulocytes was found in the conditions where supernatant of SEB-stimulated epithelial cells was applied. Conclusion: Staphylococcus aureus enterotoxin B exerts a direct pro-inflammatory effect on HNEC, with induction of chemokine and growth factor release, resulting in the migration and prolonged survival of granulocytes in vitro. [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus Enterotoxin B (SEB) has immunomodulatory effects in allergic airway disease. The potential contribution of SEB to the sensitization process to allergens remains obscure. Objective In order to study the effects of staphylococcal-derived toxins on the sensitization to ovalbumin (OVA) and induction of allergic airway inflammation, we have combined the nasal application of OVA with different toxins. Methods Nasal applications of OVA and saline, SEA, SEB, toxic shock syndrome toxin (TSST)-1, protein A or lipopolysaccharide (LPS) were performed on alternate days from day 0 till 12. On day 14, mice were killed for the evaluation of OVA-specific IgE, cytokine production by mediastinal lymph node (MLN) cells and bronchial hyperreactivity (BHR) to inhaled metacholine. The effect of SEB on dendritic cell (DC) migration and maturation, and on T cell proliferation was evaluated. Results Concomitant endonasal application of OVA and SEB resulted in OVA-specific IgE production, whereas this was not found with SEA, TSST-1, protein A, LPS or OVA alone. Increased DC maturation and migration to the draining lymph nodes were observed in OVA/SEB mice, as well as an increased T cell proliferation. Bronchial inflammation with an influx of eosinophils and lymphocytes was demonstrated in OVA/SEB mice, together with hyperresponsiveness and the production of IL-4, IL-5, IL-10 and IL-13 by MLN stimulated with OVA. Conclusions Our data demonstrate that SEB facilitates sensitization to OVA and consecutive bronchial inflammation with features of allergic asthma. This is likely due to augmentation of DC migration and maturation, as well as the allergen-specific T cell proliferation upon concomitant OVA and SEB application. Cite this as: W. Huvenne, I. Callebaut, M. Plantinga, J. A. J. Vanoirbeek, O. Krysko, D. M. A. Bullens, P.Gevaert, P. Van Cauwenberge, B. N. Lambrecht, J. L. Ceuppens, C. Bachert and P. W. Hellings, Clinical & Experimental Allergy, 2010 (40) 1079–1080. [ABSTRACT FROM AUTHOR]

There is increasing evidence for involvement of the immune system in functional gastrointestinal disorder (FGID), including onset after acute gastrointestinal infections, genotypes resulting in altered cytokine expression and abnormal presence of immune cells. Our aim was to assess cellular and humoral immune responses in (i) FGIDs, compared to healthy subjects and (ii) acute vs unspecified onset FGIDs. Lymphocytic [interleukin (IL)-5, IL-10, IL-13 and interferon γ (IFN-γ)] and monocytic [IL-10, IL-12, tumour necrosis factor (TNF)-α] cytokine production was characterized at baseline and after stimulation with phytohemagglutinine and anti-CD28 or lipopolysaccharide (LPS) in controls ( n = 32), irritable bowel syndrome (IBS) ( n = 30), functional dyspepsia (FD) ( n = 23) and non-cardiac chest pain (NCCP) ( n = 15). Serum IL-6 and IL-10 concentrations were compared, and the immunophenotype was assessed using fluorescent-activated cell sorter. Findings were compared for acute vs unspecified onset FGID. Compared to controls, stimulated lymphocyte expression of IL-5 and IL-13 was enhanced in IBS, FD and NCCP (all P < 0.05). Conversely, the stimulated monocytic IL-12 and lymphocytic IL-10 expression were reduced in IBS and FD, while IFN-γ expression was also reduced in FD patients. Except for an increase in the numbers of CD3+CD45RA+CD45RO+ cells, no distinct cellular profile was detected. Patients with a presumed acute onset of their symptoms had higher serum IL-10 levels and more CD3+CD45RA+CD45RO+ cells, while TNF-α levels following stimulation with LPS were higher in FD patients reporting an acute onset. A shift towards a Th2 cytokine profile is present in FGID, while the cellular immunophenotype remains largely unchanged. Further research is indicated and could provide new therapeutic strategies for these disorders. [ABSTRACT FROM AUTHOR]

Background The increased susceptibility of asthmatics to rhinovirus infection has recently been related to deficient IFN-λ1 (IL-29) and IFN-λ2/3 (IL-28) production by bronchial epithelial cells and macrophages. Objectives Here, we studied IFN-λ mRNA expression in the airways of stable asthmatics in comparison with healthy subjects and in relation to asthma symptoms, non-invasive parameters of airway inflammation and lung function parameters. Methods Airway cells were obtained by sputum induction, in 14 healthy and 35 asthmatic adults and 12 asthmatic school-aged children. IFN-λ was studied at the mRNA level by quantitative RT-PCR. Results Asthmatic adults have increased sputum IL-28 mRNA but similar IL-29 mRNA expression in comparison with healthy subjects. In asthmatics, both sputum IL-28 and IL-29 mRNA expression correlate with the sputum CD3γ mRNA expression (reflecting infiltrated T cells). IL-28 (but not IL-29) mRNA levels correlate with the relative and absolute number of eosinophils present in the sputum sample. Sputum IL-29 mRNA (but not IL-28) correlates negatively with asthma symptoms in steroid-naïve patients and is significantly higher in steroid-treated than in steroid-naïve patients. Finally, both IL-28 and IL-29 mRNA levels are higher in asthmatic children than in asthmatic adults. Conclusion Our results show that asthmatic subjects have substantial type III IFN-λ mRNA levels in the airways. Our data furthermore suggest that IL-29 could have an immunoprotective role in the lower airways. [ABSTRACT FROM AUTHOR]

Background: In contrast to the epidemiological and clinical association between allergic rhinitis and asthma, upper airway inflammation is less characterized in patients with nonatopic asthma and virtually unexplored in chronic obstructive pulmonary disease (COPD). Here, sinonasal pathology is studied in patients with allergic asthma, nonallergic asthma and COPD. Methods: Ninety patients with stable bronchial disease were included in the study, of which 35 were diagnosed with allergic asthma, 24 with nonallergic asthma and 31 with COPD. Concurrently, 61 control subjects without pulmonary disease were included and matched for age and smoking habits respectively with the asthma and the COPD group. Sinonasal symptoms were evaluated on a visual analogue scale and rhinosinusitis-related impairment of quality of life was assessed with the sino-nasal outcome test-22 (SNOT-22) questionnaire. Nasal mucosal abnormalities were quantified with nasal endoscopy and nasal secretions collected for measuring inflammatory mediators. Results: Allergic asthmatics, nonallergic asthmatics and COPD patients reported more nasal symptoms than their respective control subjects, had a higher SNOT-22 score and presented more mucosal abnormalities in the nose. Nasal secretions of both allergic and nonallergic asthmatics contained higher levels of eotaxin, G-CSF, IFN-γ and MCP-1 than controls. Allergic asthmatics had higher nasal IP-10 levels as well. COPD-patients had higher nasal levels of eotaxin, G-CSF and IFN-γ than controls. Conclusion: Patients with allergic and nonallergic asthma and COPD show increased nasal symptoms and more nasal inflammation. Hence, our data confirm the ‘united airways’ concept to be beyond the scope of allergic asthma. [ABSTRACT FROM AUTHOR]

Background The role of bacterial enterotoxins like Staphylococcus aureus enterotoxin B (SEB) in allergic asthma remains unknown. We used a mouse model of airway allergy to study the effects of nasal or bronchial contact with SEB on bronchial allergic inflammation. Methods The features of allergic asthma were induced in ovalbumin (OVA)-sensitized mice (days 1–13) by repeated exposures to nebulized OVA (days 33–37). Nasal or bronchial application of SEB was performed on three occasions (days 33–35–37), and the effects on bronchial inflammation, IgE titres and expression levels of mRNA for T helper type 2 cytokines and other inflammatory mediators were evaluated. Results Both nasal and bronchial SEB enhanced the allergen-induced bronchial inflammation, as reflected by more eosinophilic inflammation in the airway lumen and in bronchial tissue. Aggravation of experimental asthma correlated with higher expression of mRNA for IL-5, IL-4, IFN-γ, IL-12 p40, eotaxin-1 and TGF-β in bronchi. In addition, nasal SEB elevated concentrations of IL-4, IL-5 and IFN-γ in serum and bronchial SEB increased titres of OVA-specific and total IgE in serum. Conclusion Our data illustrate the potential of both nasal as well as bronchial SEB to aggravate several features of allergic asthma in a mouse model. [ABSTRACT FROM AUTHOR]

Background T-helper type 2 (Th2) cells play an important role in the pathogenesis of allergic diseases. Recent studies have demonstrated that allergen-specific T cells can also be found in the blood of healthy individuals. Both IL-10 and IFN-γ might modulate the induction and maintenance of allergen-specific tolerance. Aim To study the phenotype and functional characteristics of allergen-specific T cells in healthy non-atopic children. Methods Peripheral blood mononuclear cells (PBMC) from 13 symptomatic house dust mite (HDM)-allergic children and from nine matched healthy control children were stimulated with recombinant (r)Der p 2, a major allergen from HDMs. Results Stimulation with rDer p 2 resulted in Th2 cytokine production in cultures of PBMC from allergic but not from healthy children. In contrast, IL-10 and IFN-γ were induced in PBMC cultures from both healthy and HDM-allergic children. Intracellular staining revealed that IL-10 and IFN-γ are largely produced by the same T cells. Stimulation of T cells from healthy children with rDer p 2 also induced expression of inducible costimulator (ICOS) on a small T cell subset. Conclusion Allergen-specific memory T cells from healthy non-atopic children produce IL-10 and IFN-γ (but not Th2 cytokines) and express ICOS upon stimulation. These cells might be responsible for a normal immune balance after allergen encounter in non-atopics. [ABSTRACT FROM AUTHOR]

The ligation of CD40 by CD154 is a critical step in the interaction between APC and T cells. In animals, antagonizing CD40L-CD40 has been shown to reduce the severity of several autoimmune and inflammatory disorders, including experimental colitis. To investigate tolerability and safety of an antagonist chimeric monoclonal anti-human CD40 antibody (ch5D12) for treatment of Crohn's disease. ch5D12 was administrated to 18 patients with moderate to severe Crohn's disease in a single dose, open-label dose-escalation phase I/IIa study. ch5D12 plasma concentrations increased dose-dependently after infusion. Two patients developed an anti-ch5D12 antibody response. Overall response and remission rates were 72 and 22%, respectively with no evidence for a dose–response effect. Treatment with ch5D12 reduced microscopic disease activity and intensity of the lamina propria cell infiltrate, but did not alter percentages of circulating T and B cells. ch5D12 was well tolerated, although some patients experienced headache, muscle aches, or joint pains, which may have been related to the study drug. Antagonizing CD154–CD40 interactions with ch5D12 is a promising therapeutic approach for remission induction in Crohn's disease. [ABSTRACT FROM AUTHOR]

: Adalimumab, a fully human monoclonal antibody to tumour necrosis factor, was recently introduced for therapy of Crohn's disease.: Since induction of apoptosis of inflammatory cells is thought to be an important mechanism of action of the antitumour necrosis factor monoclonal antibody infliximab, we studied the induction of apoptosis of activated peripheral blood monocytes by adalimumab.: Apoptosis was analysed at the levels of the cell membrane, mitochondria and DNA by flow cytometry.We found that both adalimumab and infliximab induced apoptosis in cultured monocytes, while etanercept did not. Apoptosis induction was caspase-dependent and detectable already after 2 h. The production of interleukin-10 and interleukin-12 by monocytes was down-regulated significantly by adalimumab and infliximab but not by etanercept, while levels of soluble tumour necrosis factor in monocyte cultures were down-regulated by all three reagents.: These data show that both adalimumab and infliximab affect monocyte cytokine production and induce apoptosis of activated monocytes. Our findings will have to be further correlated to therapeutic efficacy of these antitumour necrosis factor reagents. [ABSTRACT FROM AUTHOR]

T helper (Th)2 cells play an important role in the development of IgE mediated diseases, with local overproduction of Th2 cytokines (IL-4. IL-5 and IL-13) at the site of allergic inflammation. Furthermore, IL-10 has been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in human atopic diseases. We studied whether circulating allergen-specific Th2 cells persist outside the season of exposure in patients mono-sensitized to birch pollen and whether healthy control individuals also have allergen specific Th2 cells. We also studied whether IL-10-producing allergen specific T cells can be found in circulation either in healthy controls or in allergic patients. Blood was drawn outside the birch-pollen season from 15 birch-pollen allergic patients. with seasonal respiratory symptoms and with (n = 12) or without (n = 3) oral allergy syndrome, and from 10 matched healthy controls. Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with recombinant Bet v I allergen, control antigen tetanus toxoid (TT) and anti-CD3 CD80. In part of the cultures, rIL-4 was added in order to reinforce the allergen specific Th2 cell responses. In the presence of rBet v I. T cells from allergic patients, but not from healthy controls. produced IL-4. IL-5 and IL-13. IL-5 production by patients T cells was further enhanced by adding more IL-4. In contrast, rBet v I together with IL-4-induced significant IL-10 production in control subjects but not in patients. Both Th1 and Th2 cytokines were equally induced by polyclonal stimulation in allergic patients and controls, but in the presence of IL-4. polyclonally induced IL-10 production was lower in the patient group. rBet v I specific Th2 cells circulate outside the season of exposure in the blood of birch pollen-allergic subjects but not in healthy controls. Allergen specific I cells were also demonstrated in controls hut these cells produce IL-10 when stimulated with rBet v I in the presence of IL-4. Our data reveal a different allergen induced cytokine profile in birch pollen allergic patients vs. controls. and suggest that a regulatory mechanism involving IL-4-induced allergen specific IL-10 production might be defective in allergic subjects. [ABSTRACT FROM AUTHOR]

An imbalance of immunoregulatory factors and/or cells contributes to uncontrolled mucosal T cell activation and inflammation in Crohn's disease (CD). Bioactive interleukin (IL)-18 has been shown to be produced by macrophages in CD lesions. We report here that T cells freshly isolated from inflamed tissue of CD patients (and not T cells from control intestinal tissue) were responsive to IL-18. In the presence of IL-18, these T cells produced more interferon (IFN)- γ and less IL-10. To analyse further the role of IL-18 in this disease, an acute and a chronic model of murine colitis were used. IL-18 mRNA was significantly enhanced in trinitrobenzene sulphonic acid (TNBS) induced colitis, and treatment with IL-18 binding protein (IL-18BPa), which neutralizes IL-18 bioactivity, significantly reduced the severity of colitis. However, IL-18BPa did not affect the course of chronic colitis in CD45RBhighCD4+ T cell reconstituted SCID mice. Production of IFN- γ in lamina propria mononuclear cell cultures from IL-18BPa-treated SCID mice was decreased, but at the same time fewer lamina propria CD4+ T cells harvested from IL-18BPa-treated mice compared to non-treated mice were in apoptosis. We conclude that IL-18 clearly has a modulatory role in the inflammatory cascade of CD and experimental colitis by affecting IFN- γ and IL-10 production, and apoptosis. In view of the divergent effects of IL-18 neutralization in the two different murine colitis models, it is unlikely that IL-18 is at the top of this cascade. [ABSTRACT FROM AUTHOR]

Background:The administration of indometacin to rats increases intestinal permeability and induces inflammatory pathology of the small bowel. This represents a potential model for Crohn’s disease. Aims:To analyse the pathogenic role of T cells, tumour necrosis factor and bacterial flora in indometacin-induced changes in small bowel permeability and inflammation. Methods:Rats were given indometacin, 13 mg/kg, on day 1 and day 2. The effects of antibiotic (metronidazole, aztreonam and amoxicillin/clavulanic acid), anti- tumour necrosis factor and interleukin-10 therapy were evaluated. The parameters used were weight change, serum haemoglobin, chromium-51 ethylenediaminetetra-acetate permeability and macro-and microscopic score on day 5. Results in conventionally harboured rats were compared with those in T-cell-free rats. Additional in vitro experiments were carried out to test the effect of metronidazole on tumour necrosis factor production. Results:Indometacin administration resulted in small bowel ulcers and inflammation, independently of T cells. Metronidazole was more potent than amoxicillin/clavulanic acid and anti-tumour necrosis factor in improving the indometacin-induced small bowel inflammation. Only part of the efficacy was through improvement of increased intestinal permeability. Aztreonam and interleukin-10 had no effect. Metronidazole also suppressed in vitro lipopolysaccharide-induced tumour necrosis factor production, suggesting a therapeutic effect of this drug through the inhibition of tumour necrosis factor. Conclusions:These data implicate anaerobic bacteria and tumour necrosis factor production, but not T cells, as essential elements of the pathogenesis of indometacin-induced small bowel inflammation. Tumour necrosis factor is also involved in the change in intestinal permeability. Metronidazole was the most efficacious drug in this model, probably because it suppressed anaerobic bacteria and directly inhibited tumour necrosis factor... [ABSTRACT FROM AUTHOR]

Background Allergic rhinitis is a risk factor for the development of asthma. About 80% of asthmatic patients also have rhinitis. However, the pattern of induction of allergic rhinitis and asthma remains unclear. Objective The purpose of this study was to investigate the development of upper airway inflammation in mice during the development of an asthma-like disease and after an acute allergen provocation. Methods BALB-c mice were sensitized intraperitoneally (i.p) to ovalbumin (OA, days 1–13) and were challenged with aerosols of either OA or saline on 8 consecutive days (days 33–40). In a second experiment, chronic exposure for 8 days was followed by 10 days of rest and then an acute nebulized allergen provocation was performed (day 50). Inflammatory parameters were investigated at different time-points. Results Upper and lower eosinophilic airway inflammation were simultaneously induced in the course of repeated inhalations of nebulized OA, as shown by analyses of nasal and broncho-alveolar lavage fluids and histological sections of the nose and bronchi. Mice that developed bronchial hyper-responsiveness also had increased thickness of the nasal mucosa on magnetic resonance image (MRI) scans. When chronic exposure was followed by acute allergen provocation, the latter caused a systemic increase in IL-5 levels, with a concomitant rise in blood and airway eosinophils, primarily in the nose. Conclusions Simultaneous induction of eosinophilic inflammation in the nose and lungs was found in a mouse model of respiratory allergy. These findings support the viewpoint that upper and lower airway disease represent a continuum of inflammation involving one common airway and provide evidence for the concept of global airway inflammation after inhalation of allergen. [ABSTRACT FROM AUTHOR]

Background: Anti-TNFα therapy with infliximab is effective for Crohn’s disease. Infliximab neutralizes the biological activities of TNFα, a cytokine involved in host-defence against certain infections. Aim: To evaluate the effects of infliximab on the gut and peripheral immune system functions. Methods: Biopsies and blood samples from three clinical trials of infliximab in Crohn’s disease were analysed. Pharmacokinetics, changes in leucocyte counts and T cell subsets, T cell function, and cytokine profiles of lamina propria mononuclear cells (LPMC) and peripheral blood mononuclear cells (PBMC) were analysed. Results: Infliximab has a serum half-life of 9.5 days and is still detectable in serum 8 weeks after infusion. Leucocyte counts showed consistent changes from baseline toward normal values after therapy. Monocytes and lymphocytes were modestly increased, while neutrophils were decreased 4 weeks after treatment. Lymphocyte subsets and T cell proliferative responses were not altered after therapy. The proportion of PBMCs capable of producing IFNγ and TNFα did not change, while Th1 cytokine production by stimulated LPMC was decreased after infliximab therapy. Conclusion: The clinical efficacy of infliximab is based on local anti-inflammatory and immunomodulatory effects in the bowel mucosa, without generalized suppression of systemic immune functions in Crohn’s disease patients. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-10, an immunomodulatory cytokine predominantly produced by monocytes/macrophages and T cells, inhibits several functions of dendritic cells (DC), monocytes and T cells including their cytokine production, but it stimulates B cell immunoglobulin (Ig) production and cytotoxic T lymphocyte (CTL) generation. A precise knowledge of the mechanisms that control the IL-10 production is therefore highly important for understanding the immunoregulation. The IL-10 production was studied in cultures of freshly isolated human T cells. A rise in intracellular calcium as well as the common γ-chain containing cytokine receptor triggering or CD28 triggering were found to be important signals for IL-10 induction. CD80, CD58, rIL-12 and rIFN-α all had efficacious and independent costimulatory activities on the IL-10 production, while PGE2 was inhibitory. Dependence on autocrine IL-2 signalling was shown by the effects of anti-IL-2 and anti-IL-2R monoclonal antibodies (MoAb), but the IL-10 production proceeded partly IL-2-independent when CD80 provided costimulation. Sensitivity to inhibition by CsA was not removed by CD80 or CD58 costimulation and/or by addition of rIL-12 or rIFN-α, pointing to the absolute requirement for calcineurin activity. These data reveal important differences in the regulatory pathways between IL-10 (a cytokine-inhibitory interleukin) and IL-2 (a cytokine-inducing interleukin), which can potentially be exploited therapeutically. The fact that CsA blocks the production of IL-10, which itself has important immunosuppressive properties, should be taken into account in defining immunosuppressive treatment schedules which include the use of CsA. [ABSTRACT FROM AUTHOR]

Summary Occupancy of CTLA‐4 (cytotoxic T‐lymphocyte antigen‐4 or CD152) negatively regulates the activation of mouse T lymphocytes, as indicated by the fate of CTLA‐4‐deficient mice, by the impact of anti‐CTLA‐4 monoclonal antibodies (mAbs) on mouse T‐cell activation in vitro and by the impact of CTLA‐4 blockade on the course of experimental tumoral, autoimmune, alloimmune or infectious disease in this animal. The function of human CTLA‐4, however, remains less clear. The expression and function of human CTLA‐4 were further explored. CTLA‐4 was expressed under mitogenic conditions only, its expression being, at least partially, dependent on the secretion of interleukin‐2. Memory T cells expressed CTLA‐4 with faster kinetics than naive T cells. The functional role of human CTLA‐4 was assessed utilizing a panel of four anti‐CTLA‐4 mAbs that blocked the interaction between CTLA‐4 and its ligands. These mAbs, in immobilized form, profoundly inhibited the activation of T cells by immobilized anti‐CD3 mAb in the absence of anti‐CD28 mAb, but co‐stimulated T‐cell activation in the presence of anti‐CD28 mAb. Finally, and importantly, blockade of the interaction of CTLA‐4 with its ligands using soluble anti‐CTLA‐4 mAbs, in intact form or as Fab fragments, enhanced T‐cell activation in several polyclonal or alloantigen‐specific CD80‐ or CD80/CD86‐dependent assays, as measured by cytokine production, cellular proliferation or cytotoxic responses. It is concluded that interaction of CTLA‐4 with its functional ligands, CD80 or CD86, can down‐regulate human T‐cell responses, probably by intracellular signalling events and independent of CD28 occupancy. [ABSTRACT FROM AUTHOR]

We investigated the phenotype and functional capacities of tumour-infiltrating lymphocytes (TIL). freshly isolated from primary renal cell carcinoma (RCC) specimens (n = 20). Three-colour flow cytometry immunophenotyping revealed that RCC TIL consist mainly of CD3 + T cells, with a clear predominance of CD4 -CD8 + over CD4+ CD8 - T cells, and a marked population of CD4 + CD8 + T cells. Natural killer (NK) cells were also strongly represented (> 25% in 15 of 20 tumour samples), while B cells constituted a minor TIL subset (< 5% in 18 of 20 tumour samples). More importantly, the T and NK cells within the tumour displayed a significantly higher expression of the early activation marker CD69 than their counter parts in adjacent normal renal tissue and in peripheral blood. Expression of CD54 and of HLA-DR was also elevated on CD3 + TIL. and HLA-DR expression was further vigorously up-regulated following ex vivo stimulation with anti-CD3, all suggesting enhanced immune activity within the tumour microenvironment, CD3 + CD4 + TIL displayed a normal capacity to up-regulate CD25 expression and to secrete both Thl-type (IL-2, tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) and Th2-type (IL-4, IL-5 and IL-10) cytokines upon triggering with anti- CD3. Furthermore, cytokine production was susceptible to modulation by CD28 costimulation. CD3 + CD8 + TIL, on the other hand, consistently demonstrated a poor up-regulation of CD25 upon triggering with anti-CD3, and displayed poor ex vivo cytolytic activity in an anti-CD3-redirected 4-h cytotoxicity assay against murine P815 cells. Collectively, our findings indicate that the CD3 + CD4 + TIL in RCC have normal functional capacities, whereas the proportionally major CD3 + CD4 + TIL are functionally impaired. The relevance of these findings to the in vivo local immune response in RCC is discussed. [ABSTRACT FROM AUTHOR]

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has proliferation- and differentiation-inducing effects on immature myeloid cells in the bone marrow, and it can modulate the function of several types of mature myeloid cells. We have stimulated purified human T cells with immobilized anti-CD3 or mitogenic anti-CD2 (a combination of monoclonal antibodies 9-1 and 9.6) which could induce GM-CSF production. The cytokines interleukin-1β (IL-1β) and IL-2 strongly enhanced GM-CSF production, while IL-4, IL-6, GM-CSF, interferon-γ (IFN-γ) and turnout necrosis factor (TNF) had no effect. Activation of protein kinase C by phorbol myristate acetate or triggering of CD28 on T cells by monoclonal antibody 9.3 provided accessory signals for enhanced GM-CSF production in activated T cells. Most important, the addition of mouse cells transfected with human B7-1 (CD80), a natural ligand for CD28, provided a potent accessory signal for GM-CSF production by activated T cells, which could not be blocked by cyclosporin A. The effect of IL-1β was in fact indirect, and resulted from enhanced IL-2 production, while the effect of B7 resulted from both IL-2-dependent and IL-2-independent pathways. We conclude that antigen-presenting cells (APC) can up-regulate GM-CSF production through IL-1β and through CD28 triggering by B7 molecules. As GM-CSF itself up-regulates B7 expression and IL-1β production by APC, a bidirectional regulatory feedback pathway between APC and T cells seems to modulate GM-CSF production. [ABSTRACT FROM AUTHOR]

Fc-γ receptor III (FcγRIII, CD16) type A is expressed on natural killer cells, on a small subset of peripheral blood monocytes and on mature macrophages. Along with differentiation into macrophages, monocytes will expresses FcγRIII when cultured with transforming growth factor-β (TGF-β). In view of the involvement of granulocyte-macrophage colony-stimulating factor (GM-CSF) in myeloid cell differentiation, we investigated the effect of this cytokine on FcγRIII expression in cultures of peripheral blood monocytes. GM-CSF antagonized TGF-β-induced expression of FcγRIII on monocytes in vitro in a dose-dependent way. The effect of GM-CSF persisted in cultures until at least day 7. The suppression was at the mRNA level, as shown by Northern analyses with a CD16 specific probe, and the signaling pathway involved tyrosine kinase activity. Interferon-γ and interleukin-2 had no effect on the induced expression of FcγRIII by TGF-γ, while interleukin-4, similar to GM-CSF, antagonized this induction. Our findings suggest that regulatory cytokine networks can drive monocytes into different effector functions and differentiation pathways. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) affects 23–30% of the European population with equal prevalence reported in Belgium. Despite guidelines on the correct use of effective treatment, up to 40% of AR patients remain uncontrolled. Allergen immunotherapy (AIT) has been shown to improve the level of control up to 84% of patients being controlled by AIT. Recently, new guidelines for AIT have been published, supporting the clinical evidence for effectiveness of various subcutaneous and sublingual products for AIT in patients who are allergic to airborne allergens. AIT in AR patients not only reduces nasal and/or ocular symptoms but also induces tolerance and has preventive potential. Adoption of AIT into daily clinical practice in Belgium and other European countries is hampered primarily by reimbursement issues of each of the single products but also by several patient- and physician-related factors. Patients need to be better informed about the effectiveness of AIT and the different routes of administration of AIT. Physicians dealing with AR patients should inform patients on tolerance-inducing effects of AIT and are in the need of a harmonized and practical guide that supports them in selecting eligible patients for AIT, in choosing evidence-based AIT products and in following treatment protocols with proven efficacy. Therefore, a stepwise and holistic approach is needed for better adoption of AIT in the real-life setting in Belgium. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Low neonatal Toll-like receptor 4-mediated interleukin-10 production is associated with subsequent atopic dermatitis" by M. E. Belderbos in the 2012 issue.

Background: Based on the lack of literature to support any treatment strategy in patients with foot drop due to peroneal nerve entrapment, a prospective study randomizing patients between surgery and conservative treatment is warranted. Since studies comparing surgery to no surgery are often challenging, we first examined the feasibility of such a randomized controlled trial., Methods/design: An internal feasibility pilot study was conducted to assess several aspects of process, resource, management, and scientific feasibility. The main objective was the assessment of the recruitment rate. The criterion to embark on a full study was the recruitment of at least 14 patients in 6 participating centers within 6 months. Cross-over rate, blinding measures, training strategies, and trial assessments were evaluated. The trial was entirely funded by the KCE Trials public funding program of the Belgian Health Care Knowledge Centre (ID KCE19-1232)., Results: The initial duration was prolonged due to the COVID-19 pandemic. Between April 2021 and October 2022, we included 19 patients of which 15 were randomized. Fourteen patients were treated as randomized. One drop-out occurred after randomization, prior to surgery. We did not document any cross-over or accidental unblinding. Training strategies were successful. Patients perceived the quality of life questionnaire as the least relevant assessment. Assessment of ankle dorsiflexion range of motion was prone to interobserver variability. All other trial assessments were adequate., Discussion: Recruitment of the anticipated 14 patients was feasible although slower than expected. The Short-Form Health Survey (SF-36) and assessment of ankle dorsiflexion range of motion will no longer be included in the full-scale FOOTDROP trial., Conclusion: The FOOTDROP study is feasible., Trial Registration: ClinicalTrials.gov, identifier NCT04695834 . Registered 4 January 2021., (© 2023. The Author(s).)

Background: Previous studies indicated that about 20% of the individuals undergoing back surgery are unable to return to work 3 months to 1 year after surgery. The specific factors that predict individual trajectories in postoperative pain, recovery, and work resumption are largely unknown. The aim of this study is to identify modifiable predictors of work resumption after back surgery., Methods: In this multisite, prospective, longitudinal study, 300 individuals with radicular pain undergoing a lumbar decompression will be followed until 1-year post-surgery. Prior to surgery, participants will perform a computer task to assess fear of movement-related pain, avoidance behavior, and their generalization to novel situations. Before and immediately after surgery, participants will additionally complete questionnaires to assess fear of movement-related pain, avoidance behavior, optimism, expectancies towards recovery and work resumption, and the duration and severity of the pain. Six weeks, 3 months, 6 months, and 12 months after surgery, they will again complete questionnaires to assess sustainable work resumption, pain severity, disability, and quality of life. The primary hypothesis is that (generalization of) fear of movement-related pain and avoidance behavior will negatively affect sustainable work resumption after back surgery. Second, we hypothesize that (generalization of) fear of movement-related pain and avoidance behavior, negative expectancies towards recovery and work resumption, longer pain duration, and more severe pain before the surgery will negatively affect work resumption, pain severity, disability, and quality of life after back surgery. In contrast, optimism and positive expectancies towards recovery and work resumption are expected to predict more favorable work resumption, better quality of life, and lower levels of pain severity and disability after back surgery., Discussion: With the results of this research, we hope to contribute to the development of strategies for early identification of risk factors and appropriate guidance and interventions before and after back surgery. Trial registration The study was preregistered on ClinicalTrials.gov: NCT04747860 on February 9, 2021., (© 2022. The Author(s).)