Evaluation of costs associated with fertility treatment leading to a live birth after one fresh transfer: A global perspective.

Considerable costs are associated with infertility treatment, but little evidence is available on the main drivers of treatment costs. This cost analysis investigated key costs for treatment with assisted reproductive technology (ART) and the proportion of costs attributed to the acquisition of recombinant human follicle-stimulating hormone (r-hFSH) alfa originator for one fresh embryo transfer (ET) leading to a live birth in Spain, Norway, the UK, Germany, Denmark, South Korea, Australia, and New Zealand. The total costs for one ART cycle with a fresh ET leading to a live birth varied between countries (€4108-€12,314). Costs for pregnancy and live birth were the major contributors in European countries, and the costs of oocyte retrieval, monitoring during ovarian stimulation, pregnancy, and live birth were the top contributors in the Asia-Pacific countries, included in this analysis. Acquisition costs for r-hFSH alfa originator contributed to only 5%-17% of the total costs of one ART cycle with one fresh ET leading to a live birth.

Effectiveness of recombinant human follicle-stimulating hormone (r-hFSH): recombinant human luteinizing hormone versus r-hFSH alone in assisted reproductive technology treatment cycles among women aged 35-40 years: A German database study.

This non-interventional study compared the effectiveness of recombinant human follicle-stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH) (2:1 ratio) versus r-hFSH alone for ovarian stimulation (OS) during assisted reproductive technology treatment in women aged 35-40 years, using real-world data from the Deutsches IVF-Register (D·I·R). Numerically higher clinical pregnancy (29.8% [95% CI 28.2, 31.6] vs. 27.8% [26.5, 29.2]) and live birth (20.3% [18.7, 21.8] vs. 18.0% [16.6, 19.4]) rates were observed with r-hFSH:r-hLH versus r-hFSH alone. The treatment effect was consistently higher for r-hFSH:r-hLH compared with r-hFSH alone in terms of clinical pregnancy (relative risk [RR] 1.16 [1.05, 1.26]) and live birth (RR 1.16 [1.02, 1.31]) in a post-hoc analysis of women with 5-14 oocytes retrieved (used as a surrogate for normal ovarian reserve), highlighting the potential benefits of r-hFSH:r-hLH for OS in women aged 35-40 years with normal ovarian reserve.

Comparative effectiveness of gonadotropins used for ovarian stimulation during assisted reproductive technologies (ART) in France: A real-world observational study from the French nationwide claims database (SNDS).

This comparative non-interventional study using data from the French National Health Database (Système National des Données de Santé) investigated real-world (cumulative) live birth outcomes following ovarian stimulation, leading to oocyte pickup with either originator recombinant human follicle-stimulating hormone (r-hFSH) products (alfa or beta), r-hFSH alfa biosimilars, or urinaries including mainly HP-hMG (menotropins), and marginally u-hFSH-HP (urofollitropin). Using data from 245,534 stimulations (153,600 women), biosimilars resulted in a 19% lower live birth (adjusted odds ratio (OR) 0.81, 95% confidence interval (CI) 0.76-0.86) and a 14% lower cumulative live birth (adjusted hazard ratio (HR) 0.86, 95% CI 0.82-0.89); and urinaries resulted in a 7% lower live birth (adjusted OR 0.93, 95% CI 0.90-0.96) and an 11% lower cumulative live birth (adjusted HR 0.89, 95% CI 0.87-0.91) versus originator r-hFSH alfa. Results were consistent across strata (age and ART strategy), sensitivity analysis using propensity score matching, and with r-hFSH alfa and beta as the reference group.

Repeat two-stage exchange arthroplasty for recurrent periprosthetic hip or knee infection: what are the chances for success?

INTRODUCTION: Two-stage revision is a frequently chosen approach to treat chronic periprosthetic joint infection (PJI). However, management of recurrent infection after a two-stage exchange remains debated and the outcome of a repeat two-stage procedure is unclear. This study investigates the success rates of repeat two-stage exchange arthroplasty and analyzes possible risk factors for failure. MATERIALS AND METHODS: We retrospectively identified 55 patients (23 hips, 32 knees) who were treated with repeat resection arthroplasty and planned delayed reimplantation for recurrent periprosthetic joint infection between 2010 and 2019 after a prior two-stage revision at the same institution. The minimum follow-up was 12 months with a median follow-up time of 34 months (IQR 22-51). The infection-free survival, associated revision surgeries, and potential risk factors for further revision were analyzed using Kaplan-Meier survival curves and comparative non-parametric testing. RESULTS: 78% (43/55) underwent reimplantation after a repeat implant removal. Of those who completed the second-stage surgery, 37% (16/43) underwent additional revision for infection and 14% (6/55) underwent amputation. The reinfection-free implant survivorship amounted to 77% (95% CI 64-89%) after 1 year and 38% (95% CI 18-57%) after 5 years. Patients with a higher comorbidity score were less likely to undergo second-stage reimplantation (median 5 vs. 3, p = 0.034). Furthermore, obese patients (p = 0.026, Fisher's exact test) and diabetics (p < 0.001, log-rank test) had a higher risk for further infection. Most commonly cultures yielded polymicrobial growth at the repeat two-stage exchange (27%, 15/55) and at re-reinfection (32%, 9/28). Pathogen persistence was observed in 21% (6/28) of re-reinfected patients. CONCLUSION: The success rates after repeat two-stage exchange arthroplasty are low. Patients must be counseled accordingly and different modes of treatment should be considered.

Good to excellent long-term survival of a single-design condylar constrained knee arthroplasty for primary and revision surgery.

PURPOSE: The purpose of the study was to determine the long-term survivorship, functional outcomes of a single-design condylar constrained (CCK) TKA in primary and revision cases as well as to assess specific risk factors for failure. It was hypothesized that primary CCK TKA had a better survival than revision knees. METHODS: One hundred and forty three patients who underwent revision TKA (n = 119) or complex primary TKA (n = 24) using a single-design condylar constrained knee system (Genesis CCK, Smith & Nephew) performed at a single institution between 1999 and 2008 were retrospectively included. The median follow-up amounted to 11.8 years (IQR 10.3-14.4). Implant survivorship was analyzed using Kaplan-Meier survival estimates and multivariate Cox regression analysis to identify risk factors for failure. Function was determined using the Oxford Knee Score (OKS). RESULTS: The implant survival was 86.4% after five, 85.5% after ten and 79.8% at 15 years. A reduced implant survivorship was found in males (HR 5.16, p = 0.001), smokers (HR 6.53, p = 0.004) and in obese patients (HR 2.26, p = 0.095). Patients who underwent primary TKA had a higher revision-free implant survivorship compared to revision TKA at 15 years (100% vs. 76%, p = 0.036). The main cause for re-revision was infection in 10% of all revision TKA performed with the CCK design included, while no case was revised for instability. The median OKS was 39 (IQR 35-44) in 102 patients available for long-term functional outcome. CONCLUSION: CCK implants are associated with excellent long-term survival when used in primary TKA; however, survival was worse when used during revision TKA. Males, smokers, obese patients and are at higher risk for revision. While instability and aseptic loosening were rare, infection remains a major concern. LEVEL OF EVIDENCE: Level IV, retrospective observational study.

Do Positive Cultures at Second Stage Re-Implantation Increase the Risk for Reinfection in Two-Stage Exchange for Periprosthetic Joint Infection?

BACKGROUND: Intraoperative cultures are important in the diagnosis and targeted treatment of periprosthetic joint infection (PJI). Positive cultures at reimplantation during a two-stage exchange are discussed as a risk factor for reinfection. The aim of this study is the investigation of the incidence and risk factors for positive cultures during reimplantation. METHODS: We retrospectively identified 204 patients (111 knees, 93 hips) who were treated between 2012 and 2016 for PJI using a two-stage exchange protocol at a median follow-up of 42 months. PJI was diagnosed using the criteria of the musculoskeletal infection society (MSIS) of 2011. All cultural findings from first and second stage surgery were recorded. The primary endpoint was revision for infection. Risk factors for positive cultures and reinfection were analyzed. RESULTS: During reimplantation 25% (51/204) of patients had at least one positive culture, in 19.1% (39/204) only a single culture. Patients with culture-negative infections had a higher risk for positive cultures at reimplantation (HR 2.946 (95% CI 1.247-6.961), P = .014) and patients with infected total hip arthroplasty (THA) (HR 3.547 (95% CI 1.7-7.4), P = .001). Patients with positive cultures during reimplantation had a higher risk for reinfection (HR 2.27 (95% CI 1.181-4.363), P = .014) as well as patients with a single positive culture (HR 2.421 (95% CI 1.139-5.143), P = .021). CONCLUSION: As positive cultures are common and increase reinfection risk irrespective of their numbers, longer antibiotic therapy following reimplantation can be an option. Single positive cultures in reimplantation surgery should not be considered contamination.

Factors associated with embryo splitting and clinical outcome of monozygotic twins in pregnancies after IVF and ICSI.

STUDY QUESTION: What factors are associated with monozygotic twins (MZT) after autologous IVF/ICSI with fresh and frozen/thawed single embryo transfer (SET) and what is the outcome of MZT? SUMMARY ANSWER: Factors associated with increased MZT were blastocyst transfer and elective single embryo transfer (eSET), with MZT showing a lower gestational age at birth and neonatal weight but higher perinatal mortality only after fresh transfer. WHAT IS KNOWN ALREADY: ART is associated with an increased incidence of MZT, which carries higher perinatal mortality. However, risk factors associated with MZT are still controversial. STUDY DESIGN SIZE DURATION: A population-based retrospective analysis of data extracted from ART cycles reported to the Latin American Registry of ART between January 2012 and December 2016 was used in order to study the frequency and outcome of MZT after SET. PARTICIPANTS/MATERIAL SETTING METHODS: In total, 2925 clinical pregnancies obtained after autologous IVF/ICSI with fresh SET were used to study biomedical factors possibly associated with MZT, such as maternal age, type of insemination, use of assisted hatching, stage of embryo development at transfer, elective or non-elective SET and preimplantation genetic testing. Another group of 3085 clinical pregnancies obtained after SET of frozen-thawed embryo transfer (FET) was also used to study the possible association between embryo freezing and MZT. Only pregnancies with complete follow-up until birth were included in this analysis. The diagnosis of MZT was established by transvaginal ultrasound performed at 6­8 weeks of amenorrhea. The rate of MZT for each potential risk factor was obtained and a multivariable logistic regression was performed in order to account for the above-mentioned factors. Pregnancies were followed until birth and the early neonatal period in order to assess the rate of miscarriage and stillbirths, gestational age at birth, neonatal weight and early neonatal mortality. MAIN RESULTS AND ROLE OF CHANCE: There were 76 MZT out of 2925 clinical pregnancies with fresh SET (2.6%) and 69 MZT out of 3085 clinical pregnancies after FET (2.2%) (odds ratio (OR) = 0.85, 95% CI 0.61­1.19). A statistically significantly increase in MZT rate was observed with blastocyst compared with cleavage stage ET (3.4 versus 2.0%, respectively; OR = 1.70, 95% CI 1.05­2.76). When confounding variables were considered, eSET was also significantly associated with an increase in the odds of MZT (OR = 1.74, 95% CI 1.04­2.92). Overall perinatal mortality was higher in MZT compared with singletons, but this rise was only significant after fresh ET. LIMITATIONS REASONS FOR CAUTION: Limitations of the current study result from the fact that MZT were diagnosed with ultrasound performed at 6­8 weeks of amenorrhea; therefore, spontaneous embryo reductions taking place earlier were missed. WIDER IMPLICATIONS OF THE FINDINGS: Reproductive health providers must inform their patients that blastocyst transfer and eSET of fresh embryos are associated with a statistically significantly increase in the odds of MZT and that perinatal mortality after fresh ET is significantly higher in MZT than in singletons. STUDY FUNDING/COMPETING INTERESTS: The Latin American Registry of ART receives direct funding from Ferring Pharmaceuticals, but no specific funding was received to undertake this study. None of the authors declare conflict of interest.

Acceptable mid- to long-term survival rates and functional outcomes following a single design rotating hinge total knee arthroplasty.

PURPOSE: This study first analyzes implant survival of this single design modular rotating hinge knee and identifies potential risk factors for failure and evaluates joint function using the postoperative WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score, active flexion and extension deficit. METHODS: 131 prostheses implanted for failure of prior total knee arthroplasty (n = 120) or complex primary procedures (n = 11) using a single modular implant (MUTARS-modular universal tumor and revision system GenuX, Implantcast, Buxtehude, Germany) between 2006 and 2014 including 73 patients treated for periprosthetic joint infection with a two-stage revision protocol were retrospectively identified. Implant survival was assessed using the Kaplan-Meier method; potential risk factors were identified using the log-rank test, as well as non-parametric analysis. Postoperative function was assessed using the WOMAC and measurement of range of motion. RESULTS: After a median follow-up of 62 months, 37 implants required implant revision (28%). Five-year survival was 69.7% [95% CI (confidence interval) 60.9-78.5] with periprosthetic (re-) infection being the main cause for failure (15%), followed by aseptic loosening (9%). In cases of periprosthetic infection, infection-free survival was 83% at 5 years (95% CI 74-92) with twelve patients suffering reinfection (16%).While body mass index (p = 0.75), age (p = 0.16) or indication for rotating hinge knee arthroplasty (p = 0.25) had no influence on survival, Charlson comorbidity score (CCI) (p = 0.07) and number of previous revision surgeries (p = 0.05) correlated with implant failure. There was trend (p = 0.1) for improved survival in fully cemented implants. Mean postoperative WOMAC was 127(range 55-191), 11 patients (15%) had limited knee extension. CONCLUSIONS: Rotating hinge total knee arthroplasty using a single modular implant shows acceptable survival rates and function compared to previous studies with (re-)infection being the most relevant mode of failure. Patients with a high CCI and multiple previous surgeries are at increased risk for failure. LEVEL OF EVIDENCE: Retrospective cohort study, III.

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications.

Innate lymphoid cells (ILC) represent a group of lymphocytes that lack specific antigen receptors and are relatively rare as compared to adaptive lymphocytes. ILCs play important roles in allergic and nonallergic inflammatory diseases due to their location at barrier surfaces within the airways, gut, and skin, and they respond to cytokines produced by activated cells in their local environment. Innate lymphoid cells contribute to the immune response by the release of cytokines and other mediators, forming a link between innate and adaptive immunity. In recent years, these cells have been extensively characterized and their role in animal models of disease has been investigated. Data to translate the relevance of ILCs in human pathology, and the potential role of ILCs in diagnosis, as biomarkers and/or as future treatment targets are also emerging. This review, produced by a task force of the Immunology Section of the European Academy of Allergy and Clinical Immunology (EAACI), encompassing clinicians and researchers, highlights the role of ILCs in human allergic and nonallergic diseases in the airways, gastrointestinal tract, and skin, with a focus on new insights into clinical implications, therapeutic options, and future research opportunities.

The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations.

Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning >20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti-infectives in Asthma was initiated to investigate the potential of anti-infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti-infectives and both microbe- and host-based immunomodulators and their feasibility for use in asthma.

Influenza burden, prevention, and treatment in asthma-A scoping review by the EAACI Influenza in asthma task force.

To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness, and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma-related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma.

Respiratory syncytial virus infection influences tight junction integrity.

Respiratory syncytial virus (RSV) is an important risk factor of asthma development and is responsible for severe respiratory tract infections. However, the influence of RSV infection on barrier function of bronchial epithelial cells in vitro and in vivo is still unclear. The aim of this study was to analyse the role of RSV in tight junction (TJ) regulation and to compare epithelial integrity between asthmatic and healthy individuals upon RSV infection. Healthy and asthmatic human bronchial epithelial cells (HBECs) were differentiated at air-liquid interface (ALI) and infected with RSV and ultraviolet (UV)-irradiated RSV. TJ expression and their integrity were analysed by quantitative polymerase chain reaction (qPCR), transepithelial resistance (TER) and paracellular flux. To determine the effect in vivo, BALB/c mice were infected intranasally with RSV or UV-irradiated RSV A2. Bronchoalveolar lavage and TJ integrity were analysed on days 1, 2, 4 and 6 post-infection by qPCR, bioplex and confocal microscopy. RSV increased barrier integrity in ALI cultures of HBEC from healthy subjects, but no effect was found in HBECs from asthmatics. This was not associated with an increase in TJ mRNA expression. In vivo, RSV induced lung inflammation in mice and down-regulated claudin-1 and occludin mRNA expression in whole lungs. Surprisingly, RSV infection was not observed in bronchial epithelial cells, but was found in the lung parenchyma. Decreased expression of occludin upon RSV infection was visible in mouse bronchial epithelial cells in confocal microscopy. However, there was no regulation of claudin-1 and claudin-7 at protein level.

Viral respiratory tract infections and asthma in early life: cause and effect?

Interactions between viral respiratory tract infections in infancy and childhood, and asthma development and exacerbation, are complex and intriguing. This review aims to unravel some of these complexities. Does severe respiratory viral infection early in life predispose to later asthma development, or is it indicative of a predisposition to allergic respiratory disease? How could variables such as age and severity of viral infection affect the interaction between respiratory viral infections and asthma? How could respiratory viral infection drive allergic sensitization? Here, we review the evidence surrounding these questions, and discuss current and future research and therapeutic approaches targeting the interplay between viral respiratory tract infection and asthma.

Lymphoid and myeloid cell populations in the non-pregnant human Fallopian tube and in ectopic pregnancy.

Lymphoid and myeloid cell populations in human endometrium are well-documented and are known to play important roles in providing immune tolerance, controlling trophoblast invasion, and mediating vascular remodeling. Immune cell populations in the Fallopian tube have not been comprehensively studied. The aim of this study was to characterize lymphoid and myeloid cell populations in non-pregnant Fallopian tube and determine whether they are altered in Fallopian tube from women with ectopic pregnancy. Fallopian tube was analyzed by flow cytometry and immunohistochemistry. Populations of CD3+ (CD4+ and CD8+) lymphocytes, LIN1-HLADR+ (CD123+ and CD11c+) dendritic cells, monocytes, neutrophils, and CD56(dim)CD16- natural killer (NK) cells were demonstrated to be present in non-pregnant Fallopian tube. CD123+ dendritic cells were predominant over CD11c+ dendritic cells. Numbers of CD11c+ cells were significantly higher in the progesterone-dominant mid-luteal phase of the menstrual cycle compared with the follicular phase. Numbers of CD45+ leukocytes, CD68+ cells, and CD11c+ cells were higher in Fallopian tube from women with ectopic pregnancy compared with mid-luteal phase Fallopian tube. These data will advance our understanding of normal human Fallopian tube physiology and disorders of Fallopian tube function, such as ectopic pregnancy.

Patent foramen ovale is not associated with an increased risk of stroke recurrence.

BACKGROUND AND PURPOSE: Despite numerous studies suggesting a relationship between paradoxical embolism from a patent foramen ovale (PFO) and stroke, the role of PFO as a risk factor for cerebral ischaemia remains controversial. We therefore sought to determine the association between a RLS detected by contrast-enhanced transcranial Doppler ultrasonography (c-TCD) and recurrent stroke in an unselected population sample. METHODS: We analyzed the records of 763 patients with diagnosis of cerebral ischaemia at our institution. All patients had undergone TCD-based detection of RLS. Embolic signals have been measured both under resting conditions and after performing a Valsalva maneuver. For follow-up, all patients were contacted by mail, which included a standardized questionnaire. Endpoints of follow-up were defined as recurrence of cerebral ischaemia, occurrence of myocardial infarction or death from any cause. RESULTS: Follow-up data were available in 639 patients (83.7%). At baseline, a RLS was detected in 140 (28%) men and in 114 (42%) women. Ten shunt-carriers (1.6%) and 32 patients (5.0%) without RLS had suffered a recurrent stroke. After adjustment for age, sex, and atrial fibrillation, the hazard ratio of RLS for stroke recurrence was 0.86 (95% CI 0.41-1.79). The condition of RLS at rest adjusted for age, sex, stroke subtype, and cardiovascular risk factors was not found to increase the risk of stroke substantially (HR 1.16 [95% CI 0.41-3.29]) CONCLUSION: Our data suggest that the risk of recurrent stroke in subjects with PFO is not significantly increased in comparison with subject without it.

Lesion patterns in patients with cryptogenic stroke with and without right-to-left-shunt.

BACKGROUND AND PURPOSE: Despite numerous studies, the role of patent foramen ovale (PFO) as a risk factor for stroke due to paradoxical embolism is still controversial. On the assumption that specific lesion patterns, in particular multiple acute ischaemic lesions on diffusion-weighted magnetic resonance imaging, indicate a cardioembolic origin, we compared the MRI findings in stroke patients with right-to-left shunt (RLS) and those without. METHODS: The records of 486 patients with diagnosis of cerebral ischaemia were reviewed. For detection of RLS, contrast-enhanced transcranial Doppler (c-TCD) was carried out in all patients. An MRI scan of the brain was performed in all patients. Affected vascular territories were divided into anterior cerebral artery, middle cerebral artery, vertebrobasilar artery system including posterior cerebral artery, brain stem and cerebellar stroke, and strokes occurring in more than one territory. RESULTS: We did not find a specific difference in neuroradiological lesion patterns in patients with RLS compared with patients without RLS. In particular, 23 of 165 patients (13.9%) with RLS showed multiple ischaemic lesions on MRI in comparison with 45 of 321 patients (14.0%) without RLS (P = 0.98). These findings also applied for the subgroup of cryptogenic strokes with and without RLS. CONCLUSION: We found no association between an ischaemic lesion pattern that is considered as being typical for stroke due to cardiac embolism and the existence of PFO. Therefore, our findings do not provide any support for the common theory of paradoxical embolism as a major cause of stroke in PFO carriers.

Healthy but not RSV-infected lung epithelial cells profoundly inhibit T cell activation.

BACKGROUND: Respiratory viruses, including respiratory syncytial virus (RSV), can cause asthma exacerbations and bronchiolitis. Both conditions are associated with enhanced cognate immune responses and inflammation and reduced immune regulation. Lung epithelial cells (LECs) can contribute to antiviral and allergic immune responses while gut epithelial cells can inhibit effector T cell responses. A study was performed to determine whether healthy LECs regulate antigen-specific T cell responses and if this regulation is lost during RSV infection. METHODS: LA4 cells, a murine LEC line, infected with RSV or primary murine LECs were co-cultured with ovalbumin-specific T cell receptor transgenic CD4+ T cells from DO11.10 mice and ovalbumin-pulsed bone marrow-derived dendritic cells (DC) to assess T cell proliferation by flow cytometry and cytokine production. RESULTS: The presence of LECs abrogated DC-induced T cell proliferation and significantly reduced T cell cytokine release. These effects of LECs were predominantly contact-dependent, primarily affected T cells directly and were partly mediated by transforming growth factor beta. Soluble factors and DC-mediated effects also contributed to T cell inhibition. RSV infection of LECs reduced their inhibitory capacity in an infection dose-dependent manner. This was independent of proinflammatory cytokines released by infected LECs, but in part due to Toll-like receptor activation and to infection-induced cell death. CONCLUSION: Healthy LECs are potent inhibitors of T cell activation, but this regulatory function is lost after RSV infection. These findings suggest a central role for LECs in maintaining the tolerogenic environment of healthy lungs. Loss of this regulatory capacity after viral infection may allow development of excessive cognate immune responses and pulmonary inflammation.

Respiratory syncytial virus infection provokes airway remodelling in allergen-exposed mice in absence of prior allergen sensitization.

BACKGROUND: The mechanisms underlying exacerbation of asthma induced by respiratory syncytial virus (RSV) infection have been extensively studied in human and animal models. However, most of these studies focused on acute inflammation and little is known of its long-term consequences on remodelling of the airway tissue. OBJECTIVE: The aim of the study was to use a murine model of prolonged allergen-induced airway inflammation to investigate the effect of RSV infection on allergic airway inflammation and tissue remodelling. METHODS: We subjected mice to RSV infection before or during the chronic phase of airway challenges with OVA and compared parameters of airway inflammation and remodelling at the end-point of the prolonged allergen-induced airway inflammation protocol. RESULTS: RSV infection did not affect the severity of airway inflammation in any of the groups studied. However, RSV infection provoked airway remodelling in non-sensitized, allergen-challenged mice that did not otherwise develop any of the features of allergic airways disease. Increased collagen synthesis in the lung and thickening of the bronchial basal membrane was observed in non-sensitized allergen-challenged mice only after prior RSV infection. In addition, fibroblast growth factor (FGF)-2 but not TGF-beta(1) was increased in this group following RSV infection. CONCLUSION: Our data show for the first time that RSV infection can prime the lung of mice that are not previously systemically sensitized, to develop airway remodelling in response to allergen upon sole exposure via the airways. Moreover, our results implicate RSV-induced FGF-2 in the remodelling process in vivo.

Inhalation of stable dust extract prevents allergen induced airway inflammation and hyperresponsiveness.

BACKGROUND: Recent epidemiological studies have shown that growing up on a traditional farm provides protection from the development of allergic disorders such as hay fever and allergic asthma. We present experimental evidence that substances providing protection from the development of allergic diseases can be extracted from dust collected in stables of animal farms. METHODS: Stable dust was collected from 30 randomly selected farms located in rural regions of the Alps (Austria, Germany and Switzerland). The dust was homogenised with glass beads and extracted with physiological sodium chloride solution. This extract was used to modulate immune response in a well established mouse model of allergic asthma. RESULTS: Treatment of mice by inhalation of stable dust extract during sensitisation to ovalbumin inhibited the development of airway hyperresponsiveness and airway eosinophilia upon challenge, as well as the production of interleukin 5 by splenocytes and of antigen specific IgG(1) and IgE. Dust extract also suppressed the generation of human dendritic cells in vitro. The biological activity of the dust extract was not exclusively mediated by lipopolysaccharide. CONCLUSIONS: Stable dust from animal farms contains strong immune modulating substances. These substances can interfere with the development of both cellular and humoral immunity against allergens, thus suppressing allergen sensitisation, airway inflammation, and airway hyperresponsiveness in a murine model of allergic asthma.