Showing papers in "Allergy, Asthma and Immunology Research in 2012"

Eosinophil Development, Regulation of Eosinophil-Specific Genes, and Role of Eosinophils in the Pathogenesis of Asthma

Abstract: Eosinophils arise from hematopoietic CD34 + stem cells in the bone marrow. They acquire IL-5Rα on their surface at a very early stage during eosinophilopoiesis, and differentiate under the strong influence of interleukin (IL)-5. They then exit to the bloodstream, and enter the lung upon exposure to airway inflammatory signals, including eotaxins. In inflamed tissues, eosinophils act as key mediators of terminal effector functions and innate immunity and in linking to adaptive immune responses. Transcription factors GATA-1, CCAAT/enhancer-binding protein, and PU.1 play instructive roles in eosinophil specification from multipotent stem cells through a network of cooperative and antagonistic interactions. Not surprisingly, the in terplay of these transcription factors is instrumental in forming the regulatory circuit of expression of eosinophil-specific genes, encoding eosinophil major basic protein and neurotoxin, CC chemokine receptor 3 eotaxin receptor, and IL-5 receptor alpha. Interestingly, a common feature is that the critical cis-acting elements for these transcription factors are clustered in exon 1 and intron 1 of these genes rather than their promoters. Elucidation of the mechanism of eosinophil development and activation may lead to selective elimination of eosinophils in animals and human subjects. Furthermore, availability of a range of genetically modified mice lacking or overproducing eosinophil-specific genes will facilitate evaluation of the roles of eosinophils in the pathogenesis of asthma. This review summarizes eosinophil biology, focusing on development and regulation of eosinophil-specific genes, with a heavy emphasis on the causative link between eosinophils and pathological development of asthma using genetically modified mice as models of asthma.

Epidermal Barrier in Atopic Dermatitis

Abstract: Atopic dermatitis (AD) is a complex disease that affects up to 20% of children and impacts the quality of patients and families in a significant man ner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Filaggrin (FLG ) is synthesized as a large precursor, profilaggrin, and is expressed in the upper layers of the epidermis. FLG plays a critical role in the epidermal barrier, and FLG mutations cause abnormal epidermal function. FLG mutations are strongly associated with early-onset, and persistent severe AD. In addition, FLG deficiency in the epidermis is related to allergic sensitization and asthma. The basic skin care including repair and protection of the skin barrier with proper hydration and topical anti-inflammatory therapy is important to control the severity of skin disease in patients with AD.

Asthma prevention by Lactobacillus rhamnosus in a mouse model is associated with CD4+CD25+Foxp3+ T cells.

Abstract: PURPOSE Probiotic bacteria can induce immune regulation or immune tolerance in allergic diseases. The underlying mechanisms have been recently investigated, but are still unclear. The aim of this study was to evaluate the protective effects of the probiotic Lactobacillus rhamnosus (Lcr35) in a mouse model of asthma and to identify its mechanism of action. METHODS Lcr35 was administered daily by the oral route at a dosage of 1×10(9) CFU/mouse in BALB/c mice for 7 days before the first sensitization. Clinical parameters and regulatory T (Treg) cells were examined. The role of CD4(+)CD25(+)Foxp3(+) Treg cells was analyzed using a Treg cell-depleting anti-CD25 monoclonal antibody (mAb). RESULTS Airway hyperresponsiveness, total IgE production, pulmonary eosinophilic inflammation, and splenic lymphocyte proliferation were suppressed after Lcr35 treatment. Th1 (IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines in the serum were suppressed, and the percentage of CD4(+)CD25(+)Foxp3(+) Treg cells in the spleen was significantly increased in the Lcr35 treatment group. Anti-CD25 mAb administration abolished the protective effects of Lcr35, indicating that CD4(+) CD25(+)Foxp3(+) Treg cells are essential in mediating the activity of Lcr35. CONCLUSIONS Oral administration of Lcr35 attenuated the features of allergic asthma in a mouse model and induced immune regulation by a CD4(+)CD25(+)Foxp3(+) Treg cell-mediated mechanism.

Treatment of Chronic Spontaneous Urticaria

Abstract: Chronic spontaneous urticaria is defined as persistent symptoms of urticaria for 6 weeks or more. It is associated with autoimmunity in approximately 45 percent of patients. Therapy is often difficult however the initial approach should employ high-dose non-sedating antihistamines; 4-6 tablets/day may be necessary. It has been shown that the response to 4 tablets/day exceeds 3, and exceeds 2, which exceeds 1. However the dose that corresponds to the maximal dose of first generation antihistamines (hydroxyzine, diphenhydramine) used previously, is 6/day. Yet over half the patients are refractory to antihistamines and other agents should be tried next. Whereas current guidelines (published) often add leukotriene antagonists and/or H2 receptor antogonists next, these are of little utility. Likewise drugs effective for urticarial vasculitis (colchicine, dapsone, sulfasalazine, hydroxychloroquine) are effective in a small percentage of patients and no study suggests that the response rate of any of them exceeds the 30% placebo responses seen in most double-blind, placebo controlled studies. The drugs that are effective for antihistamine-resistant chronic spontaneous urticaria are corticosteroids, cyclosporine, and Omalizumab. Use of steroids is limited by toxicity. If used at all, a dose of no more than 10 mg/day should be employed with a weekly reduction of 1 mg. The response rates to cyclosporine and Omalizumab are each close to 75%. Cyclosporine can be used effectively if care is taken to monitor blood pressure, urine protein, blood urea nitrogen, and creatinine, every 6 weeks. Omalizumab has the best profile in terms of efficacy/toxicity and, once approved by federal agencies for use in chronic spontaneous urticaria, a dramatic change in the treatment paradigm, whether associated with autoimmunity or not, is predicted. A phase 3 trial is currently in place. Refractoriness to both Omalizumab and cyclosporine is expected to be less than 5 percent of patients. Other agents, can then be tried.

Recent developments in United airways disease.

Abstract: The nose and lung are both part of the respiratory tract. Often the diseases affecting the nose and/or the bronchi are treated separately. However, in recent years, numerous studies have highlighted the fact that the respiratory system is a single entity and the concept of "united airway disease" has become more and more important. The unity of the respiratory tract is confirmed both from a morphological and from a functional point of view. Nevertheless, this concept is also confirmed for the respiratory immune system, innervation and vascularization interesting all along the tract, from the nose to the bronchioles. When treating rhinitis, it is often necessary to assess the presence of asthma. Patients with sinusitis should be evaluated for a possible concomitant asthma. Conversely, patients with asthma should always be evaluated for possible nasal disease. The medications that treat nasal diseases appear to be useful in improving control of asthma and in reducing bronchial hyperresponsiveness as well. Physicians should always keep these notions in mind, and evaluate and treat respiratory diseases taking into account the unity of the respiratory tract.

House Dust Mite Allergy in Korea: The Most Important Inhalant Allergen in Current and Future

Abstract: The house-dust mite (HDM), commonly found in human dwellings, is an important source of inhalant and contact allergens. In this report, the importance of HDM allergy in Korea and the characteristics of allergens from dust mite are reviewed with an emphasis on investigations performed in Korea. In Korea, Dermatophagoides farinae is the dominant species of HDM, followed by D. pteronyssinus. Tyrophagus putrescentiae is also found in Korea, but its role in respiratory allergic disease in Korea is controversial. The relatively low densities of mite populations and concentrations of mite major allergens in dust samples from Korean homes, compared to westernized countries, are thought to reflect not only different climatic conditions, but also cultural differences, such as the use of ‘ondol’ under-floor heating systems in Korean houses. HDM are found in more than 90% of Korean houses, and the level of exposure to HDM is clinically significant. About 40%-60% of Korean patients suffering from respiratory allergies, and more than 40% of patients suffering from atopic dermatitis, are sensitized to HDM. Mite allergens can be summarized according to their inherent auto-adjuvant activities and/or their binding affinities to the adjuvant-like substances: proteolytic enzymes, lipid binding proteins, chitin binding proteins, and allergens not associated with adjuvant-like activity. In general, allergens with a strong adjuvant-like activity or adjuvant-binding activity elicit potent IgE reactivity. In Korea, Der f 2 is the most potent allergen, followed by Der f 1. Immune responses are modulated by the properties of the allergen itself and by the adjuvant-like substances that are concomitantly administered with the antigens. Characterization of allergenic molecules and elucidation of mechanisms by which adjuvant-like molecules modulate allergic reactions, not only in Korea but also worldwide, will provide valuable information on allergic diseases, and are necessary for the development of diagnostic tools and therapeutic strategies.

The revised edition of korean calendar for allergenic pollens.

Abstract: The old calendar of pollens did not reflect current pollen distribution and concentrations that can be influenced by changes of weather and environment of each region in South Korea. A new pollen calendar of allergenic pollens was made based on the data on pollen concentrations obtained in eight regions nationwide between 1997 and 2009. The distribution of pollen was assessed every day at 8 areas (Seoul, Guri, Busan, Daegu, Jeonju, Kwangju, Kangneung, and Jeju) for 12 years between July 1, 1997 and June 30, 2009. Pollens were collected by using Burkard 7-day sampler (Burkard Manufacturing Co Ltd, UK). Pollens which were stained with Calberla's fuchsin staining solution were identified and counted. Pine became the highest pollen in May, and the pollen concentrations of oak and birch also became high. Ragweed appeared in the middle of August and showed the highest pollen concentration in the middles of September. Japanese hop showed a high concentration between the middle of August and the end of September, and mugwort appeared in the middles of August and its concentration increased up until early September. In Kangneung, birch appeared earlier, pine showed a higher pollen concentration than in the other areas. In Daegu, Oriental thuja and alder produced a large concentration of pollens. Pine produced a large concentration of pollens between the middle of April and the end of May. Weeds showed higher concentrations in September and mugwort appeared earlier than ragweed. In Busan the time of flowering is relatively early, and alder and Oriental thuja appeared earliest among all areas. In Kwangju, Oriental thuja and hazelnut appeared in early February. Japanese cedar showed the highest pollen concentration in March in Jeju. In conclusion, update information on pollen calendar in South Korea should be provided for allergic patients through the website to manage and prevent the pollinosis.

The Cockroach and Allergic Diseases

Abstract: The cockroach represents one of the most common sources of indoor allergens worldwide, and 40%-60% of patients with asthma in urban and inner-city areas possess IgE antibodies to cockroach allergens. In Korean homes, four cockroach species have been found, of which the most commonly encountered is the German cockroach. The pathogenic mechanism underlying the association between cockroach allergens and allergic diseases has not been fully elucidated. Allergenicity is associated with the cockroach allergens themselves, enzymatic protease activity, and ligands for pattern recognition receptors. Although allergen-specific adaptive immune responses orchestrate the cockroach allergic response, recent data suggest that the innate immune system is also a critical contributor to pathogenesis. We review the current evidence for the demographics of cockroach exposure and sensitization, characteristics of cockroach allergens, and inflammatory responses to cockroach allergens initiated through protease-dependent pathways.

Role of adipokines and hormones of obesity in childhood asthma.

Abstract: PURPOSE The aim of this study was to evaluate serum levels of leptin, ghrelin, and adiponectin in obese and non-obese children with asthma and in healthy non-asthmatic children, and analyze their relationships with clinical outcomes. METHODS This study enrolled 40 obese and 51 non-obese children with asthma and 20 healthy children. Body mass index and serum leptin, ghrelin, and adiponectin levels were determined in all children. Asthma symptom scores and lung function test results were recorded for subjects with asthma. RESULTS Serum leptin levels (11.8±7.9, 5.3±6.8, and 2.1±2.4 ng/mL in the obese asthmatic, non-obese asthmatic, and control groups, respectively) and adiponectin levels (12,586.2±3,724.1; 18,089.3±6,452.3; and 20,297.5±3,680.7 ng/mL, respectively) differed significantly among the groups (P<0.001 for all). Mean ghrelin levels were 196.1±96.8 and 311.9±352.8 pg/mL in the obese and non-obese asthmatic groups, respectively, and 348.8±146.4 pg/mL in the control group (P=0.001). The asthma symptom score was significantly higher in the obese children with asthma than in the non-obese children with asthma (P<0.001). Leptin and adiponectin levels were correlated with the asthma symptom score in non-obese children with asthma (r=0.34 and r=-0.62, respectively). CONCLUSIONS Obesity leads to more severe asthma symptoms in children. Moreover, leptin, adiponectin, and ghrelin may play important roles in the inflammatory pathogenesis of asthma and obesity co-morbidity.

Effectiveness of Same Versus Mixed Asthma Inhaler Devices: A Retrospective Observational Study in Primary Care

Abstract: Purpose Correct use of inhaler devices is fundamental to effective asthma management but represents an important challenge for patients. The correct inhalation manoeuvre differs markedly for different inhaler types. The objective of this study was to compare outcomes for patients prescribed the same inhaler device versus mixed device types for asthma controller and reliever therapy. Methods This retrospective observational study identified patients with asthma (ages 4-80 years) in a large primary care database who were prescribed an inhaled corticosteroid (ICS) for the first time. We compared outcomes for patients prescribed the same breath-actuated inhaler (BAI) for ICS controller and salbutamol reliever versus mixed devices (BAI for controller and pressurised metered-dose inhaler [pMDI] for reliever). The 2-year study included 1 baseline year before the ICS prescription (to identify and correct for confounding factors) and 1 outcome year. Endpoints were asthma control (defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and severe exacerbations (hospitalisation or oral corticosteroids for asthma). Results Patients prescribed the same device (n=3,428) were significantly more likely to achieve asthma control (adjusted odds ratio, 1.15; 95% confidence interval [CI], 1.02-1.28) and recorded significantly lower severe exacerbation rates (adjusted rate ratio, 0.79; 95% CI, 0.68-0.93) than those prescribed mixed devices (n=5,452). Conclusions These findings suggest that, when possible, the same device should be prescribed for both ICS and reliever therapy when patients are initiating ICS.

Most Highly Cytokinergic IgEs Have Polyreactivity to Autoantigens

Abstract: Purpose: Monomeric IgE molecules, when bound to the high-affinity receptor, exhibit a vast heterogeneity in their ability to induce survival promotion and cytokine production in mast cells. At one end of this spectrum, highly cytokinergic (HC) IgEs can induce potent survival promotion, degranulation, cytokine production, migration, etc., whereas at the other end, poorly cytokinergic (PC) IgEs can do so inefficiently. In this study, we investigated whether IgEs recognize autoantigens and whether IgEs’ binding of autoantigens correlates with difference s in HC versus PC properties. Methods: Enzyme-linked immunosorbent assays were performed to test whether IgEs bind antigens. Histamine-releasing factor in human sera was quantified by western blotting. Cultured mast cells derived from human cord blood were used to test the effects of human sera on cytokine production. Results: Most (7/8) of mouse monoclonal HC IgEs exhibited polyreactivity to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), β-galactosidase, thyroglobulin and/or histamine-releasing factor. By contrast, mouse PC IgEs failed to react with these antigens. A human monoclonal HC IgE also showed polyreactivity to histamine-releasing factor, dsDNA and ssDNA. Interestingly, sera from atopic dermatitis patients showed increased reactivity to ssDNA and β-galactosidase and increased levels of histamine-releasing factor. Some atopic dermatitis patients, but not healthy individuals, had substantial serum levels of HRF-reactive IgE. Sera from atopic dermatitis patients with high titers of DNA-reactive IgE could induce several fold more IL-8 secretion in human mast cells than sera from healthy individuals. Conclusions: The results show that most HC, but not PC, IgEs exhibit polyreactivity to autoantigens, supporting the autoimmune mechanism in the pathogenesis of atopic dermatitis.

Asthma and Rhinitis in South America: How Different They are From Other Parts of the World

Abstract: Asthma and rhinitis epidemiology has wide variations around the world. The aim of this review was verify the prevalence of asthma and rhinitis in South America and report differences from other regions of the world. We reviewed studies with International Study of Asthma and Allergies in Childhood (ISAAC) methodology in South America, Phases I and III. In South America the ISAAC Phase I ranked four countries among top ten in prevalence of asthma and three countries among top ten in prevalence of rhinoconjunctivitis. ISAAC Phase III showed little changes in asthma and rhinitis prevalence in South American countries. The prevalence increases of asthma and rhinitis in South American centers indicate that the burden of both is continuing to rise, but the differences in prevalence are lessening.

Immunologic Evaluation of Drug Allergy

Abstract: Hypersensitivity drug reactions (HDR) consist of an individual abnormal response with the involvement of the immunological system. In addition to specific immunological mechanisms where specific antibodies or sensitised T cells participate, release of inflammatory mediators by non-specific immunological recognition may also occur. Within this category are one of the most common groups of drugs, the non-steroidal anti-inflammatory drugs. In addition to chemical drugs new emerging ones with an increasing protagonism are biological agents like humanised antibodies and others. For IgE dependent reactions both in vivo and in vitro tests can be used for the immunological evaluation. Sensitivity of these is not optimal and very often a drug provocation test must be considered for knowing the mechanism involved and/or establishing the diagnosis. For non-immediate reactions also both in vivo and in vitro tests can be used. Sensitivity for in vivo tests is generally low and in vitro tests may be needed for the immunological evaluation. Immunohistochemical studies of the affected tissue enable a more precise classification of non-immediate reactions. The monitorization of the acute response of the reactions has given clues for understanding these reactions and has promising results for the future of the immunological evaluation of HDR.

Effects of Omalizumab Treatment in Patients With Refractory Chronic Urticaria

Abstract: Purpose: Chronic urticaria (CU) is a common and debilitating disease, and the need for effective treatment has increased. Omalizumab may be an alternative regimen in patients with CU who do not respond to conventional treatments. The aim of this study is to investigate the efficacy and to observe the clinical results of omlizumab in patients with refractory CU. Methods: We conducted a retrospective analysis of 26 patients with refractory CU who were treated with omalizumab. Omalizumab was administered every 2 or 4 weeks, depending on body weight and the total serum IgE level, for 24 weeks. Results: Fourteen patients (53.8%) achieved remission after the treatment; they had a significantly higher prevalence of personal (P=0.033) and family history of allergic diseases (P=0.002) than those who did not achieve remission. During omalizumab treatment, the urticaria activity score declined significantly (12.11±1.97 to 2.7±4.23; P=0.001) and the CU-quality of life score improved significantly (34.65± 13.58 to 60.88±11.11; P=0.004). There were significant decreases in the use of systemic steroids (42.3%-11.5%; P=0.027) and immunomodulators (65.4%-19.2%; P=0.002). The dose of antihistamines required to control CU also decreased significantly (215.66±70.06 to 60.85±70.53 mg/week of loratadine equivalents; P<0.001). No serious adverse event was noted. Conclusions: These findings suggest that omalizumab can be an effective and safe treatment in patients with refractory CU.

The Role of Mycoplasma pneumoniae Infection in Asthma

Abstract: Respiratory infections can cause wheezing episodes in children and can influence the onset and severity of asthma via complex and intersecting mechanisms. Infections can trigger atopic asthma, and atopy can cause wheezing during airway infections and modify the course of airway infections. Mycoplasma pneumoniae (M. pneumoniae), primarily recognized as a causative agent of community-acquired pneumonia, has recently been linked to asthma. Infections with M. pneumoniae can precede the onset of asthma, exacerbate asthmatic symptoms, and cause difficulties with asthma management.1 The clinical association between M. pneumoniae infection and exacerbation of asthma symptoms has been suspected for longer than two decades; however, the nature of the correlation is still far from clear. In 1970, Berkovich et al.2 provided the first prospective study showing serological evidence of infection with either M. pneumoniae or a respiratory virus in 27 of 84 (32%) asthma patients. Huhti et al.3 analyzed 63 patients after severe episodes of acute asthma and found that 19% had associated viral or mycoplasma infections. Biscardi et al.4 reported that 20% (24/119) of the patients with previously diagnosed asthma had simultaneous acute M. pneumoniae infection and asthma exacerbation; of 51 patients experiencing their first episode, acute infection with M. pneumoniae was identified in 26 (50%) of the patients. Therefore, based on the current literature, M. pneumoniae appears to be an important trigger for the acute exacerbation of asthma, accounting for 3.3%-50% of exacerbations. Several recent studies have implicated M. pneumoniae infection in the pathophysiology of asthma in subsets of patients. In two of the most influential studies, Kraft et al.5 and Martin et al.6 used polymerase chain reactions (PCRs) to detect M. pneumoniae in the lower pulmonary airways in 25 of 55 (45%) adult patients with chronic stable asthma, compared with 1 of 11 (9%) controls. Using serology and PCR, Esposito et al.7 found M. pneumoniae significantly more often in children with acute episodes of wheezing than in controls, and infection was significantly associated with a history of recurrent wheezing. Lieberman et al.8 showed in a prospective study using serological detection that M. pneumoniae infection was significantly associated with acute exacerbation of bronchial asthma. Furthermore, treatment with antibiotics against M. pneumoniae significantly improved pulmonary function in asthmatics with M. pneumoniae infection, suggesting a role for infection in chronic asthmatics.9 Although the evidence linking M. pneumoniae infection with exacerbation and chronic asthma is convincing, the role of M. pneumoniae as the cause of the initial onset of asthma remains unclear. In 1994, Yano et al.10 was first to describe a patient in whom a previous acute mycoplasmal respiratory infection led to an initial onset of bronchial asthma. In a follow-up study in 50 children, Mok et al.11 reported that five children (10%) with M. pneumoniae respiratory illness developed clinical signs of asthma. All five children, however, had a family and personal history of atopy. It seems that acute infection with M. pneumoniae can initiate asthma in some previously asymptomatic patients and in some individuals with atopy. However, regarding a quantitative role of these bacteria or a direct cause-and-effect association as asthma initiators, additional large population-based prospective or cohort studies are necessary before definitive conclusions can be drawn. The mechanisms of M. pneumoniae interactions with human airways are complex and multifactorial. Underlying mechanisms of M. pneumoniae infection-induced or exacerbated asthma may involve the stimulation of predisposing immune responses. Factors involved in these immune responses may include the induction of Th2 cytokines, immune cells, and IgE production; physiological changes such as bronchial obstruction, angiogenesis, edema, and cell wall thickening; and even neural mechanisms.5,6,10-12 Further elucidation of these mechanisms may enable the development of novel therapeutic strategies for the prevention and treatment of infection-induced asthma. The immune cells of bronchoalveolar lavage fluid in children with M. pneumoniae pneumonia were found to comprise high percentages of neutrophils and lymphocytes.12 Thus, the exacerbation of asthma may be related to neutrophil cytokine signaling and degranulation, and cell lysis at the respiratory epithelial cell surface.13,14 In addition, asthmatics with infection had a significantly greater number of mast cells than asthma patients without infection.6 These observations suggest that M. pneumoniae infections, particularly in children, may result in a dominant Th2 response that induces increased IgE release, thereby predisposing patients to atopy. Increased airway wall thickness has been observed in several different studies in asthma patients. Continued function requires extensive microvascular systems, and adding thickness to the airway wall further reduces airway conductance.15 Angiogenesis and edema have been associated with airway remodeling in asthma. These responses to M. pneumoniae infection of the airways may induce chronic asthma.16 However, studies about how this feature of asthma is affected during bacterial infection and the impact on treatment of the disease have only recently commenced. Animal models of chronic airway infection with M. pulmonis (the murine equivalent of human M. pneumoniae) have been used to describe the mechanisms underlying angiogenesis, vascular remodeling, and airway wall thickening observed in asthma.15 Airway remodeling results from inflammatory responses that allow the movement of leukocytes and plasma proteins into the airway epithelium. This vascular leakage is promoted by vascular endothelial growth factor (VEGF).15 As presented in this issue of Allergy, Asthma & Immunology Research, Jeong et al.17 investigated the changes in VEGF and interleukin-5 (IL-5) serum levels in atopic children with M. pneumoniae pneumonia. The authors showed that the serum levels of VEGF and IL-5 were increased in atopic children with mycoplasma pneumonia compared with levels in other groups. Furthermore, the serum levels of VEGF and IL-5 were increased at the recovery phase compared with the admission phase. These results suggest an association between M. pneumoniae infection and VEGF or IL-5 in the pathogenesis of atopic asthma in children. A limitation to this study was the reliance on the past and family history of allergic diseases and IgE concentration to define atopy. Future studies will require a more definitive definition of atopy in study subjects. In addition, a long-term follow-up study examining the development of asthma in non-atopic individuals with mycoplasma infection would be interesting. Further research will be required to demonstrate a link between the development of hypersensitivity and M. pneumoniae infection. Despite recent advances in diagnostic technology and the development of animal models representative of human disease, well-designed and controlled human clinical studies and experimentation with animal models are needed to elucidate the role of M. pneumoniae infection in the predisposition for or protection from asthma. Future large, general population-based prospective studies will be necessary to investigate the development of asthma induced by M. pneumoniae infection in humans.

Updates in the Relationship Between Human Rhinovirus and Asthma

Abstract: Human rhinovirus (HRV) is a nonenveloped, single stranded RNA virus belonging to the family Picornaviridae. HRV infections can cause both upper and lower respiratory illnesses in children and adults. Lower respiratory illnesses are more likely to occur in specific high risk groups, including infants, and children and adults with asthma. The relationships between rates of infection and the risk of clinical illness and exacerbation are not completely understood. Recent studies employing polymerase chain reaction and other molecular techniques indicate that there are new branches on the HRV family tree, and one characteristic of recently detected viruses is that they cannot be detected by standard tissue culture. Here we review the current literature and discuss new advances in understanding the link between HRV and asthma.

Evaluation of atorvastatin for the treatment of patients with asthma: a double-blind randomized clinical trial.

Abstract: Purpose Statins are known as cholesterol-lowering agents, but have been suggested for the treatment of asthma because of their anti-inflammatory effects. In this study, the potential therapeutic effects of atorvastatin were investigated in asthmatic patients. Methods A total of 62 patients with persistent mild to moderate asthma who presented at asthma clinics of Arak University of Medical Sciences were recruited in a double-blind randomized clinical trial. The asthma clinical control score was assessed based on the standardized Asthma Control Test. Lung volume, i.e., percentage of forced expiratory volume in one second (FEV1%) and percentage of forced vital capacity (FVC%), and peripheral blood eosinophils were also measured. The intervention group was treated with atorvastatin 40 mg per day for 8 weeks, while the control group received a placebo. Asthma controller treatments were not changed. At the beginning and end of the study, serum cholesterol and triglyceride levels were measured to evaluate adherence of the patients to the treatment. Results The asthma control score did not significantly differ between the intervention and control groups (P=0.06). Difference in FEV1%, FVC%, and blood eosinophil count between the intervention and control groups were not statistically significant (P>0.05). The differences in post-treatment cholesterol and low-density lipoprotein cholesterol levels were significant (P Conclusions Our study shows that atorvastatin is not effective in the treatment of persistent mild to moderate asthma.

A Fatal Case of Intravascular Coagulation After Bee Sting Acupuncture

Abstract: Bee stings can cause severe adverse reactions, leading to anaphylaxis, cardiovascular collapse, and death. In some cases, bee venom also induces disseminated intravascular coagulation (DIC). However, to our knowledge, there has been no fatal case of intravascular coagulation accompanied by anaphylaxis caused by bee sting acupuncture. Here, we report a fatal case of a 65-year-old woman with DIC, following anaphylactic shock after bee sting acupuncture. This case emphasizes that practitioners should consider anaphylaxis followed by coagulation abnormalities when a patient's vital signs are unstable after bee sting acupuncture.

Expression and Roles of MMP-2, MMP-9, MMP-13, TIMP-1, and TIMP-2 in Allergic Nasal Mucosa.

Abstract: Purpose: Allergic rhinitis (AR) and asthma share many characteristics, but structural changes are observed far less often in AR. Matrix metalloproteinases (MMPs) constitute a family of Zn-dependent endopeptidases that can decompose the extracellular matrix and basement membrane, and regulate cell infiltration. We analyzed the expression of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), in allergic nasal mucosa after nasal allergen challenge (NAC) and determined their relationship to inflammatory cells. Methods: Nasal mucosa specimens were obtained at surgery performed for hypertrophied turbinates. We performed NAC with house dust mite (HDM) allergen disks and control disks, and took biopsies at 30 minutes, 6 hours, and 12 hours after NAC. Cells expressing MMP-2, MMP-9, MMP-13, TIMP-1, and TIMP-2, as well as eosinophils and mast cells, were analyzed immunohistochemically. The MMPs and TIMPs in allergic nasal mucosa were quantified using enzyme-linked immunosorbent assays. Results: At 30 minutes post-NAC, HDM-exposed nasal mucosa exhibited significantly more MMP-2+, MMP-9+, MMP13+, TIMP-1+, and TIMP-2+ cells compared with control mucosa, and the numbers of MMP-9+ and TIMP-1+ cells correlated strongly with the number of mast cells. At 6 hours post-NAC, the numbers of MMP+ and TIMP+ cells did not differ significantly between HDM-exposed mucosa and control mucosa, but the ratios of MMP+ cells to TIMP+ cells were higher in HDM-exposed mucosa. At 12 hours post-NAC, the number of MMP-13+ cells tended to be higher in HDM-exposed mucosa and was strongly correlated with the number of eosinophils. Quantitatively, the levels of MMP-2 and MMP-13 were significantly higher than the MMP-9 level, and the TIMP-2 level was significantly higher than the TIMP-1 level in allergic nasal mucosa. Conclusions: We demonstrated increased expression of MMP-2, MMP-9, and MMP-13 in allergic nasal mucosa, high MMPs-to-TIMP-1 ratios, and a strong correlation between MMP-9 and mast cells and between MMP-13 and eosinophils. The imbalance between MMPs and TIMPs may contribute to the migration of inflammatory cells such as eosinophils and mast cells to the nasal mucosa of AR patients, suggesting a possible active role of MMPs in AR.

A case of propofol-induced oropharyngeal angioedema and bronchospasm.

Abstract: Propofol (2,6-diisopropylphenol) is an ultrashort-acting sedative agent with sedative and amnestic effects that is used not only for anesthesia but also for sedation during minor outpatient procedures and endoscopic examinations. Rare cases of anaphylaxis following propofol administration have been reported in the medical literature. Documentation of anaphylaxis is often lacking because the cause and effect relationship is often hard to prove. Only a minority of patients get referred for allergy testing to confirm the offending drug. Here we report a 74-year-old woman who had an anaphylactic reaction with severe oropharyngeal edema and bronchospasm for a few minutes after receiving propofol during endoscopic examination. An allergy skin test was positive for both propofol and soybean. Soybean in the intralipid is one component of propofol, and we concluded that this anaphylaxis was caused by soybean.

The predictors of poorly controlled asthma in elderly.

Abstract: PURPOSE To evaluate asthma control in elderly individuals and identify the factors that predict poor control. METHODS A retrospective, observational study evaluating 108 elderly individuals with asthma (59 females: ≥60 years, mean age: 70.5 years) was conducted at Ajou University Hospital from October 2010 to March 2011. Subjects were classified into two groups according to scores on the asthma control test (ACT). Group I consisted of 38 patients with ACT scores ≤19 (poor controllers) and group II included 70 patients with ACT scores >19 (controllers). Clinical data was analyzed. Spirometry was performed, and the ACT and asthma quality-of-life survey were completed. Medication possession ratios were calculated to evaluate compliance. RESULTS Of the 108 enrolled subjects, 54.6% were female, 7.5% were obese, and 49.0% were atopic. The mean age of the patients was 70.5, and the average of time patients had suffered from asthma was 15.5 years. Comorbid conditions were found in more than 80% of the patients. Allergic rhinitis was most common comorbid condition; this was followed by cardiovascular disease and degenerative arthritis (76.9%, 65.7%, and 51.9%, respectively). Many patients (35.2%) were in poorly controlled states characterized by significantly lower asthma quality of life scores (P<0.001) and higher admission rates (P=0.034). Multivariate logistic regression analysis showed that a history of pulmonary tuberculosis was a predictor of poorly controlled asthma in elderly individuals even after adjusting for age, sex, smoking, lung function and other comorbidities (OR=4.70, CI=1.06-20.81, P=0.042). CONCLUSIONS The asthma of more than one-third of elderly individuals with this condition was poorly controlled, and a history of pulmonary tuberculosis may have contributed to this outcome. Proper evaluation and management of comorbid conditions in elderly patients with asthma is essential for the achievement of better control of the disease and a higher quality of life for those who suffer from it.

Mycoplasma pneumoniae Infection Affects the Serum Levels of Vascular Endothelial Growth Factor and Interleukin-5 in Atopic Children

Abstract: Purpose Previous studies have outlined mechanisms by which Mycoplasma pneumonia (M. pneumonia) infection may promote allergic lung inflammation and airway remodeling, and increasing evidence from human studies suggests that atypical bacterial infections contribute to asthma exacerbation, chronic asthma, and disease severity with changes in cytokine expression. The present study evaluated changes in serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-5 in atopic children with Mycoplasma pneumoniae pneumonia. Methods We recruited a total of 72 children with pneumonia. The patients were divided into 4 groups: atopic children with M. pneumonia pneumonia (group I, n=24), non-atopic children with M. pneumonia pneumonia (group II, n=23), atopic children with viral pneumonia (group III, n=13), and non-atopic children with viral pneumonia (group IV, n=12). Serum levels of IL-5, IL-13, VEGF, and tumor necrosis factor-α were measured at admission and at recovery using enzyme-linked immunosorbent assays. Results Serum levels of VEGF and IL-5 were elevated in group I compared with the other groups at both admission phase and clinical recovery phase. In group I, serum levels of VEGF and IL-5 were higher at recovery phase than at admission phase (VEGF: 1,102.2±569.4 vs. 874.9±589.9 pg/mL, respectively; IL-5: 150.5±63.9 vs. 120.2±46.7 pg/mL, respectively). Conclusions The serum levels of VEGF and IL-5 were more increased in atopic children with M. pneumonia pneumonia than in the other groups. In this group, the serum levels of VEGF and IL-5 were more increased at recovery phase than at admission phase. The results of this study suggest that increases in VEGF and IL-5 may contribute to the development of hypersensitivity during M. pneumonia infection. These cytokines may act through their respective pro-inflammatory pathways to aggravate the allergic status and induce airway hypersensitivity during M. pneumonia pneumonia in atopic children.

Standardization of House Dust Mite Extracts in Korea

Abstract: PURPOSE House dust mites are the most important cause of respiratory allergy in Korea. Standardization of allergen extracts is essential for improving diagnostics and immunotherapeutics. This study was undertaken to evaluate the allergenicity of standardized house dust mite allergen extracts from Korean house dust mite isolates. METHODS Allergen extracts were prepared from cultured Korean house dust mites (Dermatophagoides farinae and D. pteronyssinus). Allergenic activities of Korean house dust mite extracts were compared to standardized extracts from a company in the United States whose allergen concentrations were expressed as Allergy Units (AUs). Specifically, we compared group 1 and 2 major allergens using two-site enzyme-linked immunosorbent assay (ELISA) kits and an in vivo intradermal test. RESULTS Major allergen concentrations were 17.0 µg/mg (5.0 µg/mg of Der f 1 and 12.0 µg/mg of Der f 2) for a D. farinae extract and 24.0 µg/mg (11.6 µg/mg of Der p 1 and 12.4 µg/mg of Der p 2) for a D. pteronyssinus extract. Using chloramphenicol (CAP) inhibition assays, AUs were 12.5 AU/µg for a D. farinae extract and 12.8 AU/µg for a D. pteronyssinus extract. Allergenic activities were 3- to 4-fold stronger when assessed by intradermal skin tests for in vivo standardization. CONCLUSIONS Allergen extracts were prepared from Korean house dust mites and the allergenicities of the extracts were estimated using AU measurements. House dust mite extracts prepared in this study could be utilized as a reference material, which will be useful for the development of diagnostic and immunotherapeutic reagents in Korea.

Diesel Exhaust Exposure, Wheezing and Sneezing

Abstract: The rising incidence of allergic disorders in developed countries is unexplained. Exposure to traffic related air pollutants may be an important cause of wheezing and asthma in childhood. Experimental evidence from human studies suggests that diesel exhaust particles, constituents of fine particulate matter less than 2.5 microns (PM(2.5)), may act to enhance IgE mediated aeroallergen sensitization and Th2 directed cytokine responses. To date, epidemiologic investigations indicate that children living in close proximity to heavily travelled roads are more likely to be atopic and wheeze. The Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort study was initiated to test the hypothesis that early high exposure to traffic related air pollutants is associated with early aeroallergen sensitization and allergic respiratory phenotypes. Using an exposure cohort design, more than 700 infants born to atopic parents were recruited at age 1 living either less than 400 meters (high traffic pollutant exposure) or greater than 1,500 meters (low exposure) from a major road. Children were medically evaluated and underwent skin prick testing with aeroallergen at screening, and re-evaluated sequentially at ages 1, 2, 3, 4, and 7. In this study, both proximity and land use regression (LUR) models of traffic air pollutant exposure have been assessed. Proximity to stop and go traffic with large concentrations of bus and truck traffic predicted persistent wheezing during infancy. The LUR model estimated elemental carbon attributable to traffic (ECAT) as a proxy for diesel exhaust particulate exposure. High ECAT was significantly associated with wheezing at age 1 as well as persistent wheezing at age 3. High mold exposure predicted a well defined asthma phenotype at age 7.

Seasonal Factors Influencing Exercise-Induced Asthma

Abstract: PURPOSE Exercise-induced bronchoconstriction (EIB) in patients with asthma occurs more frequently in winter than in summer. The concentration of house dust mite (HDM) allergens in beds also shows seasonal variation. This study examined the relationship between seasonal differences in the prevalence of EIB and sensitization to HDMs in patients with asthma. METHODS The medical records of 74 young adult male patients with asthma-like symptoms who underwent bronchial challenge with methacholine, 4.5% saline and exercise, and allergen skin prick tests, were reviewed. The subjects were divided into summer (n=27), spring/fall (n=26) and winter (n=21) groups according to the season during which they underwent testing. RESULTS The positive responses to exercise differed according to season (48.1% in summer, 73.1% in spring/fall, and 90.5% in winter; P 0.05). CONCLUSIONS Positive skin test reactions to HDMs and EIB occurred in winter, spring/fall, and summer in decreasing order of frequency. Seasonal variation in the prevalence of EIB may be related to seasonal variation in sensitization to HDMs, accompanied by differences in indirect, but not direct, AHR.

IgE Sensitization to Cephalosporins in Health Care Workers

Abstract: PURPOSE Cephalosporins can induce occupational allergies, such as asthma, urticaria, and anaphylaxis We investigated the prevalence and risk factors of sensitization to cephalosporin METHODS A total of 161 health care workers (HCW), including 138 nurses and 23 pharmacists, and 86 unexposed non-atopic healthy controls were recruited from a single tertiary hospital and the general population A questionnaire regarding work-related symptoms was administered along with skin prick tests (SPT) to the three most commonly used cephalosporins (cefotiam, ceftriaxone, and ceftizoxime) Serum specific IgE antibodies to conjugates of the three cephalosporins and human serum albumin (HSA) were measured by enzyme-linked immunosorbent assay (ELISA) Binding specificities were confirmed by ELISA inhibition tests RESULTS The prevalence of work-related symptoms in association with cephalosporins was 174% The sensitization rate to any cephalosporin was 31% by SPT Sensitization rates determined by measurement of serum specific IgE antibodies were 174% for any cephalosporin, 104% for cefotiam, 68% for ceftriaxone, and 37% for ceftizoxime A personal history of any antibiotic allergy was a risk factor for work-related symptoms (OR, 2493; 95% CI, 261-238), but not for the presence of serum specific IgE antibodies to cephalosporins (OR, 09; 95% CI, 018-453) A personal history of atopic dermatitis was a risk factor for the presence of serum specific IgE antibodies to cefotiam-HSA conjugate (OR, 630; 95% CI, 123-323) CONCLUSIONS A high cephalosporin sensitization rate (174%) was detected by ELISA in HCW exposed to cephalosporins Monitoring of serum specific IgEs to cephalosporin-HSA conjugates will be useful for detecting sensitized subjects

Flow cytometry-assisted basophil activation test as a safe diagnostic tool for aspirin/NSAID hypersenstivity

Abstract: Purpose Aspirin and non-steroidal anti-inflammatory drugs (ASA/NSAIDs) are common causes of drug hypersensitivity. An oral provocation test is the only definitive diagnostic test. This study assessed the reliability of a flow cytometry-assisted basophil activation test (FAST) as a safe diagnostic method for ASA/NSAID-induced hypersensitivity, as its high sensitivity and specificity have been demonstrated for many other drugs.

Fulminant and Fatal Multiple Organ Failure in a 12-Year-Old Boy With Mycoplasma pneumoniae Infection

Abstract: Mycoplasma pneumoniae (Mp) is a unique pathogen that causes not only pulmonary but also extrapulmonary manifestations that must be rapidly diagnosed. A 12-year-old boy, with no relevant medical history, presented with fever, severe epigastric pain, and vomiting. Laboratory findings showed fulminant and cholestatic hepatitis, hemolytic anemia, thrombocytopenia, acute kidney injury, disseminated intravascular coagulopathy, acute myocardial infarction, and rhabdomyolysis. His clinical condition rapidly deteriorated during intubation and continuous renal replacement therapy. Despite intensive treatment, he did not recover. We report a case of fulminant and fatal multiple organ failure in a previously healthy boy with Mp infection, describing the possible pathomechanisms of multiple organ failure involved in the disease.

Decreased Expression of FOXP3 in Nasal Polyposis

Abstract: Purpose: The pathogenesis of nasal polyposis (NP) is unclear. Eosinophils and mast cells are considered to play important roles in this process. In addition, the levels of Th2-type cells are increased, irrespective of the atopic status of the patient with NP. In this context, we and others have shown high levels of thymus and activation-related chemokine/CCL17, macrophage-derived chemokine, eotaxin, and RANTES in patients with NP. Forkhead box P3 (FOXP3) plays a key role in CD4+CD25+ regulatory T-cell function and represents a specific marker for regulatory T cells (Tregs). Decreased expression of FOXP3 has been reported in allergic diseases. The present study was designed to evaluate the presence and potential roles of Tregs, defined by the expression of FOXP3 protein, in NP. Methods: Using immunohistochemistry, we estimated the numbers of FOXP3+ cells in the epithelium and lamina propria of the NPs of 17 patients with chronic rhinosinusitis with NP and the nasal mucosa of 15 patients with allergic rhinitis (AR). The number of FOXP3+ cells in NPs was compared with that in the nasal mucosa of patients with AR, and the numbers of FOXP3+ cells in atopic and non-atopic NP were also compared. Results: The number of FOXP3+ cells in the lamina propria of patients with NP was significantly lower than that in the nasal mucosa of the AR patients (2.79 vs. 5.99, P=0.008). There was no statistically significant difference noted for the numbers of FOXP3+ cells between the epithelium of the NP and the nasal mucosa (3.60 vs. 2.39, P=0.180). Furthermore, the numbers of CD4+FOXP3+ cells were lower in NPs than in the allergic nasal mucosa. There was no difference in the number of FOXP3+ cells between the atopic and non-atopic NP patients. Conclusions: Fewer Tregs (i.e., decreased FOXP3 expression) are found in NPs than in the nasal mucosa of AR patients. As the severity of eosinophilic, Th2-type inflammation and the levels of inflammatory mediators are much higher in NPs than in the nasal mucosa of AR patients, an inverse co-relationship may exist between these parameters and the number of Tregs. The deficiency of Tregs in NP may account for the more pronounced Th2-type inflammation seen in these patients.

Role of Angiogenic Factors in Airway Remodeling in an Allergic Rhinitis Murine Model

Abstract: PURPOSE There is growing evidence that nasal airway remodeling occurs in allergic rhinitis (AR). Although angiogenesis is an important component of airway remodeling in asthma, its involvement in AR has been little studied. Furthermore, information regarding the role of potent angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), in the nasal airway remodeling process is limited. This study was conducted to investigate the role of VEGF and PDGF in nasal airway remodeling, and to assess the preventive effects of anti-angiogenic drugs on this process in a murine AR model. METHODS Mice were systemically sensitized and subjected to inhalation of ovalbumin (OVA) twice a week for 3 months. Control mice were challenged with phosphate buffered saline, while the treatment group received SU1498, a VEGF receptor inhibitor, and/or AG1296, a PDGF receptor inhibitor, via intraperitoneal injection 4 hours prior to each OVA inhalation. Staining using hematoxylin and eosin, Masson's trichrome, and periodic acid-Schiff were separately performed to assess eosinophil infiltration, subepithelial fibrosis, and goblet cell hyperplasia, respectively, in the nasal airway. Immunohistochemical staining for matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) was also conducted. RESULTS Repetitive intranasal inhalation of OVA resulted in significant increases in eosinophil infiltration, subepithelial fibrosis, goblet cell count, and MMP-9/TIMP-1 expression. Administration of SU1498 or AG1296 prevented these abnormal responses. CONCLUSIONS The results of this study suggest that a causal relationship may exist between angiogenic factors and nasal airway remodeling in AR. Inhibition of VEGF or PDGF receptors may, in turn, suppress the remodeling process through the regulation of MMP-9/TIMP-1 expression.