Successful Generation of CD19 Chimeric Antigen Receptor T Cells from Patients with Advanced Systemic Lupus Erythematosus.

Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell-targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell-suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.

[Impact of the transition period from childhood to adulthood in cystic fibrosis]. / Impact de la période de transition de l'enfance à l'âge adulte dans la mucoviscidose.

INTRODUCTION: The aim of this study was to evaluate the impact of the transition period from childhood to adulthood in patients with cystic fibrosis (CF) being followed up in our reference center. METHODS: The clinical, functional, inflammatory and microbiological parameters of all transition patients were compared two years before (T-2) and two years after the transfer (T+2) from paediatric to adult centers and further analysed according to whether the transition conditions were optimal or suboptimal. RESULTS: Twenty-eight patients were included. The mean age at the transfer visit was 19.5 years (±3.5). There were no deaths during the study period. Consultations were more numerous at T-2 [14.5 (±5.9) vs. 12.0 (±5.1), P<0.004]. Chronic colonization with Pseudomonas aeruginosa was more frequent at T+2 (46.4% vs. 17.9%, P=0.021). A progressive decrease in FEV1 and FVC was observed between T-2 and T+2. The number of pulmonary exacerbations was lower in the optimal transition group. CONCLUSION: The period of transition from childhood to adulthood in patients with CF appears to be associated with functional and microbiological changes.

A case report of successful eradication of new isolates of Burkholderia cenocepacia in a child with cystic fibrosis.

Chronic respiratory infection with Burkholderia cenocepacia (Bc) in patients with cystic fibrosis (CF) is associated with accelerated decline in lung function and increased mortality. It is therefore important to attempt to eradicate new isolates, especially in children. However, there are no standardized guidelines to eradicate Bc. We report a case of successful eradication of new isolates of Bc in a 2-year-old child with CF using a combination of IV, nebulized antibiotics and sinus surgery.

Emergence of livestock-associated MRSA isolated from cystic fibrosis patients: Result of a Belgian national survey.

BACKGROUND: This study aims to determine the prevalence and characteristics of Staphylococcus aureus in Belgian cystic fibrosis (CF) patients. METHODS: Non-duplicate respiratory samples from 510 CF-patients (2012-2013) were examined. One isolate per patient was analysed unless different phenotypes were recovered. Isolates were investigated for mecA/mecC, toxins presence, spa-typing, MLST and SCCmec-typing. Potential livestock-associated (LA) isolates were examined for their immune-evasion-cluster (IEC) genes. RESULTS: S. aureus (n = 380), including 41 small-colony variants (SCVs), were isolated from 66.7% patients. The prevalence of methicillin-resistant S. aureus (MRSA) colonization was 4.9%. Two MRSA isolates carried toxic shock syndrome toxin 1 (TSST-1). Most MRSA (65%) belonged to two nosocomial epidemic clones (CC5, CC8) widespread in Belgium. Methicillin susceptible S. aureus (MSSA) showed great genetic diversity. Five of 33 isolates belonging to potential LA-lineages were IEC negative, including three methicillin-resistant isolates, suggesting an animal origin. CONCLUSIONS: The MRSA-prevalence in Belgian CF-patients remained constant (2001-2013), but SCV-prevalence increased. Most MRSA belonged to health-care-associated clones. Three patients carrying LA-MRSA were found, requiring further investigation to determine the risk factors for LA-MRSA acquisition.

[The motivational week: A new approach in smoking cessation]. / La semaine motivationnelle : une nouvelle approche dans le sevrage tabagique.

INTRODUCTION: Smoking cessation is complex and challenging. The motivational week is a multidisciplinary approach that has been established in order to increase the chances of quitting smoking. The purpose of this study was to determine the rates of abstinence achieved and the predictive factors for quitting. METHODS: Clinical data, smoking status, levels of dependence and motivation as well as rates of continuous abstinence in the short and long-term of all patients who participated in the motivational week were analysed. RESULTS: Two hundred and thirteen patients were included. The mean age was 49.8 years (10.6). The rates of continuous abstinence were 40.4% at 6 months, 29.1% at 12 months and 21.6% at 2 years. Using logistic regression, having depression or a history of depression was associated with reduced likelihood of smoking cessation: OR: 0.32 [95%CI: 0.16-0.76; P=0.003] at 6 months, OR: 0.35 [95%CI: 0.16-0.77; P=0.009] at 12 months and OR: 0.27 [95%CI: 0.11-0.65; P=0.004] at 2 years. CONCLUSIONS: The motivational week seems to be an approach which is effective long-term and could be used in smoking cessation. This study confirms that depression is an unfavourable factor for quitting.

The clinical benefits of long-term supplementation with omega-3 fatty acids in cystic fibrosis patients - A pilot study.

Effectiveness of omega-3 supplementation in cystic fibrosis (CF) remains controversial. This study sought to evaluate clinical status, exercise tolerance, inflammatory parameters, and erythrocyte fatty acid profile after 1 year of oral omega-3 supplementation in CF patients. Fifteen ΔF508-homozygous patients undergoing chronic azithromycin were randomized to receive omega-3 fish oil supplementation at a dose of 60mg/Kg/day or placebo. In comparison with the previous year, in the supplemented group, the number of pulmonary exacerbations decreased at 12 months (1.7 vs. 3.0, p<0.01), as did the duration of antibiotic therapy (26.5 days vs. 60.0 days, p<0.025). Supplementation significantly increased the levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as early as <3 months of administration, with concomitant decreases in arachidonic acid (AA) levels. This pilot study suggests that long-term omega-3 supplementation offers several clinical benefits as to the number of exacerbations and duration of antibiotic therapy in CF patients.

[Management of tobacco smoking in general practice]. / Prise en charge du tabagisme en médecine générale.

Tobacco is a hard drug causing triple dependence. The medical management of tobacco smokers is thus complex and challenging. It requires a global approach combining non-pharmacological and pharmacological treatment. The general practitioner, having a privileged status, plays an important role. The recommended management is the strategy of the 5As (Ask, Advice, Assess, Assist, Arrange). This article proposes the management of tobacco smoking and cessation, in general practice, in the adult smoker, as well as the specificities of tobacco smoking and cessation in the pregnant woman and the teenager.

Clinical aspects of chronic ENT inflammation in children.

In children, all ENT cavities are particularly prone to the development of chronic inflammation. This is due to many predisposing factors, of which the most common are unfavourable anatomy, absence of nasal blowing, day care attendance, allergy, immature immunity, gastro-oesophageal reflux and tobacco smoke exposure. The aim of this paper is to outline the most specific paediatric clinical aspects of chronic pharyngo-tonsillitis, rhinosinusitis, otitis media, adenoiditis and laryngotracheitis and the important influence that some of these pathologies exert on the others.

[Acute respiratory dyspnea in children]. / La dyspnée aiguë chez l'enfant.

Acute respiratory dyspnea is very frequent in children and must be quickly treated to obtain the best prognosis. The diagnosis depends from the natural history of the disease and from the quality of clinical assessment. The use of an algorithm according to the presence of stridor or bronchospasm is very contributive to the diagnosis. The paper reviews the pathophysiology of dyspnea in children and the more common diseases that are causing respiratory distress. Finally, treatment of respiratory failure and management of specific diseases are defined.

Basophil activation tests for the diagnosis of food allergy in children.

BACKGROUND: Positive skin prick tests (SPT) for food allergens and specific IgE (sIgE) in serum indicate sensitization but do not enable distinction between sensitized but tolerant and clinically allergic patients. OBJECTIVE: Herein, we evaluate the clinical relevance of basophil activation tests (BATs) for peanut or egg allergy diagnosis. METHODS: Thirty-two peanut-allergic, 14 peanut-sensitized (sIgE(+) and/or SPT(+) to peanuts) but tolerant children and 29 controls with no history of an adverse reaction to peanuts were included. Similarly, 31 egg-allergic, 14 egg-sensitized children (sIgE(+) and/or SPT(+) to egg white) and 22 controls were studied. Flow cytometric analysis of CD63 expression or CD203c upregulation on basophils and the production of leukotrienes (LT) were performed in response to an in vitro crude peanut extract or ovalbumin (OVA) challenge. RESULTS: After in vitro peanut challenge, the basophils from peanut-allergic children showed significantly higher levels of activation than those from controls (P<0.001). After OVA challenge, a similar distinction (P<0.001) was observed between egg-allergics and controls. Interestingly, the majority of egg- or peanut-sensitized children failed to activate basophils, respectively, in response to OVA and peanut challenge. The sensitivity of the CD63, CD203c and LT assay was 86.7%, 89.5% and 76.0% with a specificity of 94.1%, 97.1% and 94.6% for peanut allergy diagnosis. The corresponding performances of BATs applied to egg allergy diagnosis were 88.9%, 62.5% and 77.8% for the sensitivity and 100%, 96.4% and 96.4% for the specificity. CONCLUSION: Neither conventional tests nor BATs are sensitive and specific enough to predict food allergy accurately. However, BATs may helpfully complete conventional tests, especially SPT, allowing improved discrimination between allergic and non-allergic individuals.

[Immunoallergology in children: diagnosis and treatment]. / Immuno-allergologie chez l'enfant: diagnostic et traitement.

Atopy is the most frequent allergic disease in western countries: about 30% of children are suffering from various forms of its manifestations. During the 20th century, its frequency gradually increased. This is not only true for sensitization (presence of specific immunoglobulin E (IgE) in the skin or in the serum), but also for clinical symptoms associated with sensitization. It is usually a disease of skin and mucosae, but atopy can also become systemic (anaphylaxis). Hygienist hypothesis (reduction of infectious diseases and Th1 pressure) gives a possible explanation to the impressive increase of allergic diseases during the last decades. In the child, atopic dermatitis and food allergies are first observed (allergic march): 5 allergens explain more than 85% of cases (white egg, milk, peanuts, fish and nuts). Skin prick tests are more sensible than specific IgE measurements in the serum; they are usually done before. Provocation tests (labial and oral) can confirm the diagnosis when necessary. Four families of aeroallergens are described (pollens, house dust mites, pets and moistures). Eviction is the first line of treatment, than drugs are prescribed to reduce symptoms and inflammation (corticosteroids, antihistamine). Desensitization and immunomodulators that can induce tolerance are also proposed in defined situations.

[Brain in the core of metabolic regulations: disorders in schizophrenic patients treated with atypical antipsychotics]. / Le cerveau au centre des régulations métaboliques: anomalies chez les patients schizophrènes traités par antipsychotiques atypiques.

Schizophrenia is associated with an increased risk of metabolic disorders such as diabetes, dyslipidaemia and the metabolic syndrome. The prevalence of type 2 diabetes in schizophrenic patients is at least twice that of the general population. Around 40 percent of patients meet criteria for the metabolic syndrome. Recently there is a growing concern on the metabolic side effects of treatment with second generation antipsychotics. According to various studies, including a prospective study performed in Flanders, treatment with clozapine and olanzapine has the highest metabolic risk, followed by quetiapine and risperidone. Amisulpride, ziprasidone and aripiprazole appear to have a low metabolic risk. Appropriate care, taking into account the possible improvement of the metabolic risks factors, is important to reduce morbidity and mortality in schizophrenic patients treated with antipsychotic medications.

Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study.

BACKGROUND: Patients with schizophrenia are at high risk of developing metabolic abnormalities. METHOD: A prospective study focusing on metabolic disturbances in patients with schizophrenia, including an oral glucose tolerance test, is currently ongoing at our University Hospital and affiliate services. The prevalence of metabolic abnormalities at baseline was assessed in a cohort of 415 patients with schizophrenia. The sample was divided into 4 groups according to duration of illness: first-episode patients (<1.5 years), recent-onset patients (between 1.5 and 10 years), subchronic patients (between 10 and 20 years) and chronic patients (>20 years). RESULTS: Metabolic abnormalities were already present in first-episode patients, and considerably increased with increasing duration of illness. When compared to the general population matched for age and gender, much higher rates of the metabolic syndrome (MetS) and diabetes were observed for patients with schizophrenia. For MetS, the increase over time was similar to that of the general population. In contrast, the difference in the prevalence of diabetes in patients with schizophrenia and the general population dramatically and linearly increased from 1.6% in the 15-25 age-band to 19.2% in the 55-65 age-band. CONCLUSION: Thus, the current data suggest that on the one hand metabolic abnormalities are an inherent part of schizophrenic illness, as they are already present in first-episode patients. On the other hand, however, our results suggest a direct effect of the illness and/or antipsychotic medication on their occurrence. The data underscore the need for screening for metabolic abnormalities in patients diagnosed with schizophrenia, already starting from the onset of the illness.

Pharmacological treatment of ambulatory schizophrenic patients in Belgium.

BACKGROUND: the objective of this study was twofold:1) Describe the use of antipsychotic treatments in ambulatory patients suffering from schizophrenia in Belgium.2) Evaluate to which extend antipsychotic treatment prescribing patterns are in accordance with published treatment guidelines. METHOD: A cross-sectional survey was carried out in 16 Belgian hospitals selected from a sample of 67 hospitals. The hospitals were equally distributed between the north and south part of the country and were representative of Belgian practice. During 2 months, participating psychiatrists were asked to record the medication use as well as demographic parameters of all consecutive ambulatory patients seen at their consultation or attending a day-hospital. Data concerning 1000 ambulatory patients with schizophrenia or schizoaffective disorder were collected. RESULTS: In Belgium, the use of atypical antipsychotics is frequent (69%) in ambulatory patients with schizophrenia. In the overall sample, 73% receive only one antipsychotic drug. The majority of patients are treated with drugs of only one antipsychotic drug group, either first- typical (29.8%) or second-generation, atypical antipsychotics (53.2%). 15.8% of patients combine different types of antipsychotics. Antipsychotic dosing is adequate for the majority of patients but about one fifth receives a higher than recommended dose as per package inserts. Polypharmacy remains within reasonable limits. The use of concomitant medication varies according the antipsychotic treatment: patients who take second-generation antipsychotics only, receive the least additional drugs. CONCLUSION: Atypical antipsychotics appear to be the first line treatment for schizophrenic psychosis. Psychiatrists working with ambulatory patients are well aware of treatment guidelines and follow them quite adequately.

[Child food allergy: results of a Belgian cohort]. / L'allergie alimentaire chez l'enfant: étude d'une cohorte belge.

INTRODUCTION: Food Allergy is a public health problem because of its increasingly prevalence, its severity and the difficulty of diagnosis. OBJECTIVE: to describe the responsible food allergens and the clinical features of food allergy in a large group of Belgian children. METHOD: 156 cases of food allergy observed between May 2002 and May 2005 were retrospectively reviewed. All patients have specific IgE. Unequivocal history, response to elimination diet, labial or oral food challenge confirmed the diagnostic. RESULTS: Median age is 26 months (range 1 months-14 years) and male to female ratio is 1.6. Fifty-nine percent of the cases are younger than 3 years. Family history of atopic disease is found in 80.3%. Foods most commonly involved are: eggs (31%), tree nuts (18.1% including hazelnuts 12.3%), cow's milk (16.1%), peanuts (13.2%), fish (4.5%), latex fruits (4.5%).The clinical manifestations are: atopic dermatitis (44.2%), urticaria (40.4%), angioedema (36.5%), gastrointestinal symptoms (21.8%), laryngeal edema (11.5%), asthma (9%), oral allergy syndrome (7.7%), systemic reactions (7.7%) and anaphylactic shock (3.8%). Multiple food allergies are rare: 78.9% of our population have one or two food allergies. CONCLUSION: This study confirms the usual distribution of food allergens in children. It shows that only four allergens (egg, tree nut, cow's milk, peanut) are responsible for 78.4% of the reactions and highlights the emergence of tree nuts allergy, particularly hazelnuts, in Belgium.

[Neuroleptic drug utilization among schizophrenic outpatients]. / Utilisation des neuroleptiques chez les patients ambulatoires souffrant de schizophrénie.

BACKGROUND: Our objective was to describe and compare neuroleptic drug utilization patterns among French schizophrenic outpatients in public and private care settings. METHODS: A cross sectional survey was carried out by a random sample of 61 public and 112 private psychiatrists who registered for one month all schizophrenic adult outpatients treated with a neuroleptic drug. Among registered patients, each psychiatrist was to include a maximum of 18 patients (public setting) or 9 patients (private setting). Statistical analysis was weighted to take into account for psychiatrist activity level, assessed by patient registration. RESULTS: Psychiatrists included 934 patients in the public care setting and 927 patients in the private care setting. Patients were (mean+/-sd) 40.1+/-12.1 years old, 60.9% men. The patients' social and clinical characteristics were less favorable in the public setting than in the private setting: no professional activity (78.9% vs 65.1%), living in institution (7.2% vs 3.7%), under legal protection (35.1% vs 14.5%), drug abuse (9.6% vs 5.6%). An atypical neuroleptic was prescribed for 63.0% of patients and a classic neuroleptic for 49.7%, an association of neuroleptics for 22.0%. In both settings, the most prescribed neuroleptics were olanzapine (28.0%) and risperidone (18.6%) with a higher mean daily dosage in the public care setting. At least one neuroleptic treatment change (drug and/or dosage) occurred during the previous year for 44.9% and 39.2% patients, in public and private settings, respectively. In both settings, reasons for changes were mainly lack of efficacy (55.1%) and side effects (49.8%). CONCLUSION: Public and private care populations were different but not as much as expected. In both settings, atypical neuroleptics were the predominant drugs used in the treatment of schizophrenia outpatients. The high frequency of drug change for lack of efficacy or side effects demonstrates the difficulties with the use of the present neuroleptic armamentarium.

[Prevention of frailty in the elderly: a demographic challenge]. / Prévention de la vulnérabilité de la personne âgée: un défi démographique.

World population is ageing. This phenomenon is unprecedented, universal, long-lasting and has important implications. Unprecedented, because never before in human history, so many individuals have reached an advanced age. Universal, because all countries are now concerned. Long-lasting, because ageing started in the second half of the XXth century and will become even more pronounced over the XXIst century. With important implications, because it has and will have substantial consequences on human life and social composition. This article reviews quantitative data on ageing to appraise its extent and implication, the goal being to extend and stimulate the debate on ageing. International data are first presented, then analysis moves to Belgium estimates.

Relevance of bone mineral density, bone quality and falls in reduction of vertebral and non-vertebral fractures.

All epidemiological studies conclude that without prompt, concerted and well-designed prevention programs, the increasing cost related to osteoporotic fractures will become an unbearable burden for the community within the next fifteen years. However, the most effective way of setting up such preventive strategies is not yet unequivocally defined. Low bone mass and microarchitectural damage of bone tissue may account for a large part of the epidemiology of vertebral fractures. Extraskeletal determinants, including low muscle strength, poor balance and gait, all resulting in an increased propensity to fall, also play a major role in the occurrence of hip fracture. Depending on the localization of the fractures, the relative importance of skeletal and extraskeletal risk factors can significantly differ. For prevention of vertebral fractures, drugs affecting bone mass and skeletal architecture may provide a substantial benefit while hip fracture prevention will be more successfully targeted by multi-faceted strategies concentrating not only on the skeletal dimension of the fracture but also aiming, either pharmacologically or through multi-intervention programs, at a reduction in the incidence and in the consequences of falls in the elderly.

Successful cryopreservation of tissue and skin fibroblast cultures from patients with mucolipidosis II (I-cell disease).

Freeze-induced injury is a commonly observed phenomenon with cultured fibroblasts from patients with I-cell disease (ICD). Cells from these patients have therefore not been widely available to investigators, which has inhibited the study of this complex disorder. Skin biopsies from three ICD patients, as well as fibroblast cultures derived from these biopsies, have been subjected to a series of freezing experiments. The results show that when standard freezing protocols are employed, skin biopsies from these patients, in contrast to cultured fibroblasts, tolerate freezing well. In addition, when subjected to prolonged incubation in the confluent state, fibroblast cultures will consistently withstand frozen storage and, upon thawing, will yield actively growing cultures, biochemically and morphologically indistinguishable from the cultures that were frozen. There was a direct correlation between incubation time at confluence and subsequent cell survival after freezing.