The first wheezing episode in small children : virus etiology, clinical characteristics and one-year outcome

Background: Early wheezing induced by rhinovirus infection has been recognized as an important risk factor for recurrent wheezing and asthma. Different rhinovirus species may also vary in their pathogenicity to cause severe illness. Oral corticosteroid has been shown to decrease the risk for recurrent wheezing episodes after the early rhinovirus induced wheezing. However, limited data exist on the first wheezing episode induced by rhinovirus. Aims and methods: The aim of this thesis was to study the virus etiology of the first wheezing episode in small children by using PCR methods, as well as to specify the role of rhinoviruses in wheezing. Rhinovirus species were analyzed using sequencing and their association with atopic characteristics in small children was studied. The one-year virus surveillance was conducted focusing on rhinoviruses. The efficacy of oral corticosteroid, prednisolone, on short- and long-term outcomes was investigated using randomized controlled trial conducted in children of 3-23 months of age. Results: Rhinovirus infection was found in 76% of children aged 3-23 months experiencing their first wheezing episode. Rhinovirus induced first wheezing episode was positively associated with atopic characteristics and prolonged cough. Of the rhinovirus species, rhinovirus C (58%) was the most common, followed by rhinovirus A (21%) and B (1.2%). Atopic characteristics and illness severity factors were more common with rhinovirus A and C than with other respiratory infections. Children with rhinovirus A or C infection had an increased risk for recurrent wheezing episodes and the initiation of regular controller medication for asthma symptoms. Children with high rhinovirus load benefitted from prednisolone in long- and short-term outcomes. Conclusions: Rhinovirus is a common pathogen in causing the first wheezing episodes in 3 -23 months old children. In wheezing children, the most important rhinovirus species are A and C. These species are associated with a high recurrence rate. Prednisolone might be effective in a subgroup of first-time wheezing children with a high rhinovirus load.Pikkulasten ensimmäinen akuutti uloshengitysvaikeus: virusetiologia, kliininen taudinkuva ja yhden vuoden seuranta Tausta: Varhainen rinoviruksen aiheuttama akuutti uloshengitysvaikeus on merkittävä riskitekijä toistuville uloshengitysvaikeuksille ja astmalle. Eri rinovirusgenotyypit voivat myös vaikuttaa taudin vaikeusasteeseen. Suun kautta otetun kortikosteroidin on osoitettu vähentävän riskiä uloshengitysvaikeuksien toistuvuudelle rinoviruksen aiheuttaman kohtauksen jälkeen. Ensimmäistä akuuttia uloshengitysvaikeutta on kuitenkin tutkittu vielä vähän. Tavoitteet ja menetelmät: Väitöskirjatutkimuksessa tutkittiin ensimmäisen akuutin uloshengitysvaikeuden virusetiologiaa pienillä lapsilla ja rinoviruksen merkitystä akuutissa kohtauksessa. Rinoviruksen genotyypit analysoitiin sekvensoimalla ja niiden yhteyttä atooppisiin piirteisiin analysoitiin. Virusetiologia tutkittiin vuoden seurannassa keskittyen erityisesti rinovirusinfektioiden toistuvuuteen. Prednisolonin teho lyhyen ja pitkän aikavälin tuloksiin analysoitiin käyttäen randomisoitua kontrolloitua tutkimusta 3-23 kuukauden ikäisillä lapsilla. Tulokset: Rinovirus löytyi 76 %:lta ensimmäistä infektioon liittyvää uloshengitysvaikeutta sairastavalta lapselta, jotka olivat iältään 3-23 kuukautta. Rinoviruksen aiheuttama ensimmäinen akuutti uloshengitysvaikeus oli yhteydessä atooppisiin piirteisiin ja pitkittyneeseen yskään. Yleisimmin löytyi rinovirus C ryhmän viruksia (58%), toiseksi yleisimmin A ryhmän viruksia (21%) ja kolmanneksi rinovirus B ryhmän viruksia (1.2%). Atooppiset piirteet ja vaikeampi taudinkuva olivat yhteydessä rinovirus A ja C aiheuttamaan infektioon. Niillä lapsilla, joilla ensimmäisen uloshengitysvaikeusepisodin aiheuttajana oli rinovirus A tai C, olin enemmän uusitumisia kuin muilla lapsilla, joilla aihettajana oli joku muu virus. Lapset, joilla rinoviruksen määrä hengitystie-eritteessä oli suuri, hyötyivät prednisolonista.Johtopäätökset: Rinovirus on merkittävä patogeeni ensimmäisessä akuutissa uloshengitysvaikeudessa 3 – 23 kuukauden ikäisillä lapsilla. Näillä lapsilla yleisimmät rinoviruksen genotyypit ovat A ja C, jotka ovat yhteydessä myös riskiin kohtauksien toistumiselle. Prednisolonista hyötyvät lapset, joilla viruksen määrä on suuri ensimmäisessä akuutissa uloshengitysvaikeuskohtauksessa.Siirretty Doriast

Yhteisöllisyyteen tähtäävien oheispalvelujen kehittäminen käyttäjälähtöisesti Esimerkkinä Lauttasaaren seurakunnan Kirkkokahvila

Tämän opinnäytetyön tarkoituksena oli kehittää Lauttasaaren seurakunnan kahvilaan oheis-palvelujen toimintamalli, jonka tavoitteena on luoda yhteisöllisyyttä lauttasaarelaisten asukkaiden arkeen. Tavoitteena oli löytää oheistoimintoja, joita voidaan tarjota kahvilan muiden toimintojen ohessa ja joista asiakkaat ovat kiinnostuneita myös muutoin kuin kirkolliseen toimintaan liittyvänä. Tähän asti seurakunnassa ei ole ollut kahvilapalveluita kaikkien asiakkaiden saatavilla kuin vasta koeluontoisesti keväästä 2012 alkaen. Työ toteutettiin koeasiakkuuksien, havainnointien, erilaisten haastattelujen ja kyselyn sekä ideariihen avulla. Kehittämisprosessissa käytettiin Stefan Moritzin palvelumuotoilun prosessimallia, jonka avulla saatiin selville kehitettäviä kohteita. Opinnäytetyö on laadullisella tutkimusotteella toteutettu kehittämishanke, jossa keskeisenä tutkimusmenetelmänä käytettiin haastatteluja. Haastattelut toteutettiin kvalitatiivisten haastattelulomakkeiden avulla. Määrällistä tutkimustapaa käytettiin tehtäessä gallup- kyselyitä lauttasaarelaisille asukkaille. Haastattelujen ja kyselyjen tuloksista kävi ilmi asukkaiden kokoontumispaikan tarve ja seurakunnan kahvilan tilat sopivat tähän tarkoitukseen. Opinnäytetyön teoreettisessa viitekehyksessä käsitellään palveluita ja niiden kehittämistä, yhteisöllisyyttä ja käyttäjälähtöisyyttä. Teoriatietoa on kirjoitettu myös lähimmäisyydestä, vastuullisesta liiketoiminnasta ja yhteiskuntavastuusta sekä hyvinvoinnista. Opinnäytetyöntekijät perehtyivät myös samankaltaisia oheistoimintoja toteuttavien kohteiden lehtiartikkeleihin ja esitteisiin sekä nettisivustoihin. Opinnäytetyön tuloksena Kirkkokahvilan oheistoiminnoiksi valikoituivat tapahtumat, joissa erilaiset ja eri-ikäiset ihmiset tapaavat toisiaan. Näistä esimerkkinä ovat muun muassa yhteistoiminnalliset illat, joissa on runojen esittämistä ja elokuvien katselua. Muita tarjottavia oheistoimintoja olivat aikapankkitoiminnan käytännön järjestelyistä sopiminen ja oman osaamisen jakaminen toisille sekä vaunuparkki. Opinnäytetyön onnistumisen esteeksi muodostui seurakunnan organisaation muutosvastaisuus, joka vaikutti oheistoimintaideoiden käynnistymiseen.This thesis was set to develop a work pattern of supplementary services to the Lauttasaari Church Coffee house and the objective was to create social relations between the inhabitants of Lauttasaari on a daily basis. The purpose was to find supplementary features that can be offered alongside other services and that also interest customers outside congregational functions. Coffee house services have been available as an experimental service since spring 2012 for a wider clientele. This thesis was implemented through experimental customers, observations, survey and brainstorming. Stefan Moritz’- process development was used and through that targets for further development were found. The results of the survey and interviews revealed a need and demand to find a place for inhabitants to assemble and the congregation premises were the answer to this. The theoretical viewpoint of this thesis covers services and the development of them, social relations and user-orientation. Theoretical information about brethrenship, responsible business manners, social responsibility and well-being has been included. Articles, brochures and internet pages related to the subject were covered as benchmarking. As a result of this thesis certain supplementary services were selected, like get-togethers for participants of different age-groups and backgrounds. As an example one could mention in-teractive evening events of poetry recitation or watching movies. Other supplementary services on offer were: practical organizing of timebank services, knowledge sharing and pram park. The biggest obstacle for a successful implementation of the thesis was the congregation’s demur that had a negative impact on starting the supplementary services

Human Tumor–Derived Matrix Improves the Predictability of Head and Neck Cancer Drug Testing

In vitro cancer drug testing carries a low predictive value. We developed the human leiomyoma–derived matrix “Myogel” to better mimic the human tumor microenvironment (TME). We hypothesized that Myogel could provide an appropriate microenvironment for cancer cells, thereby allowing more in vivo–relevant drug testing. We screened 19 anticancer compounds, targeting the epidermal growth factor receptor (EGFR), MEK, and PI3K/mTOR on 12 head and neck squamous cell carcinoma (HNSCC) cell lines cultured on plastic, mouse sarcoma–derived Matrigel (MSDM), and Myogel. We applied a high-throughput drug screening assay under five different culturing conditions: cells in two-dimensional (2D) plastic wells and on top or embedded in Matrigel or Myogel. We then compared the efficacy of the anticancer compounds to the response rates of 19 HNSCC monotherapy clinical trials. Cancer cells on top of Myogel responded less to EGFR and MEK inhibitors compared to cells cultured on plastic or Matrigel. However, we found a similar response to the PI3K/mTOR inhibitors under all culturing conditions. Cells grown on Myogel more closely resembled the response rates reported in EGFR-inhibitor monotherapy clinical trials. Our findings suggest that a human tumor matrix improves the predictability of in vitro anticancer drug testing compared to current 2D and MSDM methods

Human Tumor–Derived Matrix Improves the Predictability of Head and Neck Cancer Drug Testing

In vitro cancer drug testing carries a low predictive value. We developed the human leiomyoma–derived matrix “Myogel” to better mimic the human tumor microenvironment (TME). We hypothesized that Myogel could provide an appropriate microenvironment for cancer cells, thereby allowing more in vivo–relevant drug testing. We screened 19 anticancer compounds, targeting the epidermal growth factor receptor (EGFR), MEK, and PI3K/mTOR on 12 head and neck squamous cell carcinoma (HNSCC) cell lines cultured on plastic, mouse sarcoma–derived Matrigel (MSDM), and Myogel. We applied a high-throughput drug screening assay under five different culturing conditions: cells in two-dimensional (2D) plastic wells and on top or embedded in Matrigel or Myogel. We then compared the efficacy of the anticancer compounds to the response rates of 19 HNSCC monotherapy clinical trials. Cancer cells on top of Myogel responded less to EGFR and MEK inhibitors compared to cells cultured on plastic or Matrigel. However, we found a similar response to the PI3K/mTOR inhibitors under all culturing conditions. Cells grown on Myogel more closely resembled the response rates reported in EGFR-inhibitor monotherapy clinical trials. Our findings suggest that a human tumor matrix improves the predictability of in vitro anticancer drug testing compared to current 2D and MSDM methods

Cytokine expression in rhinovirus- vs. respiratory syncytial virus-induced first wheezing episode and its relation to clinical course

Rhinovirus (RV) and respiratory syncytial virus (RSV) are common causes of bronchiolitis. Unlike an RSV etiology, an RV etiology is associated with a markedly increased risk of asthma. We investigated the cytokine profiles of RV- and RSV-induced first wheezing episode and their correlation with prognosis. We recruited 52 sole RV- and 11 sole RSV-affected children with a severe first wheezing episode. Peripheral blood mononuclear cells (PBMCs) were isolated during acute illness and 2 weeks later and stimulated in vitro with anti-CD3/anti-CD28. Culture medium samples were analyzed for 56 different cytokines by multiplex ELISA. Recurrences were prospectively followed for 4 years. In adjusted analyses, the cytokine response from PBMCs in the RV group was characterized by decreased expression of interleukin 1 receptor antagonist (IL-1RA), interleukin 1 beta (IL-1 beta), and monocyte chemoattractant protein-1 (MCP-1) and increased expression of eosinophil chemotactic protein 2 (eotaxin-2), thymus- and activation-regulated chemokine (TARC), and epithelial-derived neutrophil-activating peptide 78 (ENA-78) in the acute phase and increased expression of fractalkine in the convalescent phase compared to those in the RSV group. An analysis of the change in cytokine expression between study points revealed an increased expression of fractalkine and IL-1 beta and decreased expression of I-309 (CCL1) and TARC in the RV group compared to those in the RSV group.. Considering hospitalization time, a significant non-adjusted group x cytokine interaction was observed in the levels of interferon gamma (IFN-gamma), macrophage-derived chemokine (MDC), IL-1RA, and vascular endothelial growth factor (VEGF), indicating that a higher expression of cytokine was associated with shorter hospitalization time in the RSV group but not in the RV group. A significant interaction was also found in interleukin 6 (IL-6), but the cytokine response was not associated with hospitalization time in the RSV or RV group. In the RV group, increased expression of I-309 (CCL1) and TARC was associated with fewer relapses within 2 months, and decreased expression of interleukin 13 (IL-13) and increased expression of I-309 (CCL1) were associated with less relapses within 12 months. Differences in cytokine response from PBMCs were observed between RV- and RSV-induced first severe wheezing episode. Our findings also reveal new biomarkers for short- and medium-term prognosis in first-time wheezing children infected with RV or RSV.Peer reviewe

Human bocavirus 1 coinfection is associated with decreased cytokine expression in the rhinovirus‐induced first wheezing episode in children

Background Rhinovirus (RV)‐induced first wheezing episodes in children are associated with a markedly increased risk of asthma. Previous studies have suggested that human bocavirus 1 (HBoV1) may modify RV‐induced immune responses in young children. We investigated cytokine profiles of sole RV‐ and dual RV‐HBoV1‐induced first wheezing episodes, and their association with severity and prognosis. Methods Fifty‐two children infected with only RV and nine children infected with dual RV‐HBoV1, aged 3–23 months, with severe first wheezing episodes were recruited. At acute illness and 2 weeks later, peripheral blood mononuclear cells were isolated, and stimulated with anti‐CD3/anti‐CD28 in vitro. Multiplex ELISA was used to quantitatively identify 56 different cytokines at both study points. Patients were prospectively followed for 4 years. Results The mean age of the children was 14.3 months, and 30% were sensitized. During the acute illness, the adjusted analyses revealed a decrease in the expression of IL‐1b, MIP‐1b, Regulated upon activation, normal T cell expressed and presumably secreted (CCL5), TNF‐a, TARC, and ENA‐78 in the RV‐HBoV1 group compared with the RV group. In the convalescence phase, the RV‐HBoV1 group was characterized by decreased expression of Fractalkine, MCP‐3, and IL‐8 compared to the RV group. Furthermore, the hospitalization time was associated with the virus group and cytokine response (interaction p < 0.05), signifying that increased levels of epidermal growth factor and MIP‐1b were related with a shorter duration of hospitalization in the RV‐HBoV1 coinfection group but not in the RV group. Conclusions Different cytokine response profiles were detected between the RV and the RV‐HBoV1 groups. Our results show the idea that RV‐induced immune responses may be suppressed by HBoV1

Efficacy of inhaled salbutamol with and without prednisolone for first acute rhinovirus-induced wheezing episode

Background Acute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta(2)-agonist in this clinical scenario. Objective To study post hoc the short-term (up to 2 months) efficacy of inhaled beta(2)-agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children. Methods The study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2-4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences. Results Median age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group x treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p .26). Conclusions In young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.Peer reviewe

Rhinovirus species and tonsillar immune responses

Background Rhinovirus A and C infections are important contributors to asthma induction and exacerbations. No data exist on the interaction of local immune responses in rhinovirus infection. Therefore, we aimed to determine the tonsillar immune responses according to rhinovirus A, B and C infections. Methods We collected tonsillar samples, nasopharyngeal aspirates and peripheral blood from 42 rhinovirus positive tonsillectomy patients. Fifteen respiratory viruses or their types were investigated from nasopharynx and tonsil tissue, and rhinovirus species were typed. The expression of 10 cytokines and 4 transcription factors (IFN-alpha, IFN-beta, IFN-gamma, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-beta, FOXP3, GATA3, RORC2 and Tbet) were studied from tonsil tissue by quantitative PCR. A standard questionnaire of respiratory symptoms and health was filled by the patient or his/her guardian. The patients were divided into three groups by the determination of rhinovirus species. Results Overall, 16 patients had rhinovirus A, 12 rhinovirus B and 14 rhinovirus C infection. In rhinovirus B positive group there were significantly less men (P = 0.0072), less operated in spring (P = 0.0096) and more operated in fall (P = 0.030) than in rhinovirus A or C groups. Rhinovirus A positive patients had more respiratory symptoms (P = 0.0074) and particularly rhinitis (P = 0.036) on the operation day. There were no significant differences between the groups in virus codetection. In adjusted analysis, rhinovirus C infections were associated with increased IFN-alpha (P = 0.045) and decreased RORC2 expression (P = 0.025). Conclusions Rhinovirus species associated differently with clinical characteristics and tonsillar cytokine responses.Peer reviewe

Efficacy of inhaled salbutamol with and without prednisolone for first acute rhinovirus-induced wheezing episode

BackgroundAcute rhinovirus-induced wheezing is common in young children and may respond to systemic corticosteroid. There are no trials on the efficacy of inhaled beta2-agonist in this clinical scenario.ObjectiveTo study post hoc the short-term (up to 2 months) efficacy of inhaled beta2-agonist with and without oral corticosteroid in the first acute rhinovirus-induced severe wheezing episode in young hospitalized children.MethodsThe study population came from two randomized controlled trials comparing oral prednisolone (2 mg/kg/d for 3 days) to placebo: Vinku (n = 35, NCT00494624) used high-dose regular nebulized salbutamol (0.15 mg/kg 2–4 h intervals) and Vinku2 (n = 60, NCT00731575, EudraCT 2006-007100-42) used inhaled salbutamol on-demand. Both studies used identical detailed follow-up assessments. The primary outcome of the former was the duration of hospitalization and of the latter the occurrence of and the time to a new physician-confirmed wheezing episode within 2 months after discharge. Treatment groups included salbutamol high-dose vs. salbutamol on-demand while adjusting for prednisolone status and acknowledging for interactions with exception of the duration of hospitalization in which prednisolone groups could not be fully used due to protocol differences.ResultsMedian age of subjects was 13 months, 32% were sensitized and 22% had doctor-diagnosed eczema. In the duration of hospitalization, salbutamol high-dose/placebo versus salbutamol on-demand/placebo groups did not differ (p = .12). In the occurrence of and time to relapse within 2 months, a significant group × treatment interaction was observed (both p = .02), such that high-dose group had less and longer time to relapses than on-demand group in prednisolone arm (both p p > .26).ConclusionsIn young, hospitalized children with first episode of rhinovirus-induced wheezing, high-dose inhaled salbutamol may interact with oral prednisolone. However, further trials are warranted.</p

Cytokine expression in rhinovirus- vs respiratory syncytial virus-induced first wheezing episode and its relation to clinical course

Rhinovirus (RV) and respiratory syncytial virus (RSV) are common causes of bronchiolitis. Unlike an RSV etiology, an RV etiology is associated with a markedly increased risk of asthma. We investigated the cytokine profiles of RV- and RSV-induced first wheezing episode and their correlation with prognosis. We recruited 52 sole RV- and 11 sole RSV-affected children with a severe first wheezing episode. Peripheral blood mononuclear cells (PBMCs) were isolated during acute illness and 2 weeks later and stimulated in vitro with anti-CD3/anti-CD28. Culture medium samples were analyzed for 56 different cytokines by multiplex ELISA. Recurrences were prospectively followed for 4 years. In adjusted analyses, the cytokine response from PBMCs in the RV group was characterized by decreased expression of interleukin 1 receptor antagonist (IL-1RA), interleukin 1 beta (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) and increased expression of eosinophil chemotactic protein 2 (eotaxin-2), thymus- and activation-regulated chemokine (TARC), and epithelial-derived neutrophil-activating peptide 78 (ENA-78) in the acute phase and increased expression of fractalkine in the convalescent phase compared to those in the RSV group. An analysis of the change in cytokine expression between study points revealed an increased expression of fractalkine and IL-1β and decreased expression of I-309 (CCL1) and TARC in the RV group compared to those in the RSV group.. Considering hospitalization time, a significant non-adjusted group × cytokine interaction was observed in the levels of interferon gamma (IFN-γ), macrophage-derived chemokine (MDC), IL-1RA, and vascular endothelial growth factor (VEGF), indicating that a higher expression of cytokine was associated with shorter hospitalization time in the RSV group but not in the RV group. A significant interaction was also found in interleukin 6 (IL-6), but the cytokine response was not associated with hospitalization time in the RSV or RV group. In the RV group, increased expression of I-309 (CCL1) and TARC was associated with fewer relapses within 2 months, and decreased expression of interleukin 13 (IL-13) and increased expression of I-309 (CCL1) were associated with less relapses within 12 months. Differences in cytokine response from PBMCs were observed between RV- and RSV-induced first severe wheezing episode. Our findings also reveal new biomarkers for short- and medium-term prognosis in first-time wheezing children infected with RV or RSV