Christina D. Schwindt

Association of atopy to asthma severity and medication use in children

The importance of aeroallergens as triggers for asthma is well recognized, but the relationship between asthma severity and atopic profiles in childhood has not been elucidated. This study assessed the relationship of allergen sensitization to asthma severity in a study of 114 asthmatic children followed for 8 weeks in three Southern California areas. Increased controller medication and β-agonist use were positively associated with number of positive skin tests and allergy to mold and pollens. Mold was associated with increased asthma symptoms. Degree of atopy and reactivity to mold and pollens plays a significant role in asthma severity in asthmatic children.

Do circulating leucocytes and lymphocyte subtypes increase in response to brief exercise in children with and without asthma

Background: Exercise can alter health in children in both beneficial (eg reduced long-term risk of atherosclerosis) and adverse (eg exercise-induced asthma) ways. The mechanisms linking exercise and health are not known, but may rest, partly, on the ability of exercise to increase circulating immune cells. Little is known about the effect of brief exercise, more reflective of naturally occurring patterns of physical activity in children, on immune cell responses. Objectives: To determine whether (1) a 6-min bout of exercise can increase circulating inflammatory cells in healthy children and (2) the effect of brief exercise is greater in children with a history of asthma. Methods: Children with mild–moderate persistent asthma and age-matched controls (n = 14 in each group, mean age 13.6 years) performed a 6-min bout of cycle-ergometer exercise. Spirometry was performed at baseline and after exercise. Blood was drawn before and after exercise, leucocytes were quantified and key lymphocyte cell surface markers were assessed by flow cytometry. Results: Exercise decreased spirometry only in children with asthma, but increased (p<0.001) most types of leucocytes (eg lymphocytes (controls, mean (SD) 1210 (208) cells/μl; children with asthma, 1119 (147) cells/μl) and eosinophils (controls, 104 (22) cells/μl; children with asthma, 88 (20) cells/μl)) to the same degree in both groups. Similarly, exercise increased T helper cells (controls, 248 (60) cells/μl; children with asthma, 232 (53) cells/μl) and most other lymphocyte subtypes tested. By contrast, although basophils (16 (5) cells/μl) and CD4+ CD45RO+ RA+ lymphocytes (19 (4) cells/μl) increased in controls, no increase in these cell types was found in children with asthma. Conclusions: Exercise increased many circulating inflammatory cells in both children with asthma and controls. Circulating inflammatory cells did increase in children with asthma, but not to a greater degree than in controls. In fact, basophils and T helper lymphocyte memory transition cells did not increase in children with asthma, whereas they did increase in controls. Even brief exercise in children and adolescents robustly mobilises circulating immune cells.

A rat model of exercise-induced asthma: a nonspecific response to a specific immunogen.

Exercise-induced bronchoconstriction (EIB) is common; however, key aspects of its pathogenesis are still unclear. We investigated the feasibility of adapting an established animal model of asthma to investigate the earliest stages of EIB. The hypothesis was that a single exposure to a normally innocuous, and brief, exercise challenge could trigger EIB symptoms in rats previously sensitized to ovalbumin (OVA) but otherwise unchallenged. Brown-Norway rats were sensitized by intraperitoneal injection of OVA at 0 and 2 wk. At week 3, animals were exposed to either aerosolized OVA (SS) or exercise (EXS). A trained, blinded, clinical observer graded EIB by respiratory sounds. Plasma and lung cytokine levels were analyzed. No control rats with or without exercise (EX, CON) showed evidence of EIB. Eighty percent of the SS group demonstrated abnormal breath sounds upon exposure to aerosolized OVA. Approximately 30% of EXS rats sensitized to OVA but exposed only to exercise had abnormal breath sounds. Lung tissue levels of TNF-α, IL-1α, growth-related oncogene/keratinocyte/chemoattractant, and IFN-γ were significantly higher (P < 0.001) in the SS group, relative to all other groups. Changes in most of these cytokines were not notable in the EXS rats, suggesting a different mechanism of EIB. Remarkably, IFN-γ, but not the other cytokines measured, was significantly elevated following brief exercise in both sensitized and unsensitized rats. Exercise led to detectable breathing sound abnormalities in sensitized rats, but less severe than those observed following classical OVA challenge. Precisely how this immune crossover occurs is not known, but this model may be useful in elucidating essential mechanisms of EIB.

Higher IL-6 and IL6:IGF Ratio in Patients with Barth Syndrome

BackgroundBarth Syndrome (BTHS) is a serious X-linked genetic disorder associated with mutations in the tafazzin gene (TAZ, also called G4.5). The multi-system disorder is primarily characterized by the following pathologies: cardiac and skeletal myopathies, neutropenia, growth delay, and exercise intolerance. Although growth anomalies have been widely reported in BTHS, there is a paucity of research on the role of inflammation and the potential link to alterations in growth factors levels in BTHS patients.MethodsPlasma from 36 subjects, 22 patients with Barth Syndrome (0.5 - 24 yrs) and 14 healthy control males (8 - 21 yrs) was analyzed for two growth factors: IGF-1 (bound and free) and Growth Hormone (GH); and two inflammatory cytokines IL-6 and TNF-α using high-sensitivity enzyme-linked immunosorbent assays.ResultsThe average IL-6 and IL6:IGF ratio levels were significantly higher in the BTHS (p = 0.046 and 0.02 respectively). As for GH, there was a significant group by age interaction (p = 0.01), such that GH was lower for BTHS patients under the age of 14.4 years and higher than controls after age 14.4 years. TNF-α levels were not significantly different, however, the TNF-α:GH was lower in BTHS patients than controls (p = 0.01).ConclusionsComparison of two anabolic growth mediators, IGF and GH, and two catabolic cytokines, IL-6 and TNF-α, in BTHS patients and healthy age-matched controls demonstrated a potential imbalance in inflammatory cytokines and anabolic growth factors. Higher rates of IL-6 (all ages) and lower GH levels were observed in BTHS patients (under age 14.5) compared to controls. These findings may implicate inflammatory processes in the catabolic nature of Barth Syndrome pathology as well as provide a link to mitochondrial function. Furthermore, interactions between growth factors, testosterone and inflammatory mediators may explain some of the variability in cardiac and skeletal myopathies seen in Barth Syndrome.

Inhaled Fluticasone and the Hormonal and Inflammatory Response to Brief Exercise

PURPOSE Inhaled corticosteroids (ICS) improve symptoms in lung diseases, such as asthma. Initial data suggest that the effects of ICS remain localized in the lung; however, recent studies demonstrate alteration to the peripheral immune system in patients with asthma. We sought to evaluate the effect of ICS on peripheral immune mediators and hypothalamic-pituitary-adrenal axis and their response to exercise in healthy men. METHODS Eleven healthy males (18-30 yr old) were placed on 2 wk of fluticasone proprionate (440 μg) twice daily. A 30-min bout of exercise was performed on a cycle ergometer at approximately 70% of peak work rate before and after the start of ICS. Blood was sampled before and after exercise. Cytokines and hypothalamic-pituitary-adrenal axis mediators were measured by ELISA, and fluticasone was measured by liquid chromatography/tandem mass spectrometry. RESULTS After ICS treatment, cortisol and adrenocorticotropin were decreased, and a blunted exercise response was observed for cortisol, adrenocorticotropin, and growth hormone. Peripheral leukocytes and neutrophils were significantly increased in response to exercise in both the untreated and the ICS-treated conditions and at baseline after ICS treatment. Interleukin-6 was elevated with ICS treatment, but the exercise response was blunted. Circulating median fluticasone levels were 0.15 ng·mL(-1) and were increased to 0.20 ng·mL(-1) in response to exercise. CONCLUSIONS Exercise revealed deficits in growth hormone production after ICS treatment not identified by static markers. Neutrophils were shown to be surrogate markers of the systemic effect of ICS. Exercise significantly increased circulating levels of fluticasone. Exercise challenge tests can be used to assess the physiological effect of exogenous corticosteroids.

Characterization of the asthmatic population of St. Vincent and the Grenadines: asthma severity levels and atopic sensitization.

Background. The developing country of St. Vincent and the Grenadines (SVG) reported a 4.5-fold increase in wheezing incidence between 1986 and 2002. It is unknown whether aeroallergens play a significant role in asthma in SVG. Objective. The objective of the study is to investigate the importance of aeroallergens and the association between age and persistence of asthma into adulthood. Methods. Subjects were recruited from the National Asthma Clinic. Asthma was diagnosed in 525 participants and severity levels assigned according to the National Heart, Lung, and Blood Institute guidelines. Participants were separated into three age groups [≤6 years (n=176), 7–18 years (n=164), and ≥19 years (n=185)]. Skin testing was performed on 171 participants to dust mite, cat, dog, cockroach, pollens, and mold. Age of asthma onset was obtained. Results. Persistent asthma was diagnosed in 235 participants (44.8%) and increased with increasing age group (p<.0001). Atopy was identified in 121/171 (70.8%) participants and was significantly higher in persistent asthma (p<.004). A significant positive association was seen between atopy and age group (p<.0004) in participants with intermittent asthma but not in participants with persistent asthma. The most common allergen among the atopic participants was house dust mite (93.4%), followed by cockroach (47.9%). Adult participants reporting asthma onset in adulthood were less atopic than those whose asthma developed ≤18 years of age (p<.05). Conclusions. The predominance of asthma with atopy in SVG implicates a role for atopy in the sudden rise in asthma cases. This asthma characteristic and the increase in persistent asthma with age in SVG are similar to those reported in the developed countries.

A case of localized adrenergic urticaria mimicking an allergic reaction to a sweat chloride test

Adrenergic urticaria (AU) is a rare type of physical urticaria triggered by stress. It is frequently confused with IgE‐mediated urticaria or other physical urticarias. This report describes a case of localized adrenergic urticaria triggered by a sweat chloride test in an adolescent male with multiple atopic disorders. A pruritic papular rash at the site of a sweat chloride test prompted an evaluation for allergic and physical urticarias using multiple skin test methods. A positive intradermal skin test to noradrenaline, which reproduced the rash observed during the sweat test, lead to the diagnosis of adrenergic urticaria. This is the first case report describing an immediate adrenergic urticarial reaction to sweat chloride testing in a patient with other atopic disorders. Pediatr Pulmonol. 2009; 44:935–938.

Vigorous Exercise Can Cause Abnormal Pulmonary Function in Healthy Adolescents

RATIONALE Although exercise-induced bronchoconstriction is more common in adolescents with asthma, it also manifests in healthy individuals without asthma. The steady-state exercise protocol is widely used and recommended by the American Thoracic Society (ATS) as a method to diagnose exercise-induced bronchoconstriction. Airway narrowing in response to exercise is thought to be related to airway wall dehydration secondary to hyperventilation. More rigorous exercise protocols may have a role in detecting exercise-induced bronchoconstriction in those who otherwise have a normal response to steady-state exercise challenge. OBJECTIVES The objective of this study was to determine the effect of two different exercise protocols--a constant work rate protocol and a progressive ramp protocol--on pulmonary function testing in healthy adolescents. We hypothesized that vigorous exercise protocols would lead to reductions in lung function in healthy adolescents. METHODS A total of 56 healthy adolescents (mean age, 15.2 ± 3.3 [SD] years) were recruited to perform two exercise protocols: constant work rate exercise test to evaluate for exercise-induced bronchoconstriction (as defined by ATS) and standardized progressive ramp protocol. Pulmonary function abnormalities were defined as a decline from baseline in FEV1 of greater than 10%. MEASUREMENTS AND MAIN RESULTS Ten participants (17.8%) had a significant drop in FEV1. Among those with abnormal lung function after exercise, three (30%) were after the ATS test only, five (50%) were after the ramp test only, and two (20%) were after both ATS and ramp tests. CONCLUSION Healthy adolescents demonstrate subtle bronchoconstriction after exercise. This exercise-induced bronchoconstriction may be detected in healthy adolescents via constant work rate or the progressive ramp protocol. In a clinical setting, ramp testing warrants consideration in adolescents suspected of having exercise-induced bronchoconstriction and who have normal responses to steady-state exercise testing.

Reduced tetanus antibody titers in overweight children: The Publishers would like to apologize for an error that occured in the title page of Autoimmunity, March 2006; 39(2): 137–141.The correct title page is below.

Under-nutrition impairs immune responses, but far less is known about the impact of over-nutrition, such as obesity, on the response to vaccines. We measured the effect of childhood overweight status on inflammatory mediators, circulating immunoglobulins and tetanus antibodies in fifteen overweight children (BMI > 85 age-adjusted percentile) and 15 age-matched normal weight controls. Fitness was measured by a progressive ramp type exercise test. Lean body mass (LBM) and fat mass were determined by DXA. Tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), interleukin-1 β (IL-1β) and interleukin-1 receptor antagonist (IL-1ra) were used to assess the inflammatory status; and circulating immunoglobulins (IgM, IgA, IgG and IgG subclasses) and specific IgG titer to tetanus were used to assess humoral immunity. Overweight children had higher LBM and percent fat mass, and lower peak VO2 normalized to body weight. IL-6 was significantly higher in the obese children (2.6 ± 0.3 vs. 1.3 ± 0.3 pg/ml, in overweight and normal weight children, respectively; p < 0.05). No significant differences were found in TNF-a, IL-1β and IL-1ra between the groups. No significant differences were found in immunoglobulin levels (IgM, IgA, IgG and IgG subclasses) between the groups. Anti-tetanus IgG antibodies were significantly lower in the overweight children compared to normal weight controls (2.4 ± 0.6 vs. 4.2 ± 0.5 IU/ml, in overweight and normal weight children, respectively; p < 0.05). The reduced specific antibody response to tetanus in obese children and adolescent might be due to mechanical factors such as lower relative vaccination dose, or reduced absorption from the injection site due to increased adipose tissue, or related to reduce immune response due to the chronic low grade inflammation expressed by the higher levels of IL-6.