Clinical & Experimental Allergy Reviews最新文献

In Japan, about a quarter of the population has Japanese cedar pollinosis. One promising treatment is sublingual immunotherapy, which is under clinical investigation in Japan and not yet covered by the national health insurance system. Since 2005, we have treated more than 200 patients with Japanese cedar pollinosis. We found that sublingual immunotherapy is more effective than drug treatment, but less effective than subcutaneous immunotherapy. Moreover, patients receiving sublingual immunotherapy or subcutaneous immunotherapy use fewer concomitant medications than patients receiving drug treatment. Therefore, sublingual immunotherapy seems to be effective and associated with decreased drug use. The effect of sublingual immunotherapy seems to increase with increasing duration of treatment; the treatment seems to be more effective when continued for ≥4 years than when discontinued after 3 years. We aimed to elucidate the mechanism of action of sublingual immunotherapy. We found that sublingual immunotherapy increases the percentage of interleukin (IL)-10–producing inducible regulatory T cells, and that IL-10 is involved in the immune response to Japanese cedar pollen. Furthermore, levels of antigen-specific immunoglobulin G4 are increased in the cedar pollen season in patients receiving sublingual immunotherapy, and serum levels of IL-33 are increased in non-responders. Our findings should contribute to the further development of sublingual immunotherapy for Japanese cedar pollinosis.

Avoidance of causative foods is the mainstay of therapy for food allergy. This therapy places a burden, to a greater or lesser extent, on food-allergic patients and their parents if they are children. They always face the probable risk of an unexpected accident resulting from intake of a causative food. Allergen-specific immunotherapy for pollinosis and bee-venom allergy has been proven efficient and common in clinical practice. Recently, reports on oral immunotherapy (OIT) for food allergy have been increasing, and OIT has drawn attention as a therapy with the possibility of providing a cure for food allergy. Initially, we review the present status of oral antigen-specific immunotherapy for food allergy. Overall, OIT for food allergy is promising with regard to an increase in tolerance to causative foods. However, several concerns regarding safety remain. Subsequently, we review new approaches for improving the safety of OIT, including sublingual immunotherapy and modified antigens for OIT. We briefly summarize our study on OIT using heated and ovomucoid-reduced egg white as an example of a hypoallergenic antigen for safer OIT.

Immunotherapy is not generally used in Japan and very few medical institutions perform it. For radical treatment, immunotherapy should be selected. However, subcutaneous immunotherapy has not yet gained acceptance. Japanese cedar pollinosis is a seasonal allergic rhinitis that is indigenous to Japan and occurs with a nationwide mean prevalence of 25%. Clinical research on sublingual immunotherapy for Japanese cedar pollinosis has made progress and it should come into practical use within 2–3 years. If sublingual immunotherapy becomes practical, it should provide a new treatment option for Japanese cedar pollinosis.

Allergic rhinitis (AR) is a major health problem with high and ever-increasing prevalence worldwide. At least one-fifth of adults in industrialized countries are estimated to have AR, defined as nasal and eye symptoms that are sufficiently severe to have a substantial negative impact on the quality of life (QoL). The former classification of AR comprised seasonal AR (SAR) and perennial AR (PAR), which did not adequately reflect the presentation and clinical course of the disease. The Allergic Rhinitis and its Impact on Asthma (ARIA) classification is based on the duration of symptoms and the disease severity. Both intermittent AR (IAR: symptoms ≤ 4 days/week or ≤ 4 consecutive weeks) and persistent AR (PER: symptoms > 4 days/week and > 4 consecutive weeks) may be mild, moderate, or severe based on the QOL impairment (sleep, daily activities/leisure, work productivity/school performance) and bothersome symptoms. Despite its disabling effects, AR remains a condition where affected individuals do not seek appropriate treatment, are undertreated and do not adhere well to treatment, which all lead to low disease control and high societal costs. The four pillars of AR treatment are allergen and pollutant avoidance, patient education, pharmacotherapy and allergen-specific immunotherapy. Oral antihistamines, together with intranasal corticosteroids and leucotriene antagonists, constitute important pharmacological options for the treatment of AR at all levels of severity. New second-generation antihistamines are H₁-receptor antagonists with high efficacy (rapid onset of action for AR symptoms, sometimes even on nasal congestion, improvement of QoL and additional anti-allergic effects) and safety (low sedation rates). Although new antihistamines have been studied and approved for SAR and PAR, only some of them have been reported to show efficacy and safety for treatment of AR under the ARIA classification: levocetirizine (high efficacy) and rupatadine (dual antihistamine and anti-PAF effects) for PER, and desloratadine (high safety) for both IAR and PER.

Many women suffer from allergic rhinitis (AR). The disease is often pre-existing and sometimes coincidental during pregnancy, and can worsen, improve, or stay the same during pregnancy. Besides ameliorating the detrimental effects of AR on the patient's quality of life, correct treatment is important for controlling concomitant asthma. If possible, it is important to highlight the risks of not taking such medications at a pre-conception visit. Although most medications for AR readily cross the placenta, there are several choices of treatment for controlling the symptoms during pregnancy. The choices may be varied depending on the disease course and symptoms, and inhaled corticosteroids are considered to be the first-line medical treatment. In addition, either a first-generation antihistamine, such as chlorpheniramine, or a second-generation antihistamine, such as cetirizine or loratadine, can be prescribed as the second-line medical treatment. As an alternative, intranasal cromolyn can be prescribed safely. Some of the leukotriene receptor antagonists and nasal decongestant sprays can only be prescribed when other methods are no longer valid and strict benefits can be expected. It is considered safe to continue immunotherapy during pregnancy.

In Japan, loratadine, fexofenadine, cetirizine and epinastine are currently approved for paediatric use. However, none of these drugs is officially approved for use in children aged under 2 years, and therefore older second-generation antihistamines such as ketotifen and oxatomide are sometimes prescribed for these patients. Because ketotifen and oxatomide have relatively strong sedative effects, one should be cautious when using these antihistamines in young children. In fact, there are reports describing the development of West syndrome, an intractable epilepsy, in 4-month-old infants taking these drugs. Recent clinical trials in Japanese children with allergic rhinitis have shown no serious adverse effects associated with several new second-generation antihistamines, supporting previous overseas reports. New second-generation antihistamines should be approved in the near future for young children in Japan.

In Japan, pollen from Japanese cedar (Cryptomeria japonica) and Japanese cypress (Chamaecyparis obtusa), species that have been planted in approximately 4.5 and 2.6 million ha, respectively, is spread wide through aerial dispersion in spring. Consequently, Japanese cedar/cypress pollinosis (JCCP) is the major phenotype of allergic rhinitis (AR) in Japan, and significantly impairs the quality of life (QOL). Compared with Japanese cedar pollinosis, the pathogenesis and management of Japanese cypress pollinosis remain unclear. Cha o 1 and Cha o 2 are major allergens in Japanese cypress pollen, and have considerable homology with Cry j 1 and Cry j 2, respectively, in Japanese cedar pollen. Several other components were recently identified in Japanese cypress pollen, and may facilitate allergic inflammation via IgE-independent mechanisms. Allergen-specific CD4⁺ Th2 cells producing interleukin (IL)-4, IL-5, IL-13 and IL-31 are believed to play central roles in the pathogenesis of AR. The major human T cell epitopes in Cha o 1 and Cha o 2 have been identified. Compared with those in Cry j 1 and Cry j 2, both common and unique T cell epitopes in the cypress allergens have been characterized. Peripheral blood mononuclear cells (PBMCs) produced these Th2-type cytokines in response to a crude extract of Japanese cypress pollen. Among these cytokines, induction of antigen-specific IL-5 and IL-31 production is closely associated with the onset and exacerbation of Japanese cypress pollinosis, respectively. Allergen-specific immunotherapy using a standardized extract of Japanese cedar pollen is effective in controlling both naso-ocular symptoms and QOL during the period of cedar pollen dispersion, although the significant efficacy tends to be reduced during the period of cypress pollen dispersion, especially when the pollen dispersion is high. IL-5 production by PBMCs in response to the crude extract of Japanese cypress pollen did not differ significantly between patients with and without the immunotherapy, suggesting that unique component(s) in Japanese cypress pollen can induce IL-5 production, which is not fully suppressed by immunotherapy with the standardized extract of cedar pollen. The Practical Guideline for Management of Allergic Rhinitis in Japan recommends that patients who experience severe symptoms of pollinosis every year should receive early interventional treatment. Although early interventional treatment with a histamine H1 receptor antagonist (H1RA) is effective for Japanese cedar pollinosis, especially at the beginning of the season, this treatment has limitations for Japanese cypress pollinosis when exposure to the pollen is high. Combined therapy with a leukotriene receptor antagonist and/or intranasal corticosteroids may be required to fully control the worsening of JCCP during the cypress pollen season.

It is considered that early intervention for pollinosis relieves symptoms during the pollen season in Japan. Therefore, initiating medication prior to pollen dispersal has recently become a popular trend under the influence of the mass media. However, the actual benefits of this kind of early intervention during the peak of the pollen season have not been evaluated enough. We review a randomized placebo-controlled trial that was conducted to examine the efficacy of early intervention (before pollen dispersal) with the oral cysteinyl leukotriene receptor antagonist (LTRA) pranlukast against pollinosis symptoms in patients with allergy to Japanese cedar and cypress pollens in 2007. The subjects were treated with pranlukast or placebo for 4 weeks at the beginning of the cedar pollen dispersal season. Subsequently, all the patients received nasal steroid therapy concomitantly with pranlukast throughout the remaining period of the pollen dispersal season. The effects were evaluated by symptom scores based on allergy diaries and quality of life (QOL) scores as determined by the Japan Rhinoconjunctivitis Quality of Life Questionnaire. In the pranlukast-pre-treated patients, the nasal symptoms (paroxysmal sneezing, runny nose and nasal congestion) were improved during the early Japanese cedar pollen dispersal season. Subsequently, concomitant therapy with pranlukast plus nasal steroids for the rest of the pollen season significantly improved the symptom and QOL scores compared with the placebo-pre-treated patients. This study shows that LTRA administration to Japanese cedar and cypress pollinosis patients starting just before and continuing throughout the pollen dispersion season in high-risk communities is effective for improving the clinical symptoms and indicators of pollinosis. Further assessment of the efficacy of early intervention with an LTRA is required in comparison with other drug therapies, with consideration of the associated cost–benefit effectiveness.

Histamine H1-receptor antagonists (antihistamines) are widely used for the treatment of allergic disorders in young children. It is well known that the newer antihistamine drugs elicit better performances of working memory and selective attention than the first-generation drugs in this class. However, the neural correlates of the poorer performances associated with the first-generation antihistamines remain relatively unknown. In this article, we review recent studies in our laboratory that examined the effects of antihistamine drugs on prefrontal cortex activities in adults and young children using near-infrared spectroscopy (NIRS), an emerging brain imaging method that is suitable for psychological experiments. In the first study, we examined the prefrontal cortex activities while adult subjects performed a working memory task at 3 hours after taking a first-generation antihistamine (ketotifen), a second-generation antihistamine (epinastine), or a placebo. We found that cortical activation at the lateral prefrontal region increased during the performance of the working memory task in subjects administered epinastine or the placebo but not in those administered ketotifen. In the second study conducted in 15 healthy pre-school children (mean age: 5.5 years), ketotifen significantly impaired the behavioural performance and cortical activation at the lateral prefrontal cortex in a working memory task compared with epinastine and the placebo. In the third study conducted in school-aged children (mean age: 7.7 years), ketotifen significantly impaired the behavioural performance and cortical activation at the lateral prefrontal cortex compared with the placebo. There were no sedative effects on the neural responses or behavioural performance after epinastine administration. These studies demonstrate for the first time the differential sedation effects of first- and second-generation antihistamines on brain haemodynamic responses in young children. We also discuss the utility of the NIRS technique in psychopharmacological studies of children.

Airway secretions are produced by glandular and epithelial exocytosis and vascular permeability. Each process plays a unique role in different disease states, and so treatment must be tailored to the pathophysiological mechanism(s). In acute allergic rhinitis, the watery rhinorrhea is predominantly plasma with only about one-third derived from histamine-induced nociceptive afferent nerve and parasympathetic reflexes. The acetylcholine acts on muscarinic M₃ receptors on glands to stimulate exocytosis from both mucous and serous cells. Parasympathetic, cholinergic reflex-mediated glandular secretion responds very well to anticholinergic drugs. More chronic inflammation as seen in chronic rhinosinusitis and bronchitis leads to goblet cell hyperplasia and increased secretion of mucin 5AC (MUC5AC), a secreted, gel-forming mucin that contains many serine–threonine repeats that are studded with large O-linked carbohydrate groups. Progressively worsening inflammation leads to the addition of sialic acid and sulphate to generate acidic mucins. The protein chains are cross-linked by disulphide bonds to form large, buoyant islands that float on the epithelial lining fluid. These sticky macromolecules form complexes with albumin and neutrophil-derived DNA, F-actin, and proteolytic enzymes, creating mucoclots. These tenacious, viscous, mucoclots can adhere to epithelial linings, which may lead to occlusion of small airways that causes reduced airflow in chronic obstructive pulmonary disease and asthma. Mucous plugging is a problem leading to the overwhelming mucous hypersecretion and solidification of ‘end-stage’ acute asthma attacks. Mucous hypersecretion of this severity has been correlated with increased morbidity and mortality in lung disease. Anticholinergic drugs are essential therapies in these conditions. Other medications for mucous hypersecretion include expectorants, anti-inflammatory agents, macrolides, inhaled DNase, and a host of unproven products. Information about signal transduction, transcriptional regulation, and mucin synthesis has provided a framework for understanding the excess production of goblet cell MUC5AC in disease, and has identified potential targets for future drug therapy.