A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy.

BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

Viral Infections and Wheezing in Preschool Children.

Wheezing is common in childhood, although only a small percentage of these children develop asthma. The child's wheezing phenotype and asthma predictive indices help predict the likelihood of a future asthma diagnosis. Viral infections are common in childhood with most wheezing episodes due to respiratory syncytial virus and rhinovirus. Many treatment options exist for wheezing children including both those who wheeze persistently and those who wheeze intermittently due to viral infections.

Prevention and treatment of recurrent viral-induced wheezing in the preschool child.

OBJECTIVE: To summarize the recent evidence in the treatment of viral-induced wheezing in the infant and preschool aged child. DATA SOURCES: Published literature obtained through PubMed database searches. STUDY SELECTIONS: Studies relevant to phenotypes and treatment of wheezing illnesses in infants and preschool children were included. RESULTS: Recurrent wheezing in preschool children is common and is frequently triggered by viral respiratory tract infections. Certain phenotypes may respond to treatments differently, depending on the risk factors identified. Inhaled corticosteroids, administered continuously or intermittently, reduce the risk of virus-induced wheezing episodes. The use of leukotriene modifying agents may have a role in wheezing episodes in a select group of preschool children. Early administration of azithromycin reduces the risk of severe lower respiratory tract illnesses in children. The effect of oral corticosteroids on wheezing episodes in young children varies by degree of episode severity. CONCLUSION: Recurrent viral-induced wheezing illnesses has been the focus of many clinical trials, which now provide an increasingly robust evidence base for management. Additional research is needed to define optimal strategies, to best match therapies to specific phenotypes and endotypes, and will eventually begin to include therapies directed specifically at the viral triggers.

Characterization of asthma endotypes: implications for therapy.

OBJECTIVE: To describe the concept of precision medicine in treating severe asthma and the utility of relevant biomarkers. DATA SOURCES: PubMed was searched for published articles on human clinical trials using biologics for T-helper type 2 cell (TH2)-low and TH2-high asthma. STUDY SELECTIONS: Studies were selected if they were double-masked, randomized, placebo-controlled trials published in peer-reviewed journals and relevant to the topic. RESULTS: Multiple immune response modifiers have been evaluated in TH2-high asthma geared at blocking interleukin (IL)-5, IL-13, immunoglobulin E, prostaglandin D2, and other pathways. Currently, 3 immune response modifiers approved by the Food and Drug Administration are available for treating severe TH2-high asthma (1 anti-immunoglobulin E and 2 anti-IL-5 monoclonal antibodies) and other TH2-high therapies are in various stages of clinical development. Thus far, many of the TH2-high therapies have shown better efficacy when certain biomarkers are elevated, especially blood eosinophils. The TH2-low endotype does not have any readily available point-of-care biomarkers, so TH2-low asthma is often diagnosed based on a lack of TH2-high biomarkers. These patients tend to have greater resistance to steroids and the development of therapies has lagged behind that for TH2-high asthma. CONCLUSION: Two major endotypes for asthma have been described, TH2-high, manifested by increased eosinophils in the sputum and airways of patients, and TH2-low, with increased neutrophils or a pauci-granulocytic profile. Using these classifications and specific biomarkers has led to promising new therapeutics, especially for TH2-high asthma.

The use of anti-IgE therapy beyond allergic asthma.

Omalizumab is a monoclonal anti-IgE antibody that has been used to treat allergic asthma for over a decade. The use of omalizumab to treat other diseases has largely been limited to case reports until the recently reported large multicenter studies that have established omalizumab as an effective treatment option for chronic spontaneous urticaria. The utility of omalizumab to treat nonallergic asthma and allergic rhinitis and the added safety and therapeutic benefits in combination with allergen immunotherapy have been demonstrated in placebo-controlled trials. Data supporting the clinical efficacy of omalizumab in treating atopic dermatitis, physical urticarias, mast cell disorders, food allergy, and various other allergic disorders have shown promise in small clinical trials and case studies. More carefully designed, large clinical trials of high quality are needed to fully appreciate the potential of omalizumab in treating various allergic and nonallergic diseases.

Promising future therapies for asthma.

Asthma affects 300 million people worldwide and that number has been increasing especially in developed countries. The current standard of care for asthma treatment is based on 2 key pathological features of asthma, airway inflammation and airway obstruction. Improving bronchodilation can be accomplished with ultra-long acting beta2 agonists or long-acting muscarinic agonists used in combination with inhaled corticosteroids. These combinations have already been used effectively for the treatment of COPD. An inhaled phosphodiesterase inhibitor has been shown to improve bronchodilation and decrease airway inflammation. Directly altering the airway smooth muscle with bronchial thermoplasty in select patients has demonstrated long-term benefits but must be measured with immediate post procedure complications. The development of monoclonal antibodies to directly target specific cytokines has had mixed results. In eosinophilic asthma blocking IL-4, IL-5 and IL-13 have improved asthma outcomes. The promise of more directed therapy for asthma appears closer than ever with increased options available for the clinician in the near future.

Immunotherapy: what lies beyond.

Allergen immunotherapy has been used to treat allergic diseases, such as asthma, allergic rhinitis, and venom allergy, since first described over a century ago. The current standard of care in the United States involves subcutaneous administration of clinically relevant allergens for several months, building up to eventual monthly injections for typically 3 to 5 years. Recent advances have improved the safety and efficacy of immunotherapy. The addition of omalizumab or Toll-like receptor agonists to standard subcutaneous immunotherapy has proved beneficial. Altering the extract itself, either through chemical manipulation producing allergoids or directly producing recombinant proteins or significant peptides, has been evaluated with promising results. The use of different administration techniques, such as sublingual immunotherapy, is common in Europe and is on the immediate horizon in the United States. Other methods of administering allergen immunotherapy have been studied, including epicutaneous, intralymphatic, intranasal, and oral immunotherapy. In this review we focus on new types and routes of immunotherapy, exploring recent human clinical trial data. The promise of better immunotherapies appears closer than ever before, but much work is still needed to develop novel immunotherapies that induce immunologic tolerance and enhanced clinical efficacy and safety over that noted for subcutaneous allergen immunotherapy.

The effects of an H3 receptor antagonist (PF-03654746) with fexofenadine on reducing allergic rhinitis symptoms.

BACKGROUND: Nasal H(3) receptors might have a role in mediating the effects of histamine in patients with allergic rhinitis. OBJECTIVE: This study explored the effect of the potent oral H(3) receptor antagonist PF-03654746 in combination with an oral H(1) receptor antagonist on the objective (acoustic rhinometry) and subjective (symptoms) responses to nasal allergen challenge. METHODS: Twenty patients with out-of-season allergic rhinitis displaying a 30% or greater decrease in minimum nasal cross-sectional area (A(min)) after bolus (ragweed) complete nasal allergen challenge at screening were studied by using a randomized, double-blind, single-dose, 4-way crossover design. Treatments included 10 mg of PF-03654746 plus 60 mg of fexofenadine (group 1), 1 mg of PF-03654746 plus 60 mg of fexofenadine (group 2), 60 mg of fexofenadine/120 mg of pseudoephedrine (group 3), and placebo (group 4). After dosing, subjects underwent complete nasal allergen challenge. Nasal symptom scores (no. of sneezes and 0- to 5-point scores for severity of congestion, itching, and rhinorrhea), A(min) (in square centimeters), and nasal volume (in cubic centimeters) were recorded 15, 30, 45, and 60 minutes after allergen. There was a minimum 10-day washout between periods. RESULTS: The following symptom scores were significantly (P ≤ .05) reduced by active treatments versus placebo: group 1, congestion of -0.7 (SE, 0.3), itching of -1.0 (SE, 0.3), rhinorrhea of -1.3 (SE, 0.3), and sneeze of -8.8 (SE, 1.5); group 2, itching of -0.6 (SE, 0.3), rhinorrhea of -0.8 (SE, 0.3), and sneeze of -9.1 (SE, 1.5); and group 3, rhinorrhea of -0.7 (SE, 0.3) and sneeze of -7.0 (SE, 1.5). There was no significant effect of any treatment on mean A(min) proportion or nasal volume proportion after nasal allergen challenge. CONCLUSIONS: In combination with fexofenadine, single doses of PF-03654746 caused a reduction in allergen-induced nasal symptoms. H(3) receptor antagonism might be a novel therapeutic strategy to further explore in patients with allergic rhinitis.

Allergic rhinitis and asthma: celebrating 100 years of immunotherapy.

Since Noon first described allergen immunotherapy a century ago the basic premise of subcutaneous injections (SCIT) of relevant aeroallergens to induce clinical tolerance has remained true [1]. Indeed, allergen immunotherapy did not change dramatically over the first 75 years, but over the past 25 years there have been a number of important advancements leading to newer approaches and novel formulations. Here we review the top 50 articles published in the past 2 years on allergens, environmental control, and immunotherapy for asthma and allergic rhinitis and the use of immunomodulators in allergic disease.

Future forms of immunotherapy and immunomodulators in allergic disease.

Future forms of immunotherapy, particularly toll-like receptor agonists, have shown promising results in animal models of allergic disease although most have failed to translate into successful human clinical trials. These results have helped to elucidate the pleotropic roles of cytokines as well as the diverse phenotypes of allergic diseases, particularly asthma. The goals of these therapies are to improve patient symptoms and quality of life, to prevent and favorably alter disease course, and to maintain a good risk/benefit ratio along with a cost-effective profile.

Future forms of immunotherapy.

Allergic respiratory diseases affect approximately 15% of the US population. Allergen immunotherapy has been a treatment option for diseases such as allergic rhinitis, allergic asthma, and venom allergy for the last 100 years. During the first 75 years, conventional subcutaneous immunotherapy did not change much. However, the last 25 years has seen substantial growth in the development of alternatives to conventional subcutaneous immunotherapy. The addition of omalizumab, an anti-IgE mAb, to immunotherapy offers the potential for increased safety and efficacy. Activation of the innate immune system through Toll-like receptor agonists with and without specific allergens appears to improve the immunologic responses and clinical outcomes in patients with allergic diseases. The use of chemically altered allergens, allergoids, recombinant allergens, and relevant T-cell epitope peptides are all approaches that have yielded positive results. Finally, alternative modes of delivery hold promise, with sublingual immunotherapy rapidly approaching mainstream use in many countries. One thing is clear: the next century of immunotherapy will be vastly different from today's current standard of care.

Immunomodulators in asthma therapy.

New developments in the field of allergy and immunology have yielded a variety of novel therapeutic approaches in recent years, and more agents are at the clinical trial stage. Among the therapeutic approaches discussed in this review are Toll-like receptor agonists, immunostimulatory oligodeoxynucleotides, orally and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor-gamma, and nuclear factor-kappaB are also being evaluated in the treatment of asthma. The anti-IgE monoclonal antibody omalizumab has established effectiveness in patients with allergic asthma, but the criteria for selecting patients who are most likely to benefit from it are less clear. This review summarizes data from human clinical trials with immunomodulators to discuss the rationale for their use, their efficacy, and adverse events associated with them.

Time-dependent effects of inhaled corticosteroids on lung function, bronchial hyperresponsiveness, and airway inflammation in asthma.

BACKGROUND: Exhaled nitric oxide (F(ENO)) and exhaled breath condensate (EBC) are noninvasive markers that directly measure airway inflammation and may potentially be useful in assessing asthma control and response to therapy. OBJECTIVE: To examine the time-dependent effects of inhaled corticosteroids on F(ENO) and EBC markers concomitantly with lung function and bronchial hyperresponsiveness. METHODS: Eleven steroid-naive adults with mild-to-moderate persistent asthma were treated with mometasone furoate dry powder inhaler, 400 microg/d, for 8 weeks, followed by a 4-week washout. Forced expiratory volume in 1 second (FEV1), the concentration of methacholine calculated to cause a 20% decline in FEV1 (PC20), F(ENO), EBC pH, and EBC nitrite measurements before, during, and after treatment were analyzed and compared. RESULTS: The mean (SEM) FEV1 increased from 3.01 (0.13) L (82% predicted) to 3.24 (0.18) L (87% predicted) by week 8 (P < .05). The PC20 level increased from 1.28 (0.31) mg/mL to 2.99 (0.51) mg/mL by treatment week 8 (P < .05) and remained relatively stable through washout week 4 (P < .05). The F(ENO) level decreased from 31.1 (4.1) ppb to 20.6 (4.5) ppb by treatment week 1 (P < .01), remained low through treatment week 8 (P < .01), then trended back to the baseline level by washout week 1 (P < .01). The median EBC pH increased from 7.81 (interquartile range, 7.49-8.09) to 8.02 (interquartile range, 7.87-8.12) by treatment week 4, but did not achieve statistical significance. The EBC nitrite level decreased from 17.6 (1.6) microM to 9.3 (0.9) microM by treatment week 8 (P < .01), and remained low throughout washout week 4 (P < .05). There was a negative correlation between F(ENO) and PC20 (Spearman rank correlation coefficient = -0.50, P < .001). CONCLUSION: The F(ENO) level responded the earliest to treatment and withdrawal of inhaled corticosteroids, whereas changes in EBC markers were delayed but more sustained.

Immunomodulators for allergic respiratory disorders.

New knowledge about the pathogenesis of allergic and immunologic diseases has led to a variety of novel targeted therapeutic approaches. Many immunomodulators are currently under development for the therapy of asthma and allergic and immunologic diseases and are undergoing human clinical trials. The study of immunomodulators in human subjects is ultimately required to determine their therapeutic utility because several agents showing promise in in vitro and animal models have failed in human studies. Novel therapeutic approaches include Toll-like receptor 4 and 9 agonists, immunostimulatory oligodeoxynucleotides, oral and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor gamma, and nuclear factor kappaB are also being evaluated for the treatment of allergic diseases, especially asthma. The anti-IgE mAb omalizumab is already used for the treatment of allergic asthma, but its potential role for other allergic diseases has yet to be clearly defined. Overall, the development of new agents that inhibit specific immunopathogenic mechanisms holds promise for beneficial outcomes for patients with the least amount of risk. However, agents that are too specific in their targets might not exhibit therapeutic benefits because of the redundancy of the immune system and the heterogeneity of diseases such as asthma. The goal of this review is to summarize the data from human clinical trials with immunomodulators, discussing the rationale for their use, efficacy results, and putative adverse events associated with them.

Anti-immunoglobulin e therapy.

The importance of immunoglobulin E (IgE) in atopic disorders such as asthma, allergic rhinitis, food allergies, and atopic dermatitis is well established. Elevation of total serum IgE is typically found in many atopic patients, and in predisposed individuals, allergen-specific IgE is produced. The availability of humanized monoclonal antibodies against IgE has provided a new therapeutic option and tool to explore the role IgE in allergic diseases and the effects of inhibiting IgE itself. Omalizumab is a humanized, monoclonal antibody that recognizes and binds to the Fc portion of the IgE molecule. Administration of omalizumab results in a rapid and substantial decrease in free IgE in serum. Consequently, the activity of cell populations involved in allergic inflammation, including mast cells, eosinophils, basophils, and antigen-presenting cells, is affected as well. Clinically, anti-IgE therapy has already been proven to be useful in the treatment of asthma and allergic rhinitis. The aim of this review is to provide an overview of the mechanisms of action of anti-IgE therapy as well as its efficacy in the treatment of allergic diseases, especially asthma. Considerations regarding dosing and safety of omalizumab will be addressed as well.

Allergy immunotherapy for primary care physicians.

Allergic diseases affect a large proportion of the population of the United States. Although there are many effective pharmacologic therapies available, only allergen-specific immunotherapy has been shown to have significant and long-lasting therapeutic and immunomodulatory effects for the management of allergic rhinitis, allergic asthma, and venom hypersensitivity. Allergen immunotherapy requires a build-up phase as the dose of the vaccine is increased until a therapeutic (maintenance) level is achieved. This maintenance dose is usually continued for 3 to 5 years. Most patients tolerate immunotherapy well, but local reactions are not uncommon. Immunotherapy should only be administered in a physician's office because some patients may experience systemic anaphylactic reactions requiring immediate therapy. Even with newer therapies on the horizon, allergen immunotherapy will continue to have an important role in the treatment of allergic diseases.