Fractional exhaled nitric oxide response to oral corticosteroids in children with mild-to-moderate asthma: Influence of race.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a noninvasive biomarker of type 2 asthma that can predict response to inhaled corticosteroid therapy. Little is known regarding the magnitude of FeNO reduction after an oral corticosteroid (OCS) course, and less is known whether there are differential responses based on race in children with mild-to-moderate asthma. OBJECTIVE: To assess the effect of a short course of OCS on FeNO in children with asthma and to determine whether the effect is influenced by race. METHODS: Children presenting with an acute asthma exacerbation, who had a FeNO measurement within the past 6 months when clinically stable, were enrolled. Spirometry and FeNO were obtained at the time of exacerbation and after a short course of prednisone. RESULTS: A total of 92 children were identified (aged 11 ± 3.3 years; white, n = 46 [50%], Hispanics, n = 30 [33%], African Americans [AAs], n = 16 [7%]). At baseline, AAs were more atopic and had higher mean FeNO values than both white (48.9 vs 25.6 ppb; P < .05) and Hispanic children (22.5 ppb; P < .05), despite being prescribed similar inhaled corticosteroid doses. During the exacerbation, AAs had the highest FeNO values, whereas there was no difference in lung function between AAs and non-AAs. After prednisone therapy, there was a 56.6% reduction in FeNO, and although AAs maintained the highest FeNO levels, the relative reduction was similar between AAs and non-AAs (53.9% vs 57.8%, respectively). CONCLUSION: FeNO levels reduced by more than 50% after an OCS course. African American children had a greater degree of type 2-driven airway inflammation at baseline, during an exacerbation and after a short course of OCS, compared with non-AAs, although the relative reduction in FeNO was similar between the groups.

Proportion of Severe Asthma Patients Eligible for Mepolizumab Therapy by Age and Age of Onset of Asthma.

BACKGROUND: Mepolizumab is an anti-IL-5 antibody approved for the treatment of severe eosinophilic asthma. However, the prevalence of patients with severe asthma eligible for mepolizumab remains unknown, especially among children. OBJECTIVE: To determine, in a population of patients with severe asthma from a tertiary referral center, the proportion of patients with an eosinophilic phenotype who would be eligible for mepolizumab, when stratified for the age of onset of asthma, and the prevalence of phenotypic features that favor mepolizumab therapy. METHODS: An extensive database of 245 adults and children referred for severe asthma was used. The prevalence of severe asthma was estimated by using the European Respiratory Society/American Thoracic Society criteria. Patients with an eosinophilic uncontrolled phenotype qualified for mepolizumab. RESULTS: In our cohort, 216 (88%) had severe asthma. Based on blood eosinophils of either greater than or equal to 150 cells/µL or greater than or equal to 300 cells/µL, 61%/41% had an eosinophilic phenotype, while 49%/34% were eligible for mepolizumab therapy. A greater percentage of adults (60%/47% of adults with asthma onset in adulthood [AoA] and 48%/26% adults with childhood-onset asthma [<18 years, CoA]) were eligible compared with children (33%/24%), for eosinophil counts of ≥150 and ≥300 cells/µL, respectively; P < .05. Compared with adults, children had a similar number of exacerbations while having better lung function (P < .05). Among adults, those with AoA were older, were more likely to have nasal polyps (28% vs 5%; P < .05), and had higher blood eosinophil counts (272 vs 150 cells/µL; P < .05) compared with those with CoA, with no difference in lung function noted between the 2 groups. Subjects showing greater than or equal to 500 eosinophils/µL, a strong indicator for mepolizumab therapy, had more nasal polyps, higher inhaled steroid dose, lower lung function, and AoA predominance than did those with less than 500 eosinophils/µL (P < .05). CONCLUSIONS: A smaller percentage of children with severe asthma were eligible for mepolizumab compared with their adult peers. Severe AoA has distinct phenotypic features that favor treatment with mepolizumab, including greater eosinophilia and nasal polyposis, in contrast to CoA, which appears to have fewer features of type 2 mucosal inflammation.

Markers of Differential Response to Inhaled Corticosteroid Treatment Among Children with Mild Persistent Asthma.

BACKGROUND: Inhaled corticosteroids are recommended as first-line therapy for children with mild persistent asthma; however, specific patient characteristics may modify the treatment response. OBJECTIVE: Identify demographic, clinical, and atopic characteristics that may modify the inhaled corticosteroid treatment response among children enrolled in the Treating Children to Prevent Exacerbations of Asthma trial. METHODS: Children aged 6 to 18 years with mild persistent asthma were randomized to 44 weeks of combined, daily, rescue, or placebo treatment. Daily treatment consisted of 40 µg of beclomethasone twice daily. Rescue treatment consisted of 40 µg of beclomethasone accompanying each symptom-driven albuterol actuation. Combined treatment consisted of both. Outcomes included time to first exacerbation and proportion of asthma control days. Fourteen baseline characteristics were selected for interaction testing on the basis of their clinical relevance. RESULTS: Two hundred eighty-eight children were randomized. Seventy-five percent were white, and 55% were male. As measured by time to first exacerbation, 4 characteristics identified children who received greater benefit from treatment: non-Hispanic ethnicity, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/µL or more, and history of oral corticosteroid use in the year before enrollment. As measured by asthma control days, 4 characteristics identified children who received greater benefit from treatment: male sex, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/µL or more, and incomplete run-in asthma control. CONCLUSIONS: Children with mild persistent asthma who have markers of atopic asthma or who have greater asthma burden may obtain greater benefit from beclomethasone therapy. Additional study is needed to confirm whether these markers can guide individualized therapy.

Daily or intermittent budesonide in preschool children with recurrent wheezing.

BACKGROUND: Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy. METHODS: We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy. RESULTS: The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen. CONCLUSIONS: A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; MIST ClinicalTrials.gov number, NCT00675584.).

Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment. METHODS: In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5-18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 µg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 µg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329. RESULTS: 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)-555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37-61), the frequency of exacerbations was lower in the daily (28%, 18-40, p=0·03), combined (31%, 21-43, p=0·07), and rescue (35%, 24-47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14-43) in the placebo group, compared with 5·6% (1·6-14) in the combined (p=0·012), 2·8% (0-10) in the daily (p=0·009), and 8·5% (2-15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis. INTERPRETATION: Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided. FUNDING: National Heart, Lung and Blood Institute.

Food allergy: transfused and transplanted.

The inadvertent transfer of food allergy from an allergic donor to an unsuspecting recipient by transfusion or organ donation is a relatively rare but intriguing event with potentially catastrophic consequences. Additionally, the development of food allergy in the recipient of a transplant from a donor who was not food allergic poses questions about why this occurs, why it is observed more frequently in some situations than others, and the mechanisms that may be involved. In this review, the transfer of food allergy by transfusion, bone marrow transplantation, and the transplantation of different solid organs is explored, and potential mechanisms in addition to the importance of careful monitoring are discussed.

Clinical reactivity to ingestion challenge with mixed mold extract may be enhanced in subjects sensitized to molds.

Manifestations of mold allergy are classically associated with inhalation of mold spores leading to symptoms of asthma and other respiratory illnesses. It is largely unknown, however, whether ingestion of aeroallergenic molds, mold spores, or other fungi found in food can also elicit hypersensitivity reactions in mold-sensitive individuals. The aim of this study was to evaluate the association between exposure to molds by oral challenge and elicitation of symptoms in mold- versus nonmold-sensitive individuals. Thirty-four adult atopic subjects were randomized into mold-sensitive groups based on skin test reactivity by skin percutaneous testing (SPT) and/or intradermal (ID) testing to a mixed mold (MM) extract preparation. All subjects underwent a single-blinded, placebo-controlled food challenge to the MM preparation. A modified scoring system was used to grade the clinical severity of symptoms elicited by challenge. All subjects tolerated challenges to the maximal oral mold dose concentration. However, higher symptom scores after challenge were found in mold-sensitive subjects compared with nonmold-sensitive subjects (p = 0.01). When mold-sensitive subjects were compared based on SPT and/or ID reactivity, higher symptom scores and lower symptom-eliciting concentrations of mold were associated with the SPT reactive subgroup compared with the subgroup with ID reactivity alone. In summary, based on our challenge results and scoring model, mold-sensitive subjects compared with nonmold-sensitive subjects experienced cumulatively higher symptom scores after oral challenge to an MM extract preparation. Future studies are warranted to confirm whether ingestion of aeroallergenic molds in food may be another contributor to symptoms in mold-sensitive individuals.

Current epidemiology of asthma: emerging patterns of asthma.

Asthma is a chronic disease associated with substantial morbidity, mortality, and health care use. Between 1980 and 1994, the self-reported prevalence of asthma increased 75% among all race, sex, and age groups in every region of the United States. Although an estimated 14.6 million persons had asthma in the United States in 1996, more recent studies have suggested a plateauing of the prevalence of the disease. Because establishing the diagnosis of asthma and characterizing the features of the disease have long been difficult for both the clinician and the researcher, studies determining the frequency of asthma across different countries and over time, seeking clues to the etiology of the disease, and monitoring for untoward variations provide the clinician with additional resources to manage patients with asthma. The purpose of this article is to provide a brief overview of the current and emerging national and international trends in the epidemiology of asthma.

Are attention deficit hyperactivity disorder and chronic fatigue syndrome allergy related? what is fibromyalgia?

Despite the progress made in the field of allergy-immunology in recent years, there are a group of diseases that the allergist-immunologist may be called on to manage in which their precise etiologies have not been identified but that appear to be initiated or exacerbated by allergic mechanisms. Attention deficit hyperactivity disorder (ADHD), chronic fatigue syndrome (CFS), and fibromyalgia (FM) fall into this category of disorders. Although the precise etiology of ADHD still remains unknown, the most prevalent theory is that it represents a neurobiologically based developmental disability leading to inadequate production of the neurotransmitter dopamine. In patients with CFS, there appears to be a fundamental dysfunction of the neuroendocrine-immunological system with deficiencies of immunological and neurological function, which, together with chronic viral infection, may lead to a sequence of events responsible for the symptoms of this disorder. FM appears to be a variant of CFS with a predominance of hypothalamic pituitary axis dysfunction. The disorder is characterized by chronic widespread pain and the finding of 11/18 tender points on examination. Now, there is emerging evidence to suggest that adverse reactions to foods or food components also may be associated with behavioral disturbances that may play a role in each of these disorders. An understanding of the interactive responses involved in the neuroendocrine-immunological network is essential for a comprehension of the pathophysiology of ADHD, CFS, and FM and the role of allergies appears to be an important triggering event in each of the disorders.

Developmental immunology: clinical application to allergy-immunology.

BACKGROUND: An increase in prevalence of allergic diseases has been seen at an unprecedented rate in many countries throughout the world. Associated with this increase in allergic disease has been a disturbing increase in morbidity and mortality of such diseases as asthma despite the availability of several new therapeutic agents over the past 2 to 3 decades. The search for both environmental factors, eg, new allergens, as well as biologic markers of genetic susceptibility, eg, respiratory viruses, has yielded considerable promise for an explanation for this rising prevalence of allergic disease. OBJECTIVE: To present a central unifying hypothesis based upon recent knowledge concerning the developing human immune system and its interaction with external environmental factors, particularly viral infections, as a basis for a clearer understanding of the changing faces of the allergic diseases throughout the lifespan of the individual. DATA SOURCES: English language articles were selected from PubMed, as well as selected abstracts that would have immediate, practical clinical implications. RESULTS: Review of the current literature strongly suggests a relationship between delayed acquisition of Th1 function in the allergy-prone infant, not only as a predictive marker of susceptibility to the development of allergic disease but also as an explanation for the unique vulnerability of these infants to viral infection, eg, bronchiolitis. Furthermore, viral infection during early development in the allergy-prone infant appears to facilitate allergic sensitization in early infancy. This interesting triad of immune deficiency, viral infection, and atopic genetic susceptibility may provide a basis for early detection of allergic disease and may offer new intervention strategies for the prevention of allergic and infectious disease in the young infant.

Abnormalities of Th1 function in non-IgE food allergy, celiac disease, and ileal lymphonodular hyperplasia: a new relationship?

BACKGROUND: Non-IgE mechanisms may also be involved food allergy (FA). Our group has been studying the immunopathogenesis clinical entities in children with gastro-intestinal symptoms and in whom biopsies of the terminal ileum show lymphoid tissue masses referred to as ileal lymphonodular hyperplasia. Our more recent studies have demonstrated Th1/Th2 cytokine profiles associated with non-IgE FA and other clinical entities. OBJECTIVE: We investigated 12 subjects with non-IgE FA (group 1) and 4 subjects with celiac disease (group 2). Cytokine profiles and immunologic studies of lymphocytes in peripheral blood and from gastro-intestinal biopsy tissues from patients in groups 1 and 2 were also evaluated. METHODS: Group 1 consisted of 12 children with clinical symptoms of anorexia, diarrhea, and abdominal pain. The diagnosis of non-IgE FA was established by positive double-blind, placebo-controlled food challenge and reduced or negative immediate-type skin testing and negative IgE radioallergosorbent tests. Group 2 consisted of four patients with celiac disease and three adult females with biopsy-proven clinical symptoms of celiac disease. RESULTS: In group 1, peripheral blood CD4 and CD8 lymphocyte distributions were normal, with a predominance of CD4+ cells with a decreased intracellular Th1 cytokine pattern and a normal Th2 intracellular cytokine pattern. In contrast, all four patients in group 2 not only displayed abnormal CD4 and CD8 peripheral blood lymphocyte distributions (CD8 > CD4), but also an abnormal predominance of CD4+ cells with an increased Th1 and a normal Th2 cytokine pattern. A similar abnormal pattern of CD4 > CD8 ratio was observed in intestinal biopsies. All 12 patients in group 1 showed lymphonodular hyperplasia in each of the biopsies and by ileoscopy. CONCLUSIONS: These studies suggest that abnormalities in Th1 function may not only play a role in some patients with non--IgE-mediated FA in whom decreased Th1 function is seen, but also in patients with celiac disease in whom an increased Th1 function is seen. The studies also suggest that lymphonodular hyperplasia may be a hallmark histologic lesion in patients with non--IgE-mediated FA.