Clinical trials in allergen immunotherapy in the age group of children and adolescents: current concepts and future needs.

Allergen immunotherapy (AIT) is the only treatment option available for allergic patients with disease-modifying intention. Both efficacy and safety has been demonstrated for multiple trials in children, adolescents and adults. Though regulatory requirements for marketing authorization have been clearly outlined and an increasing number of high quality trials has been initiated, multiple concepts and details in study design may be further elaborated, harmonized and improved. An international group of experts in the field of AIT has thoroughly reviewed and discussed current concepts and provided an outlook on further improvement especially in the age group of children and adolescents. Emphasis of the group's discussion as a basis for this article was put on (i) the regulatory background of marketing authorization of AIT products including the 'Pediatric Investigational Plan', (ii) patient reported outcomes and endpoints in AIT trials, (iii) considerations regarding the 'minimal clinically important difference', (iv) the role of placebo effects in AIT clinical trials and clinical routine and (v) the potential of mobile Health for future development of AIT. Current concepts in AIT have been optimized throughout the recent decades, but there remains room for improvement e.g., in the topics outlined in this article.

Magnitude of efficacy measurements in grass allergy immunotherapy trials is highly dependent on pollen exposure.

BACKGROUND: The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)-tablet treatment. METHODS: The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT-tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT-tablet and placebo as a function of average grass pollen counts was modelled by linear regression. RESULTS: The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R(2)  = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season. CONCLUSIONS: In seasonal allergy trials with grass SLIT-tablet, the observed treatment effect is highly dependent on pollen exposure with the magnitude being greater with higher pollen exposure. This is an important relationship to consider when interpreting individual clinical trial results.

Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes T(H)1 cytokine expression while downregulating T(H)2 cytokine expression in PBMCs from human patients with ragweed allergy.

BACKGROUND: Recent studies have demonstrated that bacterially derived immunostimulatory sequences (ISSs) of DNA can activate the mammalian innate immune system and promote the development of T(H)1 cells. Promotion of T(H)1 immunity by means of immunotherapy in allergic patients has led to the alleviation of symptoms that result from allergen-specific T(H)2 responses. OBJECTIVE: Our purpose was to investigate whether the T(H)1-enhancing properties of ISSs could be used to alter the T(H)2-dominated immune response of allergic PBMCs in vitro. METHODS: Ragweed protein-linked ISS (PLI) was generated from a specific, highly active 22-base ISS and Amb a 1, the immunodominant allergen in ragweed pollen, to combine the T(H)1-enhancing properties of ISSs with allergen selectivity, and its activity was investigated in PBMC cultures from subjects with ragweed allergy. RESULTS: PLI was markedly successful at reversing the dominant allergen-induced T(H)2 profile while greatly enhancing IFN-gamma production. Delivering ISSs in a linked form proved to be much more effective at modulating the resulting cytokine profile than delivering free ISSs in a mixture with unlinked Amb a 1. PLI also demonstrated cytokine-modulating properties, even when used to stimulate cells that had already been primed for 6 days with Amb a 1. The antigen specificity of the action of PLI was confirmed by the observations that PLI enhances Amb a 1--specific T-cell proliferation. CONCLUSION: These data indicate that delivery of ISSs within an antigen-specific context exhibits potent cytokine-modulating activity and, combined with its reduced allergenicity, makes this molecule a strong candidate for use in improved immunotherapy applications.

The consideration of immunotherapy in the treatment of allergic asthma.

BACKGROUND: Immunotherapy (IT) has undergone rigorous trials to evaluate its therapeutic benefit in the treatment of allergic respiratory disease. The tools of molecular biology have provided a framework with which to begin to understand the mechanistic effects of IT on the underlying inflammatory component of allergic respiratory disease. RESULTS: The clinical relevance of these observations belies our understanding of allergic inflammation as the subsoil for the development of abnormal airway physiology, heightened bronchial reactivity, and the development of chronic asthmatic symptomatology. CONCLUSIONS: IT provides the potential to downregulate this inflammatory cascade, reduce IgE antibody production, and attenuate symptoms. Conceptually, early intervention of allergic disease holds the most promise as a therapeutic intervention capable of arresting the progression of the disease, altering the severity of the disease, and/or preventing the development of the respiratory disease process.

Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity.

BACKGROUND: Allergen immunotherapy is inconvenient and associated with the risk of anaphylaxis. Efforts to improve the safety of immunotherapy by means of chemical modification of allergens have not been successful because it greatly reduced their antigenicity. Recently, immunostimulatory DNA sequences (ISS or CpG motifs) have been shown to act as strong T(H)1 response-inducing adjuvants. OBJECTIVE: We sought to determine whether conjugation of ISS to the major short ragweed allergen Amb a 1 results in enhanced immunotherapeutic potential in mice and decreased allergenicity in human subjects. METHODS: A 22-mer ISS oligodeoxynucleotide (ISS-ODN) was coupled to Amb a 1 and used for immunization of mice, rabbits, and monkeys. RESULTS: In mice the Amb a 1-ISS conjugate induced a T(H)1 response (IFN-gamma secretion), whereas Amb a 1 induced a T(H)2 response (IL-5 secretion). The T(H)1 response was not observed with an Amb a 1-non-ISS conjugate. Coinjection of Amb a 1 with ISS-ODN was much less effective in inducing a T(H)1 response. In mice primed for a T(H)2 response, injection with Amb a 1-ISS conjugate induced a de novo T(H)1 response and suppressed IgE antibody formation after challenge with Amb a 1. Amb a 1-ISS conjugate induced high-titer anti-Amb a 1 IgG antibodies in rabbits and cynomolgus monkeys, whereas Amb a 1 alone or Amb a 1 coinjected with ISS-ODN did not induce a detectable response. Amb a 1-ISS conjugate was less allergenic than Amb a 1 alone, as shown by a 30-fold lower histamine release from human basophils of patients with ragweed allergy, whereas mixing ISS-ODN with Amb a 1 did not reduce histamine release. CONCLUSION: Amb a 1-ISS conjugate has an enhanced T(H)1-biased immunogenicity and reduced allergenicity. It may offer a more effective and safer approach for allergen immunotherapy than currently available methods.

The consideration of immunotherapy in the treatment of allergic asthma.

Immunotherapy has undergone rigorous trials to assess its therapeutic benefit in the treatment of allergic respiratory disease. The tools of molecular biology have provided a framework with which to begin to understand the mechanistic effects of immunotherapy on the underlying inflammatory component of allergic respiratory disease. The clinical relevance of these observations belies our understanding of allergic inflammation as the subsoil for the development of abnormal airway physiology, heightened bronchial reactivity, and the development of chronic asthmatic symptoms. Immunotherapy provides the potential to downregulate this inflammatory cascade, reduce IgE antibody production, and attenuate symptoms. Conceptually, early intervention of allergic disease holds the most promise as a therapeutic intervention capable of arresting the progression of the disease, altering the severity of the disease, and/or preventing the development of the respiratory disease process.

Managing asthma in adults.

Asthma is a chronic inflammatory disorder of the airways with a spectrum of presentations--from intermittent but mild symptoms to persistent symptoms with chronicity. The key to successful management of the disease process is not only to treat the acute symptoms of wheezing, breathlessness, chest tightness, and cough but also to suppress the underlying inflammatory component. Management requires an integrated approach that incorporates patient education, control of environmental triggers, the judicious use of an appropriate agent to suppress underlying inflammation, addition of adjunctive therapy to optimize primary control, and the supplemental use of a bronchodilator to control breakthrough symptoms. Inhaled corticosteroids are the most effective agents for primary control of patients with persistent asthma. The nonsteroidal antiinflammatory agents cromolyn and nedocromil are alternative choices for primary control. Adjunctive or secondary controllers include maintenance bronchodilators such as salmeterol and long-acting theophylline as well as leukotriene modifiers. Concurrent therapy with an inhaled corticosteroid and a long-acting beta agonist has been shown to provide better asthma control than therapy with either an inhaled corticosteroid plus a leukotriene modifier, an inhaled corticosteroid plus theophylline, or higher doses of an inhaled corticosteroid alone.

Intranasal budesonide aqueous pump spray (Rhinocort Aqua) for the treatment of seasonal allergic rhinitis. Rhinocort Aqua Study Group.

To determine the relative efficacy, compare the incidence of adverse events, and ascertain the systemic glucocorticoid effect of the nasal application of several doses of budesonide, 406 patients with seasonal ragweed-induced allergic rhinitis were randomized in a double-blind, parallel group design to receive intranasal budesonide aqueous pump spray (Rhinocort Aqua) 32 micrograms, 64 micrograms, 128 micrograms, 256 micrograms, or placebo once daily for 4 weeks. A total of 231 adults and 175 children participated in the study conducted at 14 centers in two geographic regions, the Midwest and the Northeast United States, during the 1994 ragweed season. Pollen counts were collected at each site by the Rotorod method. The primary efficacy parameter was the change from baseline nasal index score (NIS) for the overall study population--defined as the sum of scores for nasal congestion, runny nose, and sneezing. The study was powered only to evaluate the overall study population for statistical significance. Significant differences in NIS were observed in each active treatment group compared with placebo (p < or = 0.003). Compared with placebo, budesonide aqueous spray significantly reduced individual symptoms of runny nose and sneezing at all doses (p < or = 0.008), and nasal congestion and nasal itching at all doses except 64 micrograms (p < or = 0.022). In the Midwest pollen belt where the 1994 ragweed season was representative of a typical pollen season, it was possible to establish a dose-response relationship for comparison of budesonide aqueous spray 256 micrograms versus 32 micrograms (p = 0.017). The incidence of adverse events was similar between budesonide aqueous-treated and placebo-treated patients. Importantly, there was no effect of budesonide aqueous spray on basal or ACTH-stimulated plasma cortisol levels in either adults or children at the end of 4 weeks of treatment. Intranasal budesonide aqueous pump spray, administered once daily, was efficacious and was generally well tolerated in both adults and children with seasonal allergic rhinitis.

The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma.

BACKGROUND: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates. OBJECTIVE: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma. METHODS: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared. RESULTS: Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated. CONCLUSION: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Metered dose inhaler: past, present, and future.

BACKGROUND: The metered dose inhaler (MDI) to treat respiratory diseases was introduced many years ago. Due to the recently proposed ban on chlorofluorocarbon (Freon) production, the survival of the conventional MDI is uncertain. It is therefore incumbent on asthma caretakers to familiarize themselves with newer versions of the inhaler. OBJECTIVE: To review the different modalities of aerosolized treatment employed in the management of asthma. This article is specifically focused on issues related to MDIs, the propellants, and the modifications since its introduction. DATA SOURCE: The MEDLINE database was used to review MDI related literature in the English language. CONCLUSION: Dry powder inhalers (especially the multi-dose type) and Freon-free pressurized MDIs appear promising and probably will replace conventional freon-propelled pressurized MDIs when Freon is no longer available.

A double-blind study of the discontinuation of ragweed immunotherapy.

BACKGROUND: Immunotherapy effectively treats the symptoms of allergic rhinitis and improves its pathophysiology. We studied whether the effects of immunotherapy on the early response to nasal challenge with antigen and seasonal symptoms persist after discontinuation. METHODS: Twenty subjects with ragweed allergy who were receiving immunotherapy and who had nasal challenges performed before initiation of treatment were selected. The patients had been receiving maintenance therapy with aqueous ragweed extract at a dose of 12 microg of Amb a 1 equivalent for a minimum of 3 years, at which point they were randomized to receive either placebo injections or to continue with the maintenance dose. Nasal challenges were performed before and 1 year after randomization. Nasal challenges were monitored by counting the number of sneezes and measuring histamine, N-alpha-tosyl-L-arginine methyl ester-esterase activity, and kinins in recovered nasal lavages. In the same year symptom diaries were collected during the ragweed season. RESULTS: The initial immunotherapy significantly reduced responses to nasal challenge in both groups. The group continuing to receive active treatment showed no significant changes from the response before randomization. In contrast, the group randomized to placebo treatment showed a partial return of histamine, kinins, and N-alpha-tosyl-L-arginine methyl ester-esterase in nasal secretions and the numbers of sneezes. IgG antibodies to ragweed declined only in the group switched to placebo treatment. Seasonal rises of IgE antibodies to ragweed did not return during the first season after treatment was stopped. Symptoms reported during the ragweed season were not different between the groups. CONCLUSIONS: One year after discontinuation of ragweed immunotherapy, nasal challenges showed partial recrudescence of mediator responses even though reports during the season appeared to indicate continued suppression of symptoms.

Clinical and immunologic effects of component peptides in Allervax Cat.

Peptides have been designed to be T cell tolerogenic for the principal allergens of the cat. These have been administered in several dosage programs to cat-sensitive patients in multicenter blinded studies. In contrast to proteins in standard extracts, IgE sensitization to peptides is an uncommon event. Pretreatment prick tests with peptides will identify the occasional sensitized patient. Other side reactions consist of allergic symptoms occurring on the day of injections. These become less severe with subsequent injections and are easily treatable with antihistamines or bronchodilators, depending on the symptoms. Treatment with cat peptides ameliorated symptoms that occur upon exposure to cats 1-6 or more weeks later. A 2-week course of 4 injections is the most effective of the regimens so far tried. T-cell-active peptides offer a promising low-risk alternative for specific treatment of respiratory allergies.

Treatment of cat allergy with T-cell reactive peptides.

We induced in allergic humans the counterpart of murine experimental T-cell tolerance. T-cell lines from cat-allergic humans were used to map T-cell epitopes for the principal allergen of cat dander, Fel d 1. Two peptides of 27 amino acids each were synthesized to contain the dominant epitopes (ALLERVAX CAT). After a safety trial, we carried out a blinded study of the dose required for efficacy. We randomly divided 95 cat-sensitive patients into placebo, 7.5 micrograms, 75 micrograms, and 750 micrograms groups. Patients received a subcutaneous injection weekly for 4 wk. Before and after treatment, patients were exposed in a room inhabited by live cats and scored by nose and lung symptoms. Baseline nasal and lung scores (+/-SEM) were 6.2 +/- 0.56 and 5.4 +/- 0.73 in the 750 micrograms group; 7.8 +/- 0.53 and 4.7 +/- 0.68 in the placebo group. Six weeks after treatment, scores adjusted for baseline differences were reduced in the 750 micrograms group: -2.3 +/- 4.9 and -2.3 +/- 0.59 compared with -0.84 +/- 0.50 and -0.85 +/- 0.62 in the placebo group. The 75 micrograms group showed intermediate effects and the 7.5 micrograms group no effect. Linear trend analysis indicated a significant dose response effect: p = 0.05 for nose and 0.03 for lung symptoms. Allergic side effects occurred an hour or more after the first 750 micrograms dose in 16 of 24 patients but required little or no treatment with one exception. T-cell reactive treatment peptides safely improved allergic responses to cats.

Effects of nedocromil sodium on inflammation and symptoms in therapeutic studies.

This review cites clinical evidence demonstrating that nedocromil sodium can reverse the clinical features of airway inflammation in asthma, as shown by decreased bronchial responsiveness, decreased diurnal variation in peak expiratory flow, improved baseline lung function, and a decrease in the frequency and severity of chronic symptoms. Clinical trials have also shown that nedocromil sodium has a statistically significant and clinically relevant effect on daytime and nighttime asthma symptoms within 3 days of starting treatment. On an analysis of relevant trials, the effect on asthmatic cough was significant within 24 hours. This rapid effect on symptoms, together with a reversal of the underlying airways inflammation, is a beneficial combination in the management of asthma.

Comparison of triamcinolone acetonide nasal inhaler with astemizole in the treatment of ragweed-induced allergic rhinitis.

BACKGROUND: Few clinical trials have directly compared the efficacy of antihistamines with topical nasal corticosteroids. OBJECTIVE: The study was performed to compare the efficacy and safety of triamcinolone acetonide nasal spray at a dose of 110 micro g in each nostril once daily with 10 mg of oral astemizole once daily for the treatment of seasonal allergic rhinitis. METHODS: A multicenter, double-blind, parallel-group study was conducted in 239 patients who were randomized to receive either triamcinolone acetonide or astemizole. A 5-day, drug-free, lead-in period was followed by 4 weeks of double-blind treatment. One hundred four patients treated with triamcinolone acetonide and 105 patients treated with astemizole could be evaluated. RESULTS: Overall, triamcinolone acetonide was more effective than astemizole in reducing total nasal symptoms, nasal stuffiness, nasal itching, and sneezing (p

Ragweed immunotherapy in adult asthma.

BACKGROUND: Although allergen immunotherapy is effective for allergic rhinitis, its role in treating asthma is unclear. METHODS: We examined the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. During an observation phase, adults with asthma who were sensitive to ragweed kept daily diaries and recorded peak expiratory flow rates between July and October. Those who reported seasonal asthma symptoms and medication use as well as decreased peak expiratory flow were randomly assigned to receive placebo or ragweed-extract immunotherapy in doses that increased weekly for an additional two years. RESULTS: During the observation phase, the mean (+/- SE) peak expiratory flow rate measured in the morning during the three weeks representing the height of the pollination season was 454 +/- 20 liters per minute in the immunotherapy group and 444 +/- 16 liters per minute in the placebo group. Of the 77 patients who began the treatment phase, 64 completed one year of the study treatment and 53 completed two years. During the two treatment years, the mean peak expiratory flow rate was higher in the immunotherapy group (489 +/- 16 liters per minute, vs. 453 +/- 17 in the placebo group [P = 0.06] during the first year, and 480 +/- 12 liters per minute, vs. 461 +/- 13 in the placebo group [P = 0.03] during the second). Medication use was higher in the immunotherapy group than in the placebo group during observation and lower during the first treatment year (P = 0.01) but did not differ in the two groups during the second year (P = 0.7). Asthma-symptom scores were similar in the two groups (P = 0.08 in year 1 and P = 0.3 in year 2). The immunotherapy group had reduced hay-fever symptoms, skin-test sensitivity to ragweed, and sensitivity to bronchial challenges and increased IgG antibodies to ragweed as compared with the placebo group; there was no longer a seasonal increase in IgE antibodies to ragweed allergen in the immunotherapy group after two years of treatment. Reduced medication costs were counterbalanced by the costs of immunotherapy. CONCLUSIONS: Although immunotherapy for adults with asthma exacerbated by seasonal ragweed exposure had positive effects on objective measures of asthma and allergy, the clinical effects were limited and many were not sustained for two years.