International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges.

Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.

International Society for Cell & Gene Therapy Position Paper: Key considerations to support evidence-based cell and gene therapies and oppose marketing of unproven products.

The field of regenerative medicine, including cellular immunotherapies, is on a remarkable growth trajectory. Dozens of cell-, tissue- and gene-based products have received marketing authorization worldwide while hundreds-to-thousands are either in preclinical development or under clinical investigation in phased clinical trials. However, the promise of regenerative therapies has also given rise to a global industry of direct-to-consumer offerings of prematurely commercialized cell and cell-based products with unknown safety and efficacy profiles. Since its inception, the International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy has opposed the premature commercialization of unproven cell- and gene-based interventions and supported the development of evidence-based advanced therapy products. In the present Guide, targeted at International Society for Cell & Gene Therapy members, we analyze this industry, focusing in particular on distinctive features of unproven cell and cell-based products and the use of tokens of scientific legitimacy as persuasive marketing devices. We also provide an overview of reporting mechanisms for patients who believe they have been harmed by administration of unapproved and unproven products and suggest practical strategies to address the direct-to-consumer marketing of such products. Development of this Guide epitomizes our continued support for the ethical and rigorous development of cell and cell-based products with patient safety and therapeutic benefit as guiding principles.

Patient access to and ethical considerations of the application of the European Union hospital exemption rule for advanced therapy medicinal products.

Hospital exemption (HE) is a regulated pathway that allows the use of advanced therapy medicinal products (ATMPs) within the European Union (EU) under restrictive conditions overseen by national medicine agencies. In some EU countries, HE is granted for ATMPs with no demonstrated safety and efficacy; therefore, they are equivalent to investigational drugs. In other countries, HE is granted for ATMPs with demonstrated quality, safety and efficacy and for which centralized marketing authorization has not been requested. The Committee on the Ethics of Cell and Gene Therapy of the International Society for Cell & Gene Therapy reflects here on the ethical issues concerning HE application from the perspective of the patient, including risk-benefit balance, accessibility and transparency, while providing evidence that HE must not be regarded as a conduit for unproven and unethical ATMP-based interventions. Indeed, HE represents a legal instrument under which a patient's need for access to novel ATMPs is reconciled with ethics. Moreover, for some unmet medical needs, HE is the only pathway for accessing innovative ATMPs. Nonetheless, HE harmonization across EU Member States and limitations of ATMP use under the HE rule when similar products have already been granted centralized marketing authorization to avoid a parallel regulatory pathway are controversial issues whose political and economic consequences are beyond the scope of this review. Finally, the institution of an EU registry of HE applications and outcomes represents a priority to improve transparency, reduce patient risks, increase efficiency of health systems, facilitate company awareness of business opportunities and boost progressive entry of ATMPs into the therapeutic repertoire of health systems.

Seroprevalence and epidemiology of hepatitis B and C viruses in pregnant women in Spain. Risk factors for vertical transmission.

BACKGROUND & AIM: Worldwide, measures are being implemented to eradicate hepatitis B (HBV) and C (HCV) viruses, which can be transmitted from the mother during childbirth. This study aims to determine the prevalence of HBV and HCV in pregnant women in Spain, focusing on country of origin, epidemiological factors and risk of vertical transmission (VT). METHODOLOGY: Multicentre open-cohort study performed during 2015. HBV prevalence was determined in 21870 pregnant women and HCV prevalence in 7659 pregnant women. Epidemiological and risk factors for VT were analysed in positive women and differences between HBV and HCV cases were studied. RESULTS: HBV prevalence was 0.42% (91/21870) and HCV prevalence was 0.26% (20/7659). Of the women with HBV, 65.7% (44/67) were migrants. The HBV transmission route to the mother was unknown in 40.3% of cases (27/67) and VT in 31.3% (21/67). Among risk factors for VT, 67.7% (42/62) of the women had viraemia and 14.5% (9/62) tested HBeAg-positive. All of the neonates born to HBV-positive mothers received immunoprophylaxis, and none contracted infection by VT. In 80% (16/20) of the women with HCV, the transmission route was parenteral, and nine were intravenous drug users. Viraemia was present in 40% (8/20) of the women and 10% (2/20) were HIV-coinfected. No children were infected. Women with HCV were less likely than women with HBV to breastfeed their child (65% vs. 86%). CONCLUSIONS: The prevalences obtained in our study of pregnant women are lower than those previously documented for the general population. Among the women with HBV, the majority were migrants and had a maternal family history of infection, while among those with HCV, the most common factor was intravenous drug use. Despite the risk factors observed for VT, none of the children were infected. Proper immunoprophylaxis is essential to prevent VT in children born to HBV-positive women.

Effectiveness of a hand hygiene program to reduce acute gastroenteritis at child care centers: A cluster randomized trial.

We aimed to assess the effectiveness of an educational and hand hygiene program in daycare centers (DCCs) and homes on acute gastroenteritis (AGE) incidence in children attending DCCs. METHODS: A randomized, controlled, and open study of 911 children aged 0-3 years attending 24 DCCs in Almería (Spain) with an 8-month follow-up was employed. Two intervention groups of DCCs families performed educational and hand hygiene measures, 1 with soap and water (soap and water group; n = 274), another with hand sanitizer (hand sanitizer group [HSG]; n = 339), and the control group (CG; n = 298) followed usual handwashing procedures. We compared AGE episode rates with Poisson regression model. RESULTS: seven hundred fourteen AGE episodes were registered, significant differences between HSG and CG children were found during December and January. A multivariate model was applied and the adjusted incidence rate ratios by rotavirus vaccination found significant differences when children were previously vaccinated, the children in the soap and water group had a higher risk of AGE episodes (incidence rate ratio: 1.28, 95% confidence interval:1.0-1.64), compared with those in the HSG. CONCLUSIONS: This study demonstrated that hand hygiene programs that included hand sanitizer were most effective in the winter months. Further, the largest reduction of AGE episodes occurred in the children that followed hand hygiene programs including hand sanitizer and educational measures for DCC staff, parents, and children, and were vaccinated for rotavirus.

Regulatory T Cell Therapy for Uveitis: A New Promising Challenge.

Uveitis is a sight-threatening primary intraocular inflammation of various origins in mainly young and active patients. Due to the absence of biomarkers in most of the cases, the current treatment of noninfectious entities remains nonspecific, using corticosteroids, conventional immunosuppressors, and more recently biological agents. Identification of regulatory T cells in different models of autoimmune uveitis together with the evaluation of this important subpopulation in different entities paved the way for new therapeutic strategies, in addition to exclusive pharmaceutical approaches. Upregulation of regulatory T cells induced by biological agents has been recently highlighted. Development of cell therapy in autoimmune diseases is at its stammering needing more experimental data and robust clinical trials to demonstrate safety and efficacy before larger developments. Specific or polyclonal Tregs may be used, but it is of utmost importance to determine the method of selection, the level of activation, and the route of administration. Mastering immune cell therapy remains a challenging goal in patients with autoimmune diseases, but it may significantly enlarge our therapeutic possibilities in severe and refractory situations.

The path to successful commercialization of cell and gene therapies: empowering patient advocates.

Often, novel gene and cell therapies provide hope for many people living with incurable diseases. To facilitate and accelerate a successful regulatory approval and commercialization path for effective, safe and affordable cell and gene therapies, the involvement of patient advocacy groups (PAGs) should be considered early in the development process. This report provides a thorough overview of the various roles PAGs play in the clinical translation of cell and gene therapies and how they can bring about positive changes in the regulatory process, infrastructure improvements and market stability.

Impact of vaccination uptake on hospitalizations due to rotavirus acute gastroenteritis in 2 different socioeconomic areas of Spain.

Rotavirus is the leading cause of hospitalization due to acute gastroenteritis (AGE) in infants and toddlers. However, rotavirus vaccination has been associated with a decline in hospitalization rates due to rotavirus AGE. A descriptive retrospective study was conducted to analyze the impact of rotavirus vaccination on the rate of hospitalizations due to AGE among children ≤2 years old in 2 areas of the province of Almería, Spain. After eight years of rotavirus vaccination, rates of hospitalizations due to rotavirus AGE are diminished. This decline is closely related to vaccine coverage in the studied areas.

Science, ethics and communication remain essential for the success of cell-based therapies.

Cell-based therapeutics, such as marrow or peripheral blood stem cell transplantation, are a standard of care for certain malignancies. More recently, a wider variety of cell-based therapeutics including the use of mesenchymal stromal/stem cells, T-cells, and others show great promise in a wider range of diseases. With increased efforts to expand cell-based treatments to several clinical settings, many institutions around the world have developed programs to explore cellular therapy's potential for safe and effective applications. In legitimate investigations, usually conducted through academic centers or biotechnology industry-sponsored efforts, these studies are regulated and peer-reviewed to ensure safety and clear determination of potential efficacy. However, in some cases, the use of cell-based approaches is conducted with insufficient preclinical data, scientific rationale, and/or study plan for the diseases claimed to be treated, with patients being charged for these services without clear evidence of clinical benefit. In this context, patients may not be properly informed regarding the exact treatment they are receiving within a consenting process that may not be completely valid or ethical. Here, the authors emphasize the importance of distinguishing "proven cell-based therapies" from "unproven" and unauthorized cell-based therapies. This publication also addresses the necessity for improved communication between the different stakeholders in the field, patient associations, and advocacy groups in particular, to favor medical innovation and provide legitimate benefits to patients. Considering the progressive growth of cell-based treatments, their increasing therapeutic value and the expectation that society has about these therapies, it is critically important to protect patients and ensure that the risk/benefit ratio is favorable. This paper is a review article. Literature referred to in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching PubMed. Some original points in this article come from the laboratory practice in our research centers and the authors' experiences.

Different penetrance of disseminated infections caused by nontuberculous Mycobacteria in Mendelian susceptibility to mycobacterial disease associated with a novel mutation.

Deficiency in the interleukin12/INFgamma pathway is a genetic condition that predisposes to some infections, including nontuberculous mycobacteria infection and extraintestinal salmonellosis. We report 2 cases in sisters who were diagnosed with a genetic defect caused by a new mutation in Interleukin-12 receptor ß1 chain (IL12Rß1) leading to different clinical presentations and responses to therapy.

[Clinical and epidemiological differences between Bordetella pertussis and respiratory syncytial virus infections in infants: a matched case control study]. / Diferencias clínicas y epidemiológicas entre las infecciones por Bordetella pertussis y por virus respiratorio sincitial en lactantes: estudio de casos controles emparejados.

INTRODUCTION: An increase in cases of pertussis, mainly in young infants, has been reported in the last few years. The clinical presentation of this disease is very similar to that produced by respiratory syncytial virus (RSV), which makes the diagnosis difficult. OBJECTIVE: To compare the clinical and epidemiological characteristics between Bordetella pertussis and RSV infections in infants admitted to hospital. MATERIAL AND METHODS: An analytical matched case-control study was conducted during the period 2008-2011. Cases were defined as infants admitted with pertussis confirmed by PCR in nasopharyngeal aspirate. Each case was matched by age, sex and date of admission to two controls defined as patients with RSV infection detected by immunochromatography in nasal aspirate. Demographic, clinical, laboratory data were compared. RESULTS: Seventy eight patients (26 cases of pertussis and 52 controls RSV+) were included. Sociodemographic characteristics were similar in both groups. Cases had more days of symptoms prior to admission, longer hospital stays, and increased frequency of epidemic family environment. Apnoea and cyanosis were more frequent. Cases of pertussis were more likely to have apnoea, cyanosis, and lymphocytosis while RSV infections had more frequent fever, vomiting and respiratory distress. CONCLUSIONS: The clinical presentations of pertussis and RSV infection are similar, but there are some characteristics that can help to distinguish between them.

Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease.

BACKGROUND & AIMS: New therapeutic strategies are needed for patients with refractory Crohn's disease (CD). We evaluated data from the Crohn's And Treg Cells Study (CATS1) to determine the safety and efficacy of antigen-specific T-regulatory (Treg) cells for treatment of patients with refractory CD. METHODS: We performed a 12-week, open-label, multicenter, single-injection, escalating-dose, phase 1/2a clinical study in 20 patients with refractory CD. Ovalbumin-specific Treg cells (ova-Tregs) were isolated from patients' peripheral blood mononuclear cells (PBMCs), exposed to ovalbumin, and administrated intravenously. Safety and efficacy were assessed using clinical and laboratory parameters. We evaluated proliferation of PBMCs in response to ovalbumin. RESULTS: Injections of ova-Tregs were well tolerated, with 54 adverse events (2 related to the test reagent) and 11 serious adverse events (3 related to the test reagent, all recovered). Overall, a response, based on a reduction in Crohn's Disease Activity Index (CDAI) of 100 points, was observed in 40% of patients at weeks 5 and 8. Six of the 8 patients (75%) who received doses of 10(6) cells had a response at weeks 5 and 8, with a statistically significant reduction in CDAI. In this group, remission (based on CDAI ≤150) was observed in 3 of 8 patients (38%) at week 5 and 2 of 8 patients (25%) at week 8. CONCLUSIONS: Administration of antigen-specific Tregs to patients with refractory CD (CATS1) was well tolerated and had dose-related efficacy. The ovalbumin-specific immune response correlated with clinical response, supporting immune-suppressive mechanisms of ova-Tregs. The consistency of results among different assessment methods supports the efficacy of ova-Tregs; this immune therapy approach warrants further clinical and mechanistic studies in refractory CD. Eudract, Number: 2006-004712-44.

Cholestasis as the initial feature of Kawasaki disease.

Hepatobiliary involvement is uncommon in Kawasaki disease, and it is usually described as obstructive jaundice. From January 01, 2000 to August 31, 2010, 31 Kawasaki disease cases were diagnosed in our center. Three of them (9.7%) developed jaundice, but there were no gallbladder or bile duct abnormalities by ultrasonography, a feature rarely reported. Resolution of cholestasis paralleled improvement of the illness.