Coping with an HIV infection. A multicenter qualitative survey on HIV positive adolescents' perceptions of their disease, therapeutic adherence and treatment.

HIV-positive adolescents face a number of challenges in dealing with their disease and its treatment. In this qualitative study, twenty-nine HIV-positive adolescents aged 13 to 20 years (22 girls), who live in Switzerland, were asked, in a semi-structured interview (duration of 40-110 minutes), to describe their perceptions and experiences with the disease itself and with therapeutic adherence. While younger adolescents most often thought of their disease as fate, older adolescents usually knew that they had received it through vertical transmission, although the topic appeared to be particularly difficult to discuss for those living with their HIV-positive mothers. Based on their attending physician's assessment, 18 subjects were judged highly adherent, 4 fairly and 7 poorly adherent. High adherence appeared linked with adequate psychological adjustment and effective coping mechanisms, as well as with the discussion and adoption of explicit medication-taking strategies. The setting and organisation of health care teams should allow for ongoing discussions with HIV-positive adolescents that focus on their perceptions of their disease, how they cope with it and with the treatment, and how they could improve their adherence.

EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.

Novel therapeutic strategies targeting regulatory T cells and downstream TCR signaling in transplantation

Avec plus de 100000 transplantations d'organes solides (TOS) par année dans le monde, la transplantation d'organes reste actuellement l'un des meilleurs traitements disponibles pour de nombreuses maladies en phase terminale. Bien que les médicaments immunosuppresseurs couramment utilisés soient efficaces dans le contrôle de la réponse immune engendrant le rejet aigu d'une greffe, la survie du greffon à long terme ainsi que la présence d'effets secondaires indésirables restent un enjeu considérable en clinique. C'est pourquoi il est nécessaire de trouver de nouvelles approches thérapeutiques innovantes permettant de contrôler la réponse immunitaire et ainsi d'améliorer les résultats à long terme. L'utilisation des lymphocytes T régulateurs (Treg), suppresseurs naturels de la réponse inflammatoire, a fait l'objet de nombreuses études ces dix dernières années, et pourrait être considérée comme un moyen intéressant d'améliorer la tolérance immunologique de la greffe. Cependant, l'un des obstacles de l'utilisation des Treg comme agent thérapeutique est leur nombre insuffisant non seulement en conditions normales, mais en particulier lors d'une forte réponse immune avec expansion de cellules immunitaires alloréactives. En raison des limitations techniques connues pour l'induction des Treg ex-vivo ou in vitro, nous avons dédié la première partie du travail de thèse à la détermination de l'efficacité de l'induction des Treg in vivo grâce à l'utilisation d'un complexe protéique IL-2/JES6-1 (IL2c). Nous avons montré que l'expansion des Treg par IL2c permettait d'augmenter la survie du greffon sur un modèle murin de transplantation de peau avec mismatch entre le donneur et le receveur pour le complexe majeur d'histocompatibilité (CMH). De plus, nous avons vu qu'en combinant IL2c à une inhibition à court terme de la voie de co-stimulation CD40L-CD40 (anti-CD154/MRl, administré au moment de la transplantation) pour empêcher l'activation des lymphocytes T, il est possible d'induire une tolérance robuste à long terme. Finalement, nos résultats soulignent l'importance de cibler une voie de co-stimulation bien particulière. En effet, l'utilisation d'IL2c combinée au blocage de la co-stimulation CD28-B7.1/2 (CTLA-4 Ig) n'induit qu'une faible prolongation de la survie de la greffe et n'induit pas de tolérance. L'application chez l'humain des traitements induisant la tolérance dans des modèles expérimentaux murins ou de primates n'a malheureusement pas montré de résultats probants en recherche clinique ; une des principales raisons étant la présence de lymphocytes B et T mémoires provenant du systeme d immunité acquise. C est pourquoi nous avons testé si la combinaison d'IL2c et MR1 améliorait la survie de la greffe dans des souris pré¬sensibilisées. Nous avons trouvé qu'en présence de lymphocytes B et T mémoires alloréactifs, l'utilisation d'IL2c et MR1 permettait une amélioration de la survie de la greffe de peau des souris immunocompétentes mais comparé aux souris receveuses naïves, aucune tolérance n'a pu être induite. Toutefois, l'ajout d'un traitement anti-LFA-1 (permettant de bloquer la circulation des lymphocytes T activées) a permis d'améliorer de manière significative la survie de la greffe. Cependant, le rejet chronique, dû à la présence de lymphocytes B activés/mémoires et la production d'anticorps donneur-spécifiques, n'a pas pu être évité. Cibler l'activation des lymphocytes T est la stratégie immunothérapeutique prépondérente après une TOS. C'est pourquoi dans la deuxième partie de cette thèse nous nous sommes intéressés au système de signalisation d'un récepteur des lymphocytes T qui dépend de la paracaspase Malti en tant que nouvelle stratégie immunosuppressive pour le contrôle des lymphocytes T alloréactifs. Nous avons montré que bien que l'inhibition de la signalisation du lymphocyte T en aval de Malti induise une tolérance envers un greffon de peau avec incompatibilités antigéniques mineures, cela ne permet cependant qu'une régulation partielle de l'alloréponse contre des antigènes du CMH. Nous nous sommes aussi intéressés spécifiquement à l'activité protéolytique de Malti. L'inhibition constitutive de l'activité protéolytique de Malti chez les souris Malti-ki s'est révélée délétère pour l'induction de la tolérance car elle diminue la fonction des Treg et augmente l'alloréactivité des cellules Thl. Cependant, lors de l'utilisation d'un inhibiteur peptidique de l'activité protéase de Malti in vitro, il a été possible d'observer une atténuation de l'alloéactivité des lymphocytes T ainsi qu'un maintien de la population des Treg existants. Ces résultats nous laissent penser que des études plus poussées sur le rôle de la signalisation médiée par Malti seraient à envisager dans le domaine de la transplantation. En résumé, les résultats obtenus durant cette thèse nous ont permis d'élucider certains mécanismes immunologiques propres à de nouvelles stratégies thérapeutiques potentielles dont le but est d'induire une tolérance lors de TOS. De plus, ces résultats nous ont permis de souligner l'importance d'utiliser des modèles davantage physiologiques contenant, notamment en tenant compte des lymphocytes B et T mémoires alloréactifs. -- Organ transplantation remains the best available treatment for many forms of end-stage organ diseases, with over 100,000 solid organ transplantations (SOT) occurring worldwide eveiy year. Although the available immunosuppressive (IS) drugs are efficient in controlling acute immune activation and graft rejection, the off-target side effects as well as long-term graft and patient survival remain a challenge in the clinic. Hence, innovative therapeutic approaches are needed to improve long-term outcome across immunological barriers. Based on extensive experimental data obtained over the last decade, it is tempting to consider immunotherapy using Treg; the natural suppressors of overt inflammatory responses, in promoting transplantation tolerance. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non- manipulated individuals, in particular when facing strong immune activation and expanding alloreactive effector cells. Because of the limitations associated with current protocols aiming at ex-vivo expansion or in vitro induction of Treg, the aim of the first part of this thesis was to determine the efficacy of direct in vivo expansion of Treg using the IL-2/JES6- 1 immune complex (IL2c). We found that whilst IL2c mediated Treg expansion alone allowed the prolonged graft survival of fìlli MHC-mismatched skin grafts, its combination with short-term CD40L-CD40 co-stimulation blockade (anti-CD 154/MR1) to inhibit T cell activation administered at the time of transplantation was able to achieve long-term robust tolerance. This study also highlighted the importance of combining Treg based therapies with the appropriate co-stimulation blockade as a combination of IL2c and CD28-B7.1/2 co- stimulation blockade (CTLA-4 Ig) only resulted in slight prolongation of graft survival but not tolerance. The translation of tolerance induction therapies modelled in rodents into non-human primates or into clinical trials has seldom been successful. One main reason being the presence of pre-existing memory T- and B-cells due to acquired immunity in humans versus laboratory animals. Hence, we tested whether IL2c+MRl could promote graft survival in pre-sensitized mice. We found that in the presence of alloreactive memory T- and B-cells, IL2c+MRl combination therapy could prolong MHC-mismatched skin graft survival in immunocompetent mice but tolerance was lost compared to the naïve recipients. The addition of anti-LF A-1 treatment, which prevents the trafficking of memory T cells worked synergistically to significantly further enhance graft survival. However, late rejection mediated by activated/memory B cells and persistent donor-specific alloantibodies still occurred. Immunotherapeutic strategies targeting the activation of T cells are the cornerstone in the current immunosuppressive management after SOT. Therefore, in the next part of this thesis we investigated the paracaspase Malti-dependent T-cell receptor signalling as a novel immunosuppressive strategy to control alloreactive T cells in transplantation. We observed that although the inhibition of Malti downstream T signalling lead to tolerance of a minor H- mismatch skin grafts, it was however not sufficient to regulate alloresponses against MHC mismatches and only prolonged graft survival. Furthermore, we investigated the potential of more selectively targeting the protease activity of Malti. Constitutive inhibition of Malti protease activity in Malti-ki mice was detrimental to tolerance induction as it diminished Treg function and increased Thl alloreactivity. However, when using a small peptide inhibitor of Malti proteolytic activity in vitro, we observed an attenuation of alloreactive T cells and sparing of the pre-existing Treg pool. This indicates that further investigation of the role of Malti signalling in the field of transplantation is required. Collectively, the findings of this thesis provide immunological mechanisms underlying novel therapeutic strategies for the promotion of tolerance in SOT. Moreover, we highlight the importance of testing tolerance induction therapies in more physiological models with pre-existing alloreactive memory T and B cells.

The use of beta-blockers is associated with the occurrence of acute kidney injury in severe alcoholic hepatitis.

BACKGROUND & AIMS: The beneficial effect of nonselective beta-blockers (NSBB) has recently been questioned in patients with end-stage cirrhosis. We analysed the impact of NSBB on outcomes in severe alcoholic hepatitis (AH). METHODS: This study was based on a prospective database of patients with severe, biopsy-proven AH. Patients admitted from July, 2006 to July, 2014 were retrospectively studied. Patients were divided into two groups (with and without NSBB) and assessed for the occurrence of Acute Kidney Injury (AKI) and transplant-free mortality during a 168-day follow-up period. RESULTS: One hundred thirty-nine patients were included, the mean Maddrey score was 71 ± 34 and 86 patients (61.9%) developed AKI. Forty-eight patients (34.5%) received NSBB. The overall 168-day transplant-free mortality was 50.5% (95%CI, 41.3-60.0%). The overall 168-day cumulative incidence of AKI was 61.9% (95%CI, 53.2-69.4%). When compared, patients with NSBB had a lower heart rate (65 ± 13 vs 92 ± 12, P < 0.0001) and a lower mean arterial pressure (MAP, 78 ± 3 vs 87 ± 5, P < 0.0001). Patients with NSBB had comparable MELD scores, Maddrey scores, and medical histories. The 168-day transplant-free mortality was 56.8% (95%CI, 41.3-69.7%) in patients with NSBB and 46.7% (95%CI, 35.0-57.6%) without NSBB (P = 0.25). The 168-day cumulative incidence of AKI was 89.6% (95%CI, 74.9-95.9%) with NSBB compared to 50.4% (95%CI: 39.0-60.7) for no NSBB (P = 0.0001). The independent factors predicting AKI were a higher MELD score and the presence of NSBB. CONCLUSIONS: The use of NSBB in patients with severe AH is independently associated with a higher cumulative incidence of AKI.

Therapeutic drug monitoring of targeted anticancer therapy.

New oral targeted anticancer therapies are revolutionizing cancer treatment by transforming previously deadly malignancies into chronically manageable conditions. Nevertheless, drug resistance, persistence of cancer stem cells, and adverse drug effects still limit their ability to stabilize or cure malignant diseases in the long term. Response to targeted anticancer therapy is influenced by tumor genetics and by variability in drug concentrations. However, despite a significant inter-patient pharmacokinetic variability, targeted anticancer drugs are essentially licensed at fixed doses. Their therapeutic use could however be optimized by individualization of their dosage, based on blood concentration measurements via the therapeutic drug monitoring (TDM). TDM can increase the probability of therapeutic responses to targeted anticancer therapies, and would help minimize the risk of major adverse reactions.

New Algorithm for Managing Childhood Illness Using Mobile Technology (ALMANACH): A Controlled Non-Inferiority Study on Clinical Outcome and Antibiotic Use in Tanzania.

INTRODUCTION: The decline of malaria and scale-up of rapid diagnostic tests calls for a revision of IMCI. A new algorithm (ALMANACH) running on mobile technology was developed based on the latest evidence. The objective was to ensure that ALMANACH was safe, while keeping a low rate of antibiotic prescription. METHODS: Consecutive children aged 2-59 months with acute illness were managed using ALMANACH (2 intervention facilities), or standard practice (2 control facilities) in Tanzania. Primary outcomes were proportion of children cured at day 7 and who received antibiotics on day 0. RESULTS: 130/842 (15∙4%) in ALMANACH and 241/623 (38∙7%) in control arm were diagnosed with an infection in need for antibiotic, while 3∙8% and 9∙6% had malaria. 815/838 (97∙3%;96∙1-98.4%) were cured at D7 using ALMANACH versus 573/623 (92∙0%;89∙8-94∙1%) using standard practice (p<0∙001). Of 23 children not cured at D7 using ALMANACH, 44% had skin problems, 30% pneumonia, 26% upper respiratory infection and 13% likely viral infection at D0. Secondary hospitalization occurred for one child using ALMANACH and one who eventually died using standard practice. At D0, antibiotics were prescribed to 15∙4% (12∙9-17∙9%) using ALMANACH versus 84∙3% (81∙4-87∙1%) using standard practice (p<0∙001). 2∙3% (1∙3-3.3) versus 3∙2% (1∙8-4∙6%) received an antibiotic secondarily. CONCLUSION: Management of children using ALMANACH improve clinical outcome and reduce antibiotic prescription by 80%. This was achieved through more accurate diagnoses and hence better identification of children in need of antibiotic treatment or not. The building on mobile technology allows easy access and rapid update of the decision chart. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201011000262218.

Managing the Sick Child in the Era of Declining Malaria Transmission: Development of ALMANACH, an Electronic Algorithm for Appropriate Use of Antimicrobials.

OBJECTIVE: To review the available knowledge on epidemiology and diagnoses of acute infections in children aged 2 to 59 months in primary care setting and develop an electronic algorithm for the Integrated Management of Childhood Illness to reach optimal clinical outcome and rational use of medicines. METHODS: A structured literature review in Medline, Embase and the Cochrane Database of Systematic Review (CDRS) looked for available estimations of diseases prevalence in outpatients aged 2-59 months, and for available evidence on i) accuracy of clinical predictors, and ii) performance of point-of-care tests for targeted diseases. A new algorithm for the management of childhood illness (ALMANACH) was designed based on evidence retrieved and results of a study on etiologies of fever in Tanzanian children outpatients. FINDINGS: The major changes in ALMANACH compared to IMCI (2008 version) are the following: i) assessment of 10 danger signs, ii) classification of non-severe children into febrile and non-febrile illness, the latter receiving no antibiotics, iii) classification of pneumonia based on a respiratory rate threshold of 50 assessed twice for febrile children 12-59 months; iv) malaria rapid diagnostic test performed for all febrile children. In the absence of identified source of fever at the end of the assessment, v) urine dipstick performed for febrile children <2 years to consider urinary tract infection, vi) classification of 'possible typhoid' for febrile children >2 years with abdominal tenderness; and lastly vii) classification of 'likely viral infection' in case of negative results. CONCLUSION: This smartphone-run algorithm based on new evidence and two point-of-care tests should improve the quality of care of <5 year children and lead to more rational use of antimicrobials.

Use of asthma medication during pregnancy and risk of specific congenital anomalies: A European case-malformed control study.

BACKGROUND: Pregnant women with asthma need to take medication during pregnancy. OBJECTIVE: We sought to identify whether there is an increased risk of specific congenital anomalies after exposure to antiasthma medication in the first trimester of pregnancy. METHODS: We performed a population-based case-malformed control study testing signals identified in a literature review. Odds ratios (ORs) of exposure to the main groups of asthma medication were calculated for each of the 10 signal anomalies compared with registrations with nonchromosomal, nonsignal anomalies as control registrations. In addition, exploratory analyses were done for each nonsignal anomaly. The data set included 76,249 registrations of congenital anomalies from 13 EUROmediCAT registries. RESULTS: Cleft palate (OR, 1.63; 95% CI, 1.05-2.52) and gastroschisis (OR, 1.89; 95% CI, 1.12-3.20) had significantly increased odds of exposure to first-trimester use of inhaled β2-agonists compared with nonchromosomal control registrations. Odds of exposure to salbutamol were similar. Nonsignificant ORs of exposure to inhaled β2-agonists were found for spina bifida, cleft lip, anal atresia, severe congenital heart defects in general, or tetralogy of Fallot. None of the 4 literature signals of exposure to inhaled steroids were confirmed (cleft palate, cleft lip, anal atresia, and hypospadias). Exploratory analyses found an association between renal dysplasia and exposure to the combination of long-acting β2-agonists and inhaled corticosteroids (OR, 3.95; 95% CI, 1.99-7.85). CONCLUSIONS: The study confirmed increased odds of first-trimester exposure to inhaled β2-agonists for cleft palate and gastroschisis and found a potential new signal for renal dysplasia associated with combined long-acting β2-agonists and inhaled corticosteroids. Use of inhaled corticosteroids during the first trimester of pregnancy seems to be safe in relation to the risk for a range of specific major congenital anomalies.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients.

Patients with a solid organ transplant have increased in numbers and in individual survival in Switzerland over the last decades. As a consequence of long-term immunosuppression, skin cancer in solid organ recipients (SOTRs) has been recognized as an important problem. Screening and education of potential SOTRs about prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, SOTRs should be seen by a dermatologist yearly for repeat education as well as early diagnosis, prevention and treatment of skin cancer. Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in the setting of long-term immunosuppression. Sun protection by behaviour, clothing and daily sun screen application is the most effective prevention. Cumulative sun damage results in field cancerisation with numerous in-situ SCC such as actinic keratosis and Bowen's disease which should be treated proactively. Invasive SCC is cured by complete surgical excision. Early removal is the best precaution against potential metastases of SCC. Reduction of immunosuppression and switch to mTOR inhibitors and potentially, mycophenolate, may reduce the incidence of further SCC. Chemoprevention with the retinoid acitretin reduces the recurrence rate of SCC. The dermatological follow-up of SOTRs should be integrated into the comprehensive post-transplant care.

Giant warts in a kidney transplant patient: regression with sirolimus.

Purpose: Recent reports have suggested that intraabdominal postoperative infection is associated with higher rates of overall and local recurrence and cancer-specific mortality. However, the mechanisms responsible for this association are unknown. We hypothesized that the greater inflammatory response in patients with postoperative intraabdominal infection is associated to an increase in local and systemic angiogenesis. Methods: We designed a prospective cohorts study with matched controls. Patients with postoperative intra-abdominal infection (abscess and/or anastomotic leakage) (group 1; n=17) after elective colorectal cancer resection operated on for cure were compared to patients with an uncomplicated postoperative course (group 2; n=17). IL-6 and VEGF levels were determined by ELISA in serum and peritoneal fluid at baseline, 48 hours and postoperative day 4 or at the time the peritoneal infection occurred. Results: No differences were observed in age, gender, preoperative CEA, tumor stage and location and type of procedure performed. Although there were no differences in serum IL-6 levels at 48 hours, this pro-inflammatory cytokine was higher in group 1 on postoperative day 4 (group 1: 21533 + 27900 vs. group 2: 1130 + 3563 pg/ml; p < 0.001). Serum VEGF levels were higher in group 1 on postoperative day 4 (group 1: 1212 + 1025 vs. group 2: 408 + 407 pg/ml; p < 0.01). Peritoneal fluid VEGF levels were also higher in group 1 at 48 hours (group 1: 4857 + 4384 vs. group 2: 630 + 461 pg/ml; p < 0.001) and postoperative day 4 (group 1: 32807 + 98486 vs. group 2: 1002 + 1229 pg/ml; p < 0.001). A positive correlation between serum IL-6 and VEGF serum levels was observed on postoperative day 4 (r=0.7; p<0.01). Conclusions: These results suggest that not only the inflammatory response but also the angiogenic pathways are stimulated in patients with intra-abdominal infection after surgery for colorectal cancer. The implications of this finding on long-term follow-up need to be evaluated.

Perioperative antiplatelet therapy.

Aspirin is recommended as a lifelong therapy that should never be interrupted for patients with cardiovascular dis- ease. Clopidogrel therapy is mandatory for six weeks after placement of bare-metal stents, three to six months after myocardial infarction, and at least 12 months after placement of drug-eluting stents. Because of the hypercoagulable state induced by surgery, early withdrawal of antiplatelet therapy for secondary prevention of cardiovascular disease increases the risk of postoperative myocardial infarction and death five- to 10-fold in stented patients who are on continuous dual antiplatelet therapy. The shorter the time between revascularization and surgery, the higher the risk of adverse cardiac events. Elective surgery should be postponed beyond these periods, whereas vital, semiurgent, or urgent operations should be performed under continued dual antiplatelet therapy. The risk of surgical hemorrhage is increased approximately 20 percent by aspirin or clopidogrel alone, and 50 percent by dual antiplatelet therapy. The present clinical data suggest that the risk of a cardiovascular event when stopping antiplatelet agents preoperatively is higher than the risk of surgical bleeding when continuing these drugs, except during surgery in a closed space (e.g., intracranial, posterior eye chamber) or surgeries associated with massive bleeding and difficult hemostasis.

Diarrhées aiguës: propositions de prise en charge ambulatoire [Acute diarrhea: proposal for outpatient management]

Dans la majorité des cas, les diarrhées aiguës sont bénignes et d'évolution spontanément favorable. Il faut cependant savoir reconnaître les situations pouvant mener à des complications, en l'occurrence identifier les diarrhées invasives, inflammatoires, caractérisées par la présence de fièvre, de douleurs abdominales, de ténesmes, de mucus et, ou de sang dans les selles. Celles-ci sont à distinguer des diarrhées sécrétoires, non invasives, non inflammatoires, sans fièvre, généralement aqueuses et volumineuses. En cas de doute diagnostique, l'identification de leucocytes par microscopie ou test à la lactoferrine dans les selles permet d'évoquer une gastroentérite invasive. Les indications à une antibiothérapie empirique dans l'attente du résultat de la coproculture sont la présence d'un syndrome dysentérique (T > 38°C, > 6 selles/24 heures, douleurs abdominales, diarrhées mucopurulentes), l'âge avancé, des comorbidités significatives, une immunosuppression et la présence d'une prothèse endovasculaire. In the majority of the cases, an acute diarrhea is mild and of spontaneously favorable evolution. It is however necessary to know how to recognize the situations being able to lead to complications, in particular to identify the invasive, inflammatory diarrheas, characterized by the presence of fever, abdominal pains, mucus and\or blood. The identification of leukocytes by microscopy or lactoferrine test is helpful. Empiric quinolones treatment is recommended in the presence of dysenteric syndrome (T > 38 degrees C, > 6 stods/24 h 00, abdominal pain muco-purulent diarrhea), advanced age, significant comorbidities, immunosuppression or presence of an endovascular prothesis