Biomarkers in sepsis and other severe infections

Infectious diseases constitute a major global health problem. The presenting clinical picture results from a mixture of direct toxic actions by the microbiological agent and of the immune response mounted by the host. There is often a rapid onset, which may constitute a diagnostic and therapeutic challenge, whereas in other cases an extensive investigation over a long time period can fail to identify a causal microbial agent. The aim with this thesis was to study the cellular immune response with phenotypical assays, in patients with severe infections with focus on sepsis. We assessed if our findings could serve as biomarkers and provide valuable diagnostic and possible also therapeutic information. In the first part (paper I) we examined surface markers on white blood cells from patients with severe infections. In some instances our analysis could differentiate between infections of bacterial and viral origin. In the second part (paper II-IV) we examined the incidence and nature of the immune alterations found in patients with sepsis and septic shock. We identified a protein (Wnt5a) that inhibited differentiation of monocytes to monocyte-derived myeloid dendritic cells (Mo-mDC), which may play a role in the DC depletion often seen in sepsis. Also, as indicated by cell surface phenotype, a large inter-individual variation of immune activation and immunosuppression was detected in patients with sepsis, with a dominance of immunosuppression in patients with septic shock. Finally, different types of immature myeloid immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) were found in patients with sepsis; Mo-MDSCs were preferentially expanded in patients with gram-negative sepsis, whereas granulocytic MDSCs (PMN-MDSCs) accumulated in patients with gram-positive sepsis. We conclude that the immune response during severe infections shows large inter-individual variations and biomarker guided therapy could be useful in individualised treatment

‘Managing pieces of a personal puzzle’ — older people’s experiences of self-management falls prevention exercise guided by a digital program or a booklet

Background: Exercise is effective in order to prevent falls in community-dwelling older people. Self-management programs have the potential to increase access and reduce costs related to exercise-based fall prevention. However, information regarding older people's views of participating in such programs is needed to support implementation. The aim of this study was to explore older people's experiences of a self-management fall prevention exercise routine guided either by a digital program (web-based or mobile) or a paper booklet. Methods: This qualitative study was part of a feasibility study exploring two completely self-managed exercise interventions in which the participants tailored their own program, guided either by a digital program or a paper booklet. Individual face-to-face semi-structured interviews were conducted with a purposeful sample of 28 participants (18 women), mean age 76yrs. Qualitative content analysis was used to analyse the data. Results: Self-managing and self-tailoring these exercise programs was experienced as Managing pieces of a personal puzzle'. To independently being able to create a program and manage exercise was described in the categories Finding my own level' and Programming it into my life'. The participants experienced the flexibility and independence provided by completely self-managed exercise as positive and constructive although it required discipline. Furthermore, different needs and preferences when managing their exercise were described, as well as varying sources of motivation for doing the exercise, as highlighted in the category Defining my source of motivation'. The category Evolving my acquired knowledge' captures the participants' views of building their competence and strategies for maintenance of the exercise. It describes a combined process of learning the program and developing reflection, which was more clearly articulated by participants using the digital program. Conclusions: This study provides new knowledge regarding experiences, preferences and motivations of older people to engage in home-based self-managed fall prevention exercise. They expressed both a capability and willingness to independently manage their exercise. A digital program seems to have strengthened the feeling of support while creating their own exercise program and tailoring it to their preferences and circumstances, which might therefore create better opportunities for adoption and adherence in the long term

Lymphocyte and monocyte flow cytometry immunophenotyping as a diagnostic tool in uncharacteristic inflammatory disorders

<p>Abstract</p> <p>Background</p> <p>Patients with uncharacteristic inflammatory symptoms such as long-standing fatigue or pain, or a prolonged fever, constitute a diagnostic and therapeutic challenge. The aim of the present study was to determine if an extended immunophenotyping of lymphocytes and monocytes including activation markers can define disease-specific patterns, and thus provide valuable diagnostic information for these patients.</p> <p>Methods</p> <p>Whole blood from patients with gram-negative bacteraemia, neuroborreliosis, tuberculosis, acute mononucleosis, influenza or a mixed connective tissue disorders, as diagnosed by routine culture and serology techniques was analysed for lymphocyte and monocyte cell surface markers using a no-wash, no-lyse protocol for multi-colour flow cytometry method. The immunophenotyping included the activation markers HLA-DR and CD40. Plasma levels of soluble TNF alpha receptors were analysed by ELISA.</p> <p>Results</p> <p>An informative pattern was obtained by combining two of the analysed parameters: (i), the fractions of HLA-DR-expressing CD4+ T cells and CD8+ T cells, respectively, and (ii), the level of CD40 on CD14+ CD16- monocytes. Patients infected with gram-negative bacteria or EBV showed a marked increase in monocyte CD40, while this effect was less pronounced for tuberculosis, borrelia and influenza. The bacterial agents could be distinguished from the viral agents by the T cell result; CD4+ T cells reacting in bacterial infection, and the CD8+ T cells dominating for the viruses. Patients with mixed connective tissue disorders also showed increased activation, but with similar engagement of CD4+ and CD8+ T cells. Analysis of soluble TNF alpha receptors was less informative due to a large inter-individual variation.</p> <p>Conclusion</p> <p>Immunophenotyping including the combination of the fractions of HLA-DR expressing T cell subpopulations with the level of CD40 on monocytes produces an informative pattern, differentiating between infections of bacterial and viral origin. Furthermore, a quantitative analysis of these parameters revealed the novel finding of characteristic patterns indicating a subacute bacterial infection, such as borreliosis or tuberculosis, or a mixed connective tissue disorder. The employed flow cytometric method is suitable for clinical diagnostic laboratories, and may help in the assessment of patients with uncharacteristic inflammatory symptoms.</p

A prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD:The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study

Introduction: Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites.Methods and analysis: 3 cohorts of children and adolescents (aged 6–17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score.Ethics and dissemination: Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public.Trial registration number: NCT01470261.<br/

ADHD in children and young people: prevalence, care pathways & service provision

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common childhood behavioural disorder – systematic reviews indicate that the community prevalence of ADHD globally is between 2% to 7%, with an average of around 5%. In addition, a further 5% of children have significant difficulties with over-activity, inattention and impulsivity that are just sub-threshold to meet full diagnostic criteria for ADHD. Estimates of the administrative (clinically diagnosed and/or recorded) prevalence vary worldwide and although increasing over time, ADHD is still relatively under-recognised and under-diagnosed in most countries, particularly in girls and older children. ADHD often persists into adulthood and is a risk factor for other mental health disorders and negative outcomes including educational under-achievement, difficulties with employment and relationships, and criminality. The timely recognition and treatment of children with ADHD-type difficulties provides an opportunity to improve their long-term outcomes. This review includes a systematic review of the community and administrative prevalence of ADHD in children and adolescents; an overview of the barriers to accessing care for ADHD; a description of costs associated with ADHD; and a broad discussion of evidence-based pathways for the delivery of clinical care, including a focus on key issues for two specific age groups - pre-school children and adolescents requiring transition of care from child to adult services

Highlighting the Role of Biomarkers of Inflammation in the Diagnosis and Management of Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is characterized by continuous pain that is often accompanied by sensory, motor, vasomotor, sudomotor, and trophic disturbances. If left untreated, it can have a significant impact on the quality of life of patients. The diagnosis of CRPS is currently based on a set of relatively subjective clinical criteria: the New International Association for the Study of Pain clinical diagnostic criteria for CRPS. There are still no objective laboratory tests to diagnose CRPS and there is a great need for simple, objective, and easily measurable biomarkers in the diagnosis and management of this disease. In this review, we discuss the role of inflammation in the multi-mechanism pathophysiology of CRPS and highlight the application of potential biomarkers of inflammation in the diagnosis and management of this disease