Changes in symptoms of asthma and rhinitis by sensitization status over ten years in a cohort of young Chilean adults.

BACKGROUND: We investigated the net changes in prevalence of symptoms of asthma and rhinitis over 10 years in a cohort of young by baseline sensitization status. METHODS: One thousand one hundred ninety three Chilean adults subjects aged 22-28 living in a semi-rural area of central Chile answered a lifestyle and the European Community Respiratory Health Survey (ECRHS) questionnaires. Bronchial hyper-responsiveness (BHR) and skin prick test (SPT) to eight allergens were measured at baseline in 2001. Ten years later, 772 participants completed the questionnaires again. Estimates of adjusted net changes in prevalence of symptoms by sensitization status at baseline and association between sensitization status at baseline and respiratory symptoms ten years later were assessed. RESULTS: A quarter of the participants were sensitized to at least one allergen in 2001. Prevalence of wheeze had a net change per year of -0.37 % (95 % Confidence Interval -0.71 to 0.02 %; p = 0.067). Self-reported nasal allergies in the last 12 months increased by 0.83 % per year (95 % CI 0.49 to 1.17 %; p < 0.001). Those sensitized to either cat fur (OR 1.76; CI 1.01 to 3.05), cockroach, (OR 2.09; 1.13 to 3.86) blend of grass and pollens (1.78; 95 % CI 1.08 to 2.92), or weeds (OR 1.77; 95 % CI 1.01 to 3.12) in 2001 were more likely to have wheeze in the last 12 months 10 years later. CONCLUSION: Symptoms of asthma remained stable or slightly changed over 10 years in adults, whilst rhinitis and nasal allergies greatly increased. Being sensitized to at least one allergen is a risk factor for persistent symptoms of asthma and rhinitis, but not for determining net changes of symptoms over time. The underlying causes for the contrasting trends between asthma and nasal allergy are unknown.

[Levels of inflammatory cytokines and plasma cortisol in respiratory syncytial virus bronchiolitis]. / Aumento de interleuquinas proinflamatorias y de cortisol plasmático en bronquiolitis por virus respiratorio sincicial: relación con la gravedad de la infección.

BACKGROUND: An increased inflammatory innate response may play a role in pathogenesis of respiratory syncytial virus (RSV) infection. AIM: To quantify pro-inflammatory cytokines (IL-6-IL-8, ÍL-2-P and TNF-a) in nasopharyngeal aspirate (NPA) and plasma, and plasma cortisol in previously healthy infants with RSV bronchiolitis. PATIENTS AND METHODS: We studied 49 infants aged less than one year of age with RSV bronchiolitis and 25 healthy controls. Severity was defined using a previously described modified score. We quantified interleukins in NPA and plasma by flow cytometry and plasma cortisol by radioimmunoanalysis. RESULTS: Among patients with RSV bronchiolitis, 25 were classified as severe and 24 as moderate or mild. Significantly higher levels of IL-6 and IL-8 in NPA and plasma and IL-lfi in NPA were found in children classified as severe, when compared to those with moderate or mild disease and controls. There was a positive correlation between IL-6 and cortisol in plasma (r = 0,55; p < 0,0001) and both were correlated with the severity of the disease. CONCLUSIONS: RSV bronchiolitis severity was associated with higher levéis of inflammatory interleukins and plasma cortisol.

Childhood environment and atopic conditions, with emphasis on asthma in a Chilean agricultural area.

BACKGROUND: An explanation of the etiology of atopic conditions based on the hygiene hypothesis remains controversial. OBJECTIVE: To analyze exposure variables in childhood to assess their impact on hay fever, asthma, and sensitization. METHODS: Data were collected on 1,232 young Chilean adults born between 1974 and 1978. Information was available on consultations for infections early in life, number of siblings, sharing a bedroom, nursery school attendance, and contact with animals in the first 5 years of life. Information on asthma symptoms and rhinitis were obtained from a standardized questionnaire. Sensitization to eight allergens and bronchial hyper responsiveness (BHR) to methacholine were assessed. The study design was non-concurrent longitudinal for infectious episodes and nutritional status in the first year and cross-sectional for the other outcomes. RESULTS: Number of siblings was associated with sensitization only (p = 0.0048). Nursery school attendance was negatively associated with positive BHR (odds ratio (OR) 0.54, 95% CI 0.30-0.95). A severe respiratory infection early in life was protective of sensitization and wheeze combined (OR 0.29, 95%CI 0.12-0.74). Contact with dogs in the first year was a protective factor of rhinitis (OR 0.47, 95%CI 0.28-0.80), but contact with poultry and cats early in life increased the risk of rhinitis (OR 1.42, 95%CI 1.06-1.88; 1.82, 95%CI 1.06-3.14). CONCLUSION: The pattern of associations between environmental exposure in early life and atopic conditions was inconsistent. The significant associations were evenly distributed as protective and risk factors of atopic conditions.

Pro-Inflammatory Cytokines in Nasopharyngeal Aspirate From Hospitalized Children With Respiratory Syncytial Virus Infection With or Without Rhinovirus Bronchiolitis, and Use of the Cytokines as Predictors of Illness Severity.

Respiratory syncytial virus (RSV) and human rhinovirus (HRV) respiratory infection in children induce production of inflammatory interleukins (ILs) in the respiratory epithelium. As IL(s) determine the severity of illness, the purpose of this study was to identify the pro-inflammatory IL(s) that could be predictor(s) of clinical severity. One hundred and fifteen patients <2 years old with bronchiolitis due to RSV and /or HRV and 38 controls were selected from a hospital and an outpatient clinic. Clinical data of all patients were recorded. Severity was defined by the number of days with oxygen need. Nasopharyngeal aspirates (NPA) were collected to perform viral diagnosis by quantitative reverse transcription and polymerase chain reaction (qRT-PCR) and to quantify ILs: TNF-α, IL-10, IL-6, IL-1ß, and IL-8, by flow cytometry. Simple and multiple regression and receiver operating characteristic (ROC) curves were used for statistical analysis. Of the patients selected 60 were single RSV, 28 RSV associated to HRV, and 27 single HRV. All patients (115) showed significantly higher IL levels when compared with controls. Levels of IL-6, IL-1ß, and IL-8 detected in NPA from RSV single and associated to HRV were significantly higher than HRV infected and positively associated with days requiring O2.Levels of IL-6, IL-1ß, and IL-8 detected in NPA from patients infected with RSV only or with both RSV and HRV are increased, and any of those 3 cytokines may have a predictive value for the number of days with need of supplemental oxygen.

Increased expression of the glucocorticoid receptor ß in infants with RSV bronchiolitis.

OBJECTIVES: The majority of studies on glucocorticoid treatment in respiratory syncytial virus (RSV) bronchiolitis concluded that there are no beneficial effects. We hypothesized that RSV-infected patients may have an increased glucocorticoid receptor (GR) ß expression, the isoform that is unable to bind cortisol and exert an antiinflammatory action. METHODS: By using real-time polymerase chain reaction, we studied the expression of α and ß GR in the peripheral blood mononuclear cells obtained from 49 RSV-infected infants (<1 year of age) with severe (n = 29) and mild to moderate (n = 20) illness. In plasma, we analyzed the level of cortisol by radioimmunoassay and inflammatory cytokines interleukin (IL)-10, IL-6, tumor necrosis factor-α, IL-1ß, IL-8, IL-12p70, IL-2, IL-4, IL-5, interferon-γ, and IL-17 by cytometric beads assay. Statistical analysis was performed by nonparametric analysis of variance. RESULTS: We found a significant increase of ß GR expression in patients with severe illness compared with those with mild disease (P < .001) and with a group of healthy controls (P < .01). The α:ß GR ratio decreased significantly in infants with severe disease compared with those with mild illness (P < .01) and with normal controls (P < .001). The expression of ß GR was positively correlated with the clinical score of severity (r = .54; P < .0001). CONCLUSIONS: The decrease of the α:ß GR ratio by an increase of ß receptors expression is related to illness severity and may partly explain the insensitivity to corticoid treatment in RSV-infected infants. The increased expression of ß GR could be a marker of disease severity.

Desplazamiento de los puntos de referencia craneales utilizados en los análisis cefalométrico de jarabak y ricketts, durante el crecimiento activo / Displacement of cranial reference landmarks used in jarabak and ricketts cephalometric analysis during active growth

El objetivo de este trabajo fue evaluar el desplazamiento de los puntos craneales: Nasion, Silla, Basion, Porion, Orbitario y Pterigoideo, utilizados como referencia en los análisis cefalométricos de Jarabak y Ricketts durante el crecimiento activo. Se seleccionaron 120 telerradiografías de perfil en formato digital, correspondientes a 60 pacientes con 2 telerradiografías cada uno, tomadas con un intervalo de tiempo mínimo de 1 año (T1 y T2), en donde T1 se encuentra antes o durante el peak de crecimiento según el Estado de Maduración Cervical Vertebral (CVM) I, II ó III de Baccetti y T2 en estadio CVM IV,V,VI (después del peak de crecimiento). Un examinador previamente calibrado, ubicó los puntos analizados y para evaluar su desplazamiento, se realizaron mediciones en T1 y T2 (3 variables para cada punto), usando como referencia 2 planos que no se modifican a partir de los 5 años de edad (LCB y Vert-T). Para determinar el desplazamiento de los puntos, se calculó la variación promedio observada entre T1 y T2 y se realizó la prueba t para muestras pareadas o Wilcoxon (según distribución) para determinar la existencia de diferencias significativas. Además, se comparó la muestra por sexo, CVM inicial y CVM final. Se encontraron variaciones entre T1 y T2 en todas las medidas, aunque sólo en 5 de ellas se encontraron diferencias significativas; no se encontró diferencias al comparar por sexo, CVM inicial y final. Es así como podemos concluir que todos los puntos craneales analizados sufren desplazamiento durante el crecimiento. Los puntos Basion y Orbitario son los que sufren mayor desplazamiento. Es necesario analizar las implicancias de estas variaciones en los resultados obtenidos de los análisis cefalométrico y evaluar la necesidad de utilizar puntos de referencia alternativos.

The objective of this study was to evaluate the displacement of cranial reference points: Nasion, Sella, Basion, Porion, Orbitale and Pterygomaxillary, used in Jarabak and Ricketts cephalometric analysis, during active growth. Hundred and twenty digitalized lateral telerradiographies, corresponding to 60 patients (2 teleradiographies each one), were collected. The radiographies were taken with a minimum interval of one year between them (T1 and T2), where T1 is taken before or during the pubertal growth peack according to the cervical vertebral maturation stages developed by baccetti (CVM) I, II or III and T2 in CVM IV,V,VI (after the growth peak). Then, a previously calibrated examinator marked reference points and cephalometric measurements were taken (2 variables for each landmark). Measurements were made using craniofacial stable structures as references (stable basicranial line and Vertical T). To detect displacement in the landmark positions, t test or Wilcoxon test according to the distribution of each variable, was used to compare the data between T1 and T2. Also, comparisons were made by sex, and by initial and final CVM. All of the variables have variations between T1 y T2, but only 5 have a statistically significant difference. There were no differences between sexes and at initial and final CVM. In conclusion, all of the reference landmarks analyzed had displacement during active growth. Point Basion and Orbitale suffered the largest displacement. It is necessary to analyze the clinical implications of this displacement in order to evaluate the convenience of using alternative reference landmarks.

Aumento de interleuquinas proinflamatorias y de cortisol plasmático en bronquiolitis por virus respiratorio sincicial: relación con la gravedad de la infección / Levels of inflammatory cytokines and plasma cortisol in respiratory syncytial virus bronchiolitis

Background: An increased inflammatory innate response may play a role in pathogenesis of respiratory syncytial virus (RSV) infection. Aim: To quantify pro-inflammatory cytokines (IL-6-IL-8, ÍL-2-P and TNF-a) in nasopharyngeal aspirate (NPA) and plasma, and plasma cortisol in previously healthy infants with RSV bronchiolitis. Patients and Methods: We studied 49 infants aged less than one year of age with RSV bronchiolitis and 25 healthy controls. Severity was defined using a previously described modified score. We quantified interleukins in NPA and plasma by flow cytometry and plasma cortisol by radioimmunoanalysis. Results: Among patients with RSV bronchiolitis, 25 were classified as severe and 24 as moderate or mild. Significantly higher levels ofIL-6 and IL-8 in NPA and plasma and IL-lfi in NPA were found in children classified as severe, when compared to those with moderate or mild disease and controls. There was a positive correlation between IL-6 and cortisol in plasma (r = 0,55; p < 0,0001) and both were correlated with the severity of the disease. Conclusions: RSV bronchiolitis severity was associated with higher levéis of inflammatory interleukins and plasma cortisol.

Safety and tolerability of inhaled budesonide in children in the Steroid Treatment As Regular Therapy in early asthma (START) trial.

The safety and tolerability of asthma medications are still a concern to many asthma patients receiving long-term treatment. Therefore, more safety data from long-term, controlled trials are needed. The aim of this study was to evaluate the safety and tolerability of long-term treatment with once-daily budesonide in children aged 5-10 yrs with mild persistent asthma of recent onset in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study. Children aged 5-10 yrs with early asthma were randomized to double-blind treatment with budesonide 200 microg or placebo once daily via Turbuhaler in addition to usual asthma therapy, for 3 yrs. Adverse events were recorded from both spontaneous reports and responses to standard questions, and asthma-related events and asthma control were recorded between visits and subsequently graded by the blinded investigators. Of the study population of 1981 children (1004 budesonide and 977 usual care), 81% (812 of 1004) in the budesonide group and 82% (797 of 977) in the usual care group experienced a total of 6414 events listed by preferred term (3209 budesonide plus usual care and 3205 placebo plus usual care). The most commonly reported events included respiratory infection, pharyngitis, rhinitis, viral infection and bronchitis, and there were no clinically relevant differences in incidence between treatments. There were no reports of tuberculosis or aspergillosis, and no evidence of increased risk of systemic or ocular adverse events with budesonide relative to placebo. There were 106 serious adverse events in the budesonide group and 128 with usual care. The most frequent, aggravated asthma, was more common with usual care than with budesonide. There were no deaths among children participating in START. In conclusion, the addition of once-daily inhaled budesonide 200 microg via Turbuhaler to usual care is safe and well tolerated in children with recent-onset mild persistent asthma.

Agreement between responses to a standardized asthma questionnaire and a questionnaire following a demonstration of asthma symptoms in adults.

Asthma epidemiology relies heavily on standardized questionnaires, but little is known about the understanding of asthma symptoms among adults in the community. In 2004, the authors assessed the level of agreement between responses to a standardized questionnaire and responses to a questionnaire completed by participants after viewing a demonstration of asthma symptoms. The study involved 601 young adults from Chile. The field-workers were trained to explain and demonstrate the asthma symptoms to the participants. The symptoms were wheeze, waking at night with breathlessness, breathlessness following exercise, and waking with cough. The kappa statistic did not exceed 0.4, and the recorded prevalence of asthma symptoms following the demonstration was 30-60% lower than that for the standardized questionnaire. Using bronchial responsiveness as the proxy gold standard, the positive likelihood ratios for wheeze and waking short of breath were higher following symptom demonstration. The low agreement between the standardized questionnaire and the postdemonstration questionnaire and the likelihood ratios' closeness to 1 for the standardized questionnaire decreases the authors' confidence in the appropriateness of this tool for estimating the prevalence of asthma in the community. For etiologic studies of asthma, it may contribute to the lack of consistency between different studies analyzing the same etiologic exposures.

T helper 1/T helper 2 cytokine imbalance in respiratory syncytial virus infection is associated with increased endogenous plasma cortisol.

OBJECTIVE: Cellular immunity has classically been described as the defense mechanism for viral infections. The development of cellular or humoral immune responses will depend on a repertoire of cytokines produced by numerous cells, including CD4+ and CD8+ T cells. These lymphocytes can be subdivided into 2 subsets, T helper 1 (Th1) and Th2, on the basis of the cytokine profiles they synthesize. Type 1 T cells produce interferon gamma (IFN-gamma), an essential cytokine in the viral cell-mediated immune response. Th2 cells selectively produce interleukin 4 (IL-4) and IL-5 that participate in the development of humoral immunity and have a prominent role in immediate-type hypersensitivity. An imbalance in the Th1/Th2 cytokine immune response has been related to pathogenesis of the respiratory syncytial virus (RSV) bronchiolitis and to the severity of the infection. Glucocorticosteroids have a role in inhibiting the IFN-gamma response, acting directly on T cells or indirectly through IL-12. In this way, an increase in plasma cortisol would induce a decrease in the Th1 products with the imbalance between Th1/Th2 cytokines and a shift to Th2 response. We hypothesized that there is a relationship among endogenous cortisol response in acute RSV infection, severity of illness, and decreased Th1 cytokine response. METHODS: We studied 42 infants under 12 months of age during an acute RSV infection. Twenty-one infants with a median age of 6 months had a severe illness and required hospitalization, whereas 21 with mild diseases with a median age of 7 months were under ambulatory control. All of them had bronchial obstruction evidenced by wheezing and/or hyperinflation on chest radiograph and positive RSV antigen detected by indirect immunofluorescence in nasopharyngeal aspirates. The control group included 21 infants in good health matched by age and gender with median age of 6 months that required blood tests for minor surgery. They were evaluated during a non-RSV epidemic period. Heparinized blood was collected on enrollment from all participating children at 9 am for total leukocyte and differential cell count, determination of lymphocyte subsets, and for intracellular detection of cytokines in single cells; mononuclear cells were cultured to determine in the supernatant cytokine production. In addition, 1 mL of plasma was separated and kept frozen at -20 degrees C for cortisol assay. In the supernatant of the cultured peripheral blood mononuclear cells (PBMCs), we quantified IL-12, IFN-gamma, IL-4, IL-5, and IL-10. Lymphocyte phenotypes and CD4+ and CD8+ T cells with intracellular IL-4, IL-10, and IFN-gamma were analyzed by triple-color immunofluorescence of single cells on a FACScan flow cytometer. RESULTS: Infants with severe illness had significantly higher plasma cortisol levels than infants with mild disease, and in both groups of infected infants, those were higher than in the control group. A significantly decreased IL-12 and IFN-gamma production by PBMCs and a fall in the percentage of CD4+ T cells expressing IFN-gamma were observed only in the severely affected infants. IL-12 concentrations were 2 pg/mL in severe illness versus 13 pg/mL in mildly infected infants and 12 pg/mL in controls. PBMCs from infants with severe illness produced less IFN-gamma than mildly infected infants and than controls when compared with severe illness. No differences between the 3 groups of infants were observed during the acute phase of the disease for IL-4, IL-5, and IL-10. IL-12 and IFN-gamma production had an inverse correlation with plasma cortisol levels. During severe RSV bronchiolitis, infants developed lymphopenia, and significantly lower eosinophil counts and percentages and absolute counts of CD4+ and CD8+ T cells. Eighty days postinfection, all values had returned to normal levels. CONCLUSIONS: In this study, we demonstrate that during the acute phase of RSV infection, there is an increase in the level of plasma cortisol that is parallel to the decrease in IL-12 and IFN-gamma production. These findings suggest an association between increased plasma cortisol and a decreased Th1-type response. The increase in plasma cortisol was greater in infants with the more severe symptomatology in association with a lower level of IL-12 and IFN-gamma production. The potential causative role of endogenous cortisol in the imbalance of the Th1/Th2 response observed during severe RSV infection requires additional investigation. Our results suggest that the immunologic changes observed in the more severely ill patients may be partially explained by the increased levels of plasma cortisol. This finding should be taken into consideration when systemic steroids are prescribed to infants infected with the RSV because there is still controversy regarding the efficacy of systemic steroid use in severe bronchiolitis.

Long-term safety of once-daily budesonide in patients with early-onset mild persistent asthma: results of the Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study.

BACKGROUND: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study is a worldwide, randomized, prospective study to investigate early intervention with inhaled corticosteroids in recent-onset mild persistent asthma. OBJECTIVE: To evaluate the safety and tolerability of long-term treatment with once-daily budesonide therapy in patients with mild persistent asthma. METHODS: Patients aged 5 to 66 years with mild persistent asthma for fewer than 2 years and no previous regular corticosteroid treatment received budesonide or placebo once daily for 3 years, in addition to their usual asthma therapy. The daily budesonide dose was 200 microg for children younger than 11 years and 400 microg for those 11 years or older. RESULTS: Overall, 7,221 patients were included in the safety analysis, and a total of 21,520 adverse events were reported (10,850 in the budesonide group and 10,670 in the placebo group). The most commonly reported events included respiratory infections, rhinitis, pharyngitis, bronchitis, viral infections, and sinusitis. The number of deaths and serious adverse events were similar for children and adults in both treatment groups. Fewer asthma-related serious adverse events were reported with budesonide (162) compared with placebo (276). Oral candidiasis was reported more frequently with budesonide (1.2%) than with placebo (0.5%); the frequencies of other adverse effects previously reported to be associated with inhaled corticosteroids (psychiatric disorders, skin disorders, and allergic reactions) were similar. CONCLUSIONS: Three-year treatment with budesonide once daily (200 or 400 microg) is safe and well tolerated in children and adults with newly detected mild persistent asthma.

Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide.

BACKGROUND: Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. OBJECTIVE: To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. METHODS: In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients). RESULTS: Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. CONCLUSIONS: Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy.