First-line treatment using high-flow nasal cannula for children with severe bronchiolitis: Applicability and risk factors for failure.

BACKGROUND: Viral bronchiolitis is the leading cause of hospitalization in children during the first 12 months of life. There is evidence to support the use of noninvasive ventilation in bronchiolitis. A recent respiratory management of bronchiolitis is the use of high-flow nasal cannula (HFNC) therapy. The primary objective of this study was to evaluate the use of HFNC as the first-line treatment for children with severe bronchiolitis and the secondary objective was to identify factors for HFNC therapy failure. METHODS: Observational prospective study in a pediatric intensive care unit (PICU), during two consecutive seasons (2013-2014 without recommendation and 2014-2015 with a study design suggesting HFNC as first-line treatment). The percentages of children treated with HFNC, nasal continuous or biphasic positive airway pressure (nCPAP/BiPAP) and invasive ventilation were compared. Associations between parameters recorded and HFCN therapy failure were established. RESULTS: The percentage of patients treated with HFNC at admission was higher during the second season (90%, n=55/61) than the first season (34%, n=14/41) (p<0.0001). In bivariate analysis, heart rate, pH, and pCO2 were significantly associated with the occurrence of HFNC therapy failure in time-varying Cox regression models using all available values (i.e., admission and repeated measures during the first 5 days of hospitalization). Only pCO2 remained independently associated as a factor of HFNC failure in the multivariate Cox model with a hazard ratio per 5mmHg of 1.37 (95%CI: 1.01-1.87; P=0.046). CONCLUSION: In our PICU, HFNC therapy for children with bronchiolitis can potentially decrease the use of nCPAP. In this study, the factor of failure was higher pCO2. Studies to evaluate PCO2 level to discriminate HFNC versus CPAP indication could be useful.

Low immunoglobulin E flags two distinct types of immune dysregulation.

During the last two decades, hyper-immunoglobulin (Ig)E syndromes have been characterized clinically and molecularly in patients with genetically determined primary immunodeficiencies. However, the detection of low IgE levels, defined here as below detection limit in the routine clinical immunology laboratory, has received little attention. We analysed the association of serum IgA, IgM and IgG levels (including IgG subclasses) with low, normal or high serum IgE levels in patients evaluated in a single-centre out-patient immunodeficiency and allergy clinic. The correlation of serum IgE levels with IgG subclasses depended on the clinical phenotype. In patients with immunodeficiencies, IgE correlated with IgG2 and IgG4 but not with IgG3. In contrast, in patients referred for signs of allergy, IgE correlated with IgG3 but not with IgG2. A low IgE result was associated with low IgG3 and IgG4 in allergy referrals, while immunodeficiency referrals with a low IgE result had significantly lower IgG1, IgG2 and IgG4 levels. Hierarchical clustering of non-IgE immunoglobulin profiles (IgM, IgA, IgG, IgG1-4) validated that non-IgE immunoglobulin levels predict the clinic referral, i.e. phenotype, of low-IgE patients. These results suggesto guide the clinical management of patients with low serum IgE levels.

The Swiss National Registry for Primary Immunodeficiencies: report on the first 6 years' activity from 2008 to 2014.

The Swiss National Registry for Primary Immunodeficiency Disorders (PID) was established in 2008, constituting a nationwide network of paediatric and adult departments involved in the care of patients with PID at university medical centres, affiliated teaching hospitals and medical institutions. The registry collects anonymized clinical and genetic information on PID patients and is set up within the framework of the European database for PID, run by the European Society of Immunodeficiency Diseases. To date, a total of 348 patients are registered in Switzerland, indicating an estimated minimal prevalence of 4·2 patients per 100 000 inhabitants. Distribution of different PID categories, age and gender are similar to the European cohort of currently 19 091 registered patients: 'predominantly antibody disorders' are the most common diseases observed (n = 217/348, 62%), followed by 'phagocytic disorders' (n = 31/348, 9%). As expected, 'predominantly antibody disorders' are more prevalent in adults than in children (78 versus 31%). Within this category, 'common variable immunodeficiency disorder' (CVID) is the most prevalent PID (n = 98/217, 45%), followed by 'other hypogammaglobulinaemias' (i.e. a group of non-classified hypogammaglobulinaemias) (n = 54/217, 25%). Among 'phagocytic disorders', 'chronic granulomatous disease' is the most prevalent PID (n = 27/31, 87%). The diagnostic delay between onset of symptoms and diagnosis is high, with a median of 6 years for CVID and more than 3 years for 'other hypogammaglobulinaemias'.

Risk factors for pneumocystis pneumonia in giant cell arteritis: a single-centre cohort study.

OBJECTIVES: Pneumocystis jiroveci pneumonia (PCP) is a life-threatening opportunistic infection. Few PCP cases in giant cell arteritis (GCA) have been described, but it remains unknown, which patients need PCP prophylaxis. METHODS: Sixty-two patients with GCA from a prospective cohort were studied to identify treatment-related predictors of PCP infection. RESULTS: Four PCP infections occurred, all in patients treated with methotrexate in addition to prednisone. Moreover, PCP is associated with higher cumulative PDN doses and severe lymphocytopenia (<400/µl). CONCLUSIONS: Our findings support PCP-prophylaxis in GCA patients who are treated with methotrexate and PDN, and need high prednisone doses to achieve remission, or develop severe lymphocytopenia.

Toso regulates differentiation and activation of inflammatory dendritic cells during persistence-prone virus infection.

During virus infection and autoimmune disease, inflammatory dendritic cells (iDCs) differentiate from blood monocytes and infiltrate infected tissue. Following acute infection with hepatotropic viruses, iDCs are essential for re-stimulating virus-specific CD8(+) T cells and therefore contribute to virus control. Here we used the lymphocytic choriomeningitis virus (LCMV) model system to identify novel signals, which influence the recruitment and activation of iDCs in the liver. We observed that intrinsic expression of Toso (Faim3, FcµR) influenced the differentiation and activation of iDCs in vivo and DCs in vitro. Lack of iDCs in Toso-deficient (Toso(-/-)) mice reduced CD8(+) T-cell function in the liver and resulted in virus persistence. Furthermore, Toso(-/-) DCs failed to induce autoimmune diabetes in the rat insulin promoter-glycoprotein (RIP-GP) autoimmune diabetes model. In conclusion, we found that Toso has an essential role in the differentiation and maturation of iDCs, a process that is required for the control of persistence-prone virus infection.

Reactive oxygen species delay control of lymphocytic choriomeningitis virus.

Cluster of differentiation (CD)8(+) T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8(+) T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1(-/-)) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.

Innate (over)immunity and adaptive autoimmune disease.

Autoimmune disease is characterized by clinical symptoms mediated by adaptive (T cell and B cell) immune reactions towards autoantigen-expressing tissue. Here we discuss that autoimmune disease is often preceded by autoreactivity, meaning the priming of autoantigen-specific immune cells without relevant tissue damage. Recent experimental evidence has demonstrated that both the induction of autoreactivity and the conversion into autoimmune disease is controlled by the activation of the nonspecific innate immune system. Also, the "inflammatory status" of the target organ critically influences the onset of overt autoimmune disease.