Omalizumab in children with uncontrolled allergic asthma: Review of clinical trial and real-world experience.

Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, an anti-IgE mAb, is the first targeted biologic therapeutic approved for the treatment of moderate-to-severe persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged ≥6 years) by the European Medicines Agency in 2009 and the US Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration's Pediatric Advisory Committee meeting are also reviewed.

Allergic disorders at a venerable age: a mini-review.

This review focuses on 3 allergic disorders of persons coming up against venerable age: asthma, allergic rhinitis, and atopic dermatitis. The prevalence of allergic diseases in the elderly ranges from 5 to 10% and appears to be rising. A gradual decline in immune function, termed immunosenescence, and age-related changes in tissue structure influence the development of these disorders. Common complications are comorbidities, polypharmacy, and adverse effects of drugs. The elderly have difficulty mounting protective immune responses against newly encountered antigens. The integrity of epithelial barriers is compromised, leading to a chronic, subclinical inflammatory state and an enhanced Th2 (allergic) immune response. Undiagnosed asthma is frequent in elderly persons (about 8%) and still more commonplace in those with respiratory symptoms. Poorly controlled asthma in the elderly undermines their functional status and leads to a loss of autonomy and social isolation that may delay seeking medical services. Aggravation of allergic rhinitis coincides with exacerbation of asthma, whereas treatment of nasal inflammation improves control of the asthma. Atopic dermatitis is a chronically relapsing inflammatory skin disease often associated with respiratory allergy.

Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. OBJECTIVE: We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD. METHODS: In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination. RESULTS: YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4(+) T-cell responses was observed. CONCLUSIONS: YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus.

The asthma disease activity score: a discriminating, responsive measure predicts future asthma attacks.

BACKGROUND: Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used. OBJECTIVES: We sought to develop a weighted and responsive measure of asthma disease activity. METHODS: Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6). RESULTS: The ADAS-6 demonstrated content validity because its components assess different manifestations of asthma: FEV(1) (percent predicted), Asthma Quality of Life Questionnaire-Symptom domain, rescue ß-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue ß-agonist use diurnal variability. The ADAS-6 demonstrated cross-sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P < .0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties. CONCLUSIONS: The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size.

Response to cutaneous immunization with low-molecular-weight subunit keyhole limpet hemocyanin.

BACKGROUND: This study was carried out to determine whether humoral and cellular immune responses would be provoked by cutaneous administration of keyhole limpet hemocyanin (KLH) and in particular by scarification of the skin (SS). METHODS: This was an unblinded, single-center, 8-week pilot study in healthy young adults. Twenty-four subjects assigned to 4 groups completed the study. Each group was immunized twice, with a 3-week interval, either by SS or intradermally (ID), with an SS dose of 50 or 250 µg and an ID dose of 100 or 250 µg. Serum was collected for antibody assays at baseline and 3 weeks after both the first and second immunizations. Delayed-type hypersensitivity (DTH) testing was performed before the first immunization and 3 weeks after the second. RESULTS: In the 250-µg SS group, there was a significant increase from day 0 to day 47 in anti-KLH IgG (p = 0.02; day 0: 3.46 ± 5.49 mg/dl, day 47: 7.54 ± 8.87 mg/dl) and anti-KLH IgA (p = 0.04; day 0: 4.78 ± 9.15 mg/dl, day 47: 11.42 ± 13.62 mg/dl). One subject in each treatment group showed a positive DTH test result representing 20% (50-µg SS), 10% (250-µg SS), 25% (100-µg ID) and 20% (250-µg ID) of the subjects. CONCLUSIONS: It was possible to induce both humoral and cellular immune responses by SS administration despite the limited antigenic potency of the low-molecular-weight KLH preparation. This approach may be useful for studying the mechanisms of immune response in allergic skin diseases such as atopic dermatitis.

Effects of inhaled mometasone furoate on growth velocity and adrenal function: a placebo-controlled trial in children 4-9 years old with mild persistent asthma.

OBJECTIVE: To assess the effects of long-term mometasone furoate delivered via a dry powder inhaler (MF-DPI) on growth velocity and hypothalamic-pituitary-adrenal axis function in children with asthma. STUDY DESIGN: Children aged 4-9 years with asthma (n = 187) were randomized to MF-DPI 100 µg (delivered dose; actuated dose is 110 µg) once daily in the morning (QD AM), 100 µg twice daily (BID), 200 µg QD AM, or placebo for 52 weeks followed by a 3-month follow-up period. The primary outcome was growth velocity calculated from stadiometric heights recorded at each visit. Secondary outcomes included serum and 12-h urinary cortisol, serum osteocalcin, and urinary N-telopeptide. RESULTS: MF-DPI 100 µg QD AM treatment did not significantly affect growth velocity compared with placebo (-0.10 ± 0.31 cm/y, p = 0.76). When the effect of a total daily dose of 200 µg MF-DPI on growth velocity was examined, no significant effect was demonstrated for MF-DPI 100 µg BID compared with placebo (-0.64 ± 0.39 cm/y, p = 0.10), although the change in mean growth velocity with MF-DPI 200 µg QD AM reached statistical significance (-0.70 ± 0.29 cm/y, p = 0.02). The effects of all examined doses of MF-DPI on mean plasma cortisol levels were similar to cortisol changes seen in the placebo group, suggesting an absence of drug-related effects. No differences in 12-h urinary cortisol or other outcomes were observed between groups. CONCLUSIONS: One year of treatment with a total daily dose of 100 µg of MF-DPI in the morning resulted in no significant difference, whereas a total daily dose of 200 µg of MF-DPI was associated with some changes in growth velocity when compared with placebo. The differences in growth velocity, and the absence of drug-related cortisol effects, support the use of a total daily dose of 100 µg of MF-DPI in children aged 4-9 years with mild persistent asthma.

Safety and tolerability of omalizumab in children with allergic (IgE-mediated) asthma.

OBJECTIVE: This pooled analysis assessed the safety of omalizumab in children with allergic (immunoglobulin E-mediated) asthma. STUDY DESIGN: Two double-blind, placebo-controlled studies in children (6 to < 12 years) with moderate-to-severe allergic asthma investigated the efficacy/safety of omalizumab. Children on optimized asthma care (inhaled corticosteroids ± other controller medications) were randomized (2:1) to omalizumab (75-375 mg sc, q2 or q4 wk) or placebo. Pooled safety findings from these trials are presented in this publication. RESULTS: The safety population included 926 children (omalizumab, n = 624; placebo, n = 302). Adverse events (AEs) were more frequently reported in the placebo (91.7%) than omalizumab (89.7%) group. The most common AEs were nasopharyngitis, upper respiratory tract infection and headache. Suspected treatment-related AEs included headache, erythema and urticaria; none of which were reported by ≥ 2% of patients receiving omalizumab. Serious AEs (SAEs) were reported by 3.4% and 6.6% of patients receiving omalizumab and placebo, respectively; the most common were appendicitis, pneumonia and bronchitis; no deaths were reported. CONCLUSIONS: Omalizumab has an acceptable safety profile, with a risk of AEs similar to placebo. This, combined with its efficacy profile, suggests that omalizumab may provide an additional asthma management option for children (6 to < 12 years) uncontrolled with current therapy that follows established guidelines.

Mometasone furoate in children with mild to moderate persistent asthma: a review of the evidence.

The high prevalence of asthma in pediatric patients underscores the need for effective and safe treatment in this population. Current treatment guidelines recommend inhaled corticosteroids (ICSs) as a preferred treatment for the control of mild to moderate persistent asthma in patients of all ages, including young children. Clinical efficacy, systemic safety, and ease of use are desirable attributes of an ICS used to treat children with persistent asthma. Recently, mometasone furoate administered via a dry powder inhaler (MF-DPI) 110 microg once daily in the evening (delivered dose of 100 microg) was approved by the US FDA for the maintenance treatment of asthma in children 4-11 years of age. Data from the clinical trial program for MF-DPI that establish the efficacy, long-term safety, and absence of systemic effects of the approved dosage in children with mild to moderate persistent asthma are reviewed. These findings indicate that once-daily dosing of MF-DPI in children aged 4-11 years significantly improves lung function and health-related quality of life while reducing rescue medication use and exacerbations despite previous treatment with other ICSs. MF-DPI is also well tolerated in children. Clinical trial results showed that, at the approved dosage, there are no effects on growth velocity or the hypothalamic-pituitary-adrenal axis. Results of pediatric studies are consistent with the clinical development program for adults and adolescents. In addition, once-daily dosing, established safety, and ease of use of MF-DPI may help to improve asthma management by addressing issues that inhibit proper adherence.

The rise of health information technology.

PURPOSE OF REVIEW: The purpose of this review is to discuss transformational changes taking effect in biology and medicine and to place them in a broad historical context. RECENT FINDINGS: Recent findings suggest that in the new millennium, information technology will promote great changes in the study of biology and the practice of medicine. Digital information, more readily assessed, analyzed and manipulated, will be used to integrate large and disparate data sets. Systems biology emerging as an interdisciplinary field will focus on complex interactions in biological systems. Health information technology will make possible efficient healthcare that is predictive, personalized, preventive and participatory. SUMMARY: Systems biologists' understanding of biological information will promote conceptual insights and practical innovations. Predictive, preventive, personalized and participatory medicine will help patients and physicians make optimal treatment decisions.

Managing outpatient asthma exacerbations.

Asthma is a chronic inflammatory disease that renders individuals vulnerable to acute exacerbations. A wide variety of allergic and nonallergic triggers can incite an asthma exacerbation. The goals of managing an asthma exacerbation are prompt recognition, rapid reversal of airflow obstruction, avoidance of relapses, and prevention of future episodes. A written asthma home management plan is essential to minimize the severity of exacerbations. Short-acting beta-agonists, oxygen, and corticosteroids remain fundamental to early intervention in acute asthma exacerbations. Anticholinergics and magnesium sulfate can help nonresponders. Combination inhalers of the long-acting beta-agonist formoterol and inhaled steroid budesonide have been effective in flexible dosing in treating early acute exacerbations and as a daily controller medication outside the United States. Initiation or intensification of long-term controller therapy, treatment of comorbid conditions, trigger avoidance, and prompt follow-up can help prevent relapses. Listening to patient preferences and concerns enhances adherence, and regular follow-up care can help prevent future episodes.

Phenotype of atopic dermatitis subjects with a history of eczema herpeticum.

BACKGROUND: A subset of subjects with atopic dermatitis (AD) are susceptible to serious infections with herpes simplex virus, called eczema herpeticum, or vaccina virus, called eczema vaccinatum. OBJECTIVE: This National Institute of Allergy and Infectious Diseases-funded multicenter study was performed to establish a database of clinical information and biologic samples on subjects with AD with and without a history of eczema herpeticum (ADEH(+) and ADEH(-) subjects, respectively) and healthy control subjects. Careful phenotyping of AD subsets might suggest mechanisms responsible for disseminated viral infections and help identify at-risk individuals. METHODS: We analyzed the data from 901 subjects (ADEH(+) subjects, n = 134; ADEH(-) subjects, n = 419; healthy control subjects, n = 348) enrolled between May 11, 2006, and September 16, 2008, at 7 US medical centers. RESULTS: ADEH(+) subjects had more severe disease based on scoring systems (Eczema Area and Severity Index and Rajka-Langeland score), body surface area affected, and biomarkers (circulating eosinophil counts and serum IgE, thymus and activation-regulated chemokine, and cutaneous T cell-attracting chemokine) than ADEH(-) subjects (P < .001). ADEH(+) subjects were also more likely to have a history of food allergy (69% vs 40%, P < .001) or asthma (64% vs 44%, P < .001) and were more commonly sensitized to many common allergens (P < .001). Cutaneous infections with Staphylococcus aureus or molluscum contagiosum virus were more common in ADEH(+) subjects (78% and 8%, respectively) than in ADEH(-) subjects (29% and 2%, respectively; P < .001). CONCLUSION: Subjects with AD in whom eczema herpeticum develops have more severe T(H)2-polarized disease with greater allergen sensitization and more commonly have a history of food allergy, asthma, or both. They are also much more likely to experience cutaneous infections with S. aureus or molluscum contagiosum.

Systemic exposure and urinary cortisol effects of fluticasone propionate formulated with hydrofluoroalkane in 4- to 11-year-olds with asthma.

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluoro-carbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24-hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open-label, 2-way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 mug twice a day or fluticasone propionate chlorofluorocarbon 88 mug twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 mug twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUC(last) (area under the plasma fluticasone propionate concentration-time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24-hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24-hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic-pituitary-adrenal axis effects as measured by 24-hour urinary cortisol excretion.