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26.  Reviewer acknowledgement 2013 
Contributing reviewers
The editors of Allergy Asthma & Clinical Immunology would like to thank all of our reviewers who have contributed to the journal in Volume 9 (2013).
PMCID: PMC3911797  PMID: 24490702
27.  A case of anaphylaxis to peppermint 
Anaphylaxis, a form of IgE mediated hypersensitivity, arises when mast cells and possibly basophils are provoked to secrete mediators with potent vasoactive and smooth muscle contractile activities that evoke a systemic response. We report a case of IgE mediated anaphylaxis to peppermint (Mentha piperita) in a male shortly after sucking on a candy.
Case presentation
A 69 year old male developed sudden onset of lip and tongue swelling, throat tightness and shortness of breath within five minutes of sucking on a peppermint candy. He denied lightheadedness, weakness, nausea, vomiting, or urticaria. He took 25 mg of diphenhydramine, but his symptoms progressed to onset of cough, wheeze and difficulty with talking and swallowing. He was rushed to the nearest emergency department, where he was treated with intramuscular epinephrine, antihistamines and steroids. On history, he reported recent onset of mouth itchiness and mild tongue and lip swelling after using Colgate peppermint toothpaste. He denied previous history of asthma, allergic rhinitis, food or drug allergies. His past medical history was remarkable for hypercholesterolemia, gastroesophageal reflux and gout. He was on simvastatin, omeprazole, aspirin, and was carrying a self-injectable epinephrine device. He moved to current residence three years ago and cultivated mint plants in his backyard. He admitted to develop nasal congestion, cough and wheeze when gardening. Physical examination was unremarkable apart from slightly swollen pale inferior turbinates. Skin prick test (SPT) was strongly positive to a slurry of peppermint candy and fresh peppermint leaf, with appropriate controls. Same tests performed on five healthy volunteers yielded negative results. Skin testing to common inhalants including molds and main allergenic foods was positive to dust mites. Strict avoidance of mint containing items was advised. Upon reassessment, he had removed mint plants from his garden which led to resolution of symptoms when gardening.
IgE mediated anaphylaxis to peppermint is rare. This case demonstrates a systemic reaction to a commonly consumed item, incapable of triggering anaphylaxis in the far majority of the population, yet causing a severe episode for our patient.
PMCID: PMC3912937  PMID: 24472564
Anaphylaxis; Peppermint; Menthol; IgE mediated
28.  Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy 
Sub-cutaneous immunotherapy is an effective treatment for allergy. It works by helping to modify or re-balance an individual’s immune response to allergens and its efficacy is greatly improved by the use of adjuvants, most commonly, aluminium hydroxide. Aluminium salts have been used in allergy therapy for many decades and are assumed to be safe with few established side-effects. This assumption belies their potency as adjuvants and their potential for biological reactivity both at injection sites and elsewhere in the body. There are very few data purporting to the safety of aluminium adjuvants in allergy immunotherapy and particularly so in relation to longer term health effects. There are, if only few, published reports of adverse events following allergy immunotherapy and aluminium adjuvants are the prime suspects in the majority of such incidents. Aluminium adjuvants are clearly capable of initiating unwanted side effects in recipients of immunotherapy and while there is as yet no evidence that such are commonplace it is complacent to consider aluminium salts as harmless constituents of allergy therapies. Future research should establish the safety of the use of aluminium adjuvants in sub-cutaneous allergy immunotherapy.
PMCID: PMC3898727  PMID: 24444186
Aluminium adjuvant; Immunotherapy; Allergy; Adverse events
29.  T cell unresponsiveness in a pediatric cystic fibrosis patient: a case report 
A girl was diagnosed with cystic fibrosis (CF) at birth, with repeatedly positive sweat tests and homozygous F508del mutations of her CF transmembrane conductance regulator (CFTR) gene. From an early age, her lung disease was more severe than her birth cohort peers despite aggressive treatment. At the age of 16 she was listed for lung transplantation, but prior to transplant was not on systemic corticosteroids or other immunosuppressive agents. In response to ex vivo stimulation, her pre-transplant peripheral blood T cells unexpectedly failed to produce detectable levels of IFN-γ, unlike cells from healthy controls or from another girl with CF and lung disease of comparable severity. Furthermore, naïve T cells freshly isolated from her peripheral blood showed a complete block of T cell differentiation into Th1, Th17 and Treg lineages, even in the presence of cytokines known to promote differentiation into the respective lineages. Her serology has been remarkably devoid of evidence of exposure to viruses that have been associated with T cell exhaustion. However, her freshly isolated naïve T cells showed sustained expression of markers of T cell exhaustion, which were further induced upon ex vivo stimulation, pointing to T cell exhaustion as the cause of the failure of naïve T cells to undergo differentiation in response to cytokine stimulation. Although excessive inflammation in CF lung can be both ineffective at clearing certain pathogens as well as destructive to the lung tissue itself, adequate inflammation is a component of an effective overall immune response to microbial pathogens. Our present findings suggest that intrinsic impairment of T cell differentiation may have contributed to the greater severity and more rapid progression of her CF lung disease than of the lung disease of most of her peers.
PMCID: PMC3896844  PMID: 24438707
T cell exhaustion; Cystic fibrosis; Naïve T cells; T cell differentiation
30.  New efficacy of LTRAs (montelukast sodium): it possibly prevents food-induced abdominal symptoms during oral immunotherapy 
The aim of the study was to elucidate whether leukotriene receptor antagonists (LTRAs) can prevent severe allergic reactions, which occur during oral immunotherapy (OIT) in children with food allergies.
Five children with food allergies [3 allergic to hen’s egg (HE), 1 to wheat, and one to cow’s milk (CM); aged between 7 and 12 years; median, 8.5 years] who were started on LTRAs during OIT were retrospectively selected from among 63 children undergoing OIT. In the rush phase, after the administration of the initial dose which was set in open food challenge test, the subsequent doses were increased by approximately 1.2 times of the previous dose and were administered every 2 hours, 4 times a day. The target doses of hen’s egg, wheat (udon noodle), and cow’s milk in the rush phase were 50 g, 200 g, and 200 ml, respectively. The ingestion of the target dose was continued at home every day for at least a year in the maintained phase.
Four participants experienced intractable abdominal pain during the rush phase; therefore, the loading dose was not increased in these children. However, the administration of LTRAs prevented their symptoms, resulting in the completion of the rush phase. One participant also experienced intractable abdominal pain during the maintenance phase. After receiving LTRAs, the target dose was able to tolerated.
The findings from this retrospective study suggest that the administration of LTRAs is useful for the prevention of adverse allergic reactions such as abdominal pain during OIT.
PMCID: PMC3904422  PMID: 24438769
Abdominal pain; Food allergy; LTRA (montelukast sodium); Rush oral immunotherapy
31.  Safety and feasibility of oral immunotherapy to multiple allergens for food allergy 
Thirty percent of children with food allergy are allergic to more than one food. Previous studies on oral immunotherapy (OIT) for food allergy have focused on the administration of a single allergen at the time. This study aimed at evaluating the safety of a modified OIT protocol using multiple foods at one time.
Participants underwent double-blind placebo-controlled food challenges (DBPCFC) up to a cumulative dose of 182 mg of food protein to peanut followed by other nuts, sesame, dairy or egg. Those meeting inclusion criteria for peanut only were started on single-allergen OIT while those with additional allergies had up to 5 foods included in their OIT mix. Reactions during dose escalations and home dosing were recorded in a symptom diary.
Forty participants met inclusion criteria on peanut DBPCFC. Of these, 15 were mono-allergic to peanut and 25 had additional food allergies. Rates of reaction per dose did not differ significantly between the two groups (median of 3.3% and 3.7% in multi and single OIT group, respectively; p = .31). In both groups, most reactions were mild but two severe reactions requiring epinephrine occurred in each group. Dose escalations progressed similarly in both groups although, per protocol design, those on multiple food took longer to reach equivalent doses per food (median +4 mo.; p < .0001).
Preliminary data show oral immunotherapy using multiple food allergens simultaneously to be feasible and relatively safe when performed in a hospital setting with trained personnel. Additional, larger, randomized studies are required to continue to test safety and efficacy of multi-OIT.
Trial registration NCT01490177
PMCID: PMC3913318  PMID: 24428859
Food allergy; Oral immunotherapy (OIT); Specific oral tolerance induction (SOTI); Multiple; Safety; Efficacy
32.  Spectrum of primary immunodeficiency disorders in Sri Lanka 
While primary immunodeficiencies (PID has been recognized in the west for decades, recognition has been delayed in the third world. This study attempts to detail the spectrum of PID, the therapy provided, and constraints in the diagnosis and treatment in a middle income country such as Sri Lanka.
Nine hundred and forty two patients with recurrent infections and features suggestive of immune deficiency, referred from the entire country in a 4 year period, to the sole immunology unit in Sri Lanka were included. The following tests were performed. Full blood counts, serum Immunoglobulin and complement C3 and C4 levels, functional antibody levels, enumeration of lymphocyte subsets, in vitro and in vivo T cell functional assays,, nitroblue tetrazolium assay to diagnose chronic granulomatous disease, hair shaft assay to diagnose Griscelli syndrome. Sequencing of the common gamma chain to identify x linked severe combined immune deficiency, and X linked agammaglobulinemia was confirmed by assaying for Btk mutations by single sequence conformation polymorphism. HIV/AIDS was excluded in all patients.
Seventy three patients were diagnosed with a primary immune deficiency. The majority (60.27%) had antibody deficiency. Common variable immune deficiency was the commonest (28.76%), followed by X linked agammaglobulinemia (XLA) (20.54%). Five patients had possible hyper IgM syndrome.
Ten patients had severe combined immune deficiency (SCID), including 2 with x linked SCID, in addition to DiGeorge syndrome (2), ataxia telangiectasia (6), autosomal dominant hyper IgE syndrome (2), chronic granulomatous disease (4), leucocyte adhesion deficiency type 1 (2) and Griscelli syndrome (3).
Patients with autoinflammatory, innate immune and complement defects could not be identified due to lack of facilities.
Antibody deficiency is the commonest PID, as in the west.IgA deficiency is rare. Autoinflammatory diseases, innate immune and complement deficiencies could not be identified due to lack of diagnostic facilities. Lack of awareness of PID among adult physicians result in delay in treatment of adult patients. While treatment of antibody deficiencies provided in state hospitals has extended life expectancy, there is no treatment available for severe T cell defects.
PMCID: PMC3880003  PMID: 24373416
Primary immunodeficiency; Common variable immune deficiency; X linked agammaglobulinemia; Severe combined immune deficiency
33.  Post-hospital syndrome in adults with asthma: a case-crossover study 
Post-hospital syndrome refers to the period of generalized risk of adverse health outcomes among patients who are recently discharged from hospital. This period is associated with a short-term increased risk of readmission which may not be related to the original condition. While the majority of studies of post-hospital syndrome have focused on all-cause readmissions, whether and to what extent such a phenomenon exists within discrete medical conditions is not yet known.
To investigate whether the risk of admission due to asthma is increased in individuals who are discharged following any-cause hospital admission.
Using administrative health data for the period 1997 to 2007 from the province of British Columbia, Canada, we created a cohort of adults with asthma. Using a case-crossover design, we assessed the association between discharge from a hospital (exposure) within 30 days before an asthma-related hospitalization (the outcome), using two 30-day control periods within the same subject. Conditional logistic regression was performed to calculate the relative risk (RR) of the outcome in association with exposure. We performed several sensitivity and subgroup analyses.
The final cohort included 3,852 patients experiencing 6,333 instances of the outcome. Mean age at the time of the outcome was 43.7 (SD 14.2), 69.0% of such outcomes belonged to females. The RR of the outcome within the next 30 days of a previous any-cause discharge was 1.40 (95% CI 1.22 - 1.59). However, the association was mainly caused by discharge from asthma-related admission [RR = 1.99 (95% CI 1.65 - 2.39)]. The RR associated with non-asthma-related discharge was 0.88 (95% CI 0.74 - 1.04) and was not statistically significant. Similar results were obtained in a range of sensitivity analyses.
Our results indicate that in patients with asthma, the 30-day risk of asthma-related admission is increased after an episode of asthma-related hospitalization, but not after an episode of non-asthma-related hospitalization.
PMCID: PMC3880050  PMID: 24364886
34.  Staphylococcal enterotoxin B influences the DNA methylation pattern in nasal polyp tissue: a preliminary study 
Staphylococcal enterotoxins may influence the pro-inflammatory pattern of chronic sinus diseases via epigenetic events. This work intended to investigate the potential of staphylococcal enterotoxin B (SEB) to induce changes in the DNA methylation pattern. Nasal polyp tissue explants were cultured in the presence and absence of SEB; genomic DNA was then isolated and used for whole genome methylation analysis. Results showed that SEB stimulation altered the methylation pattern of gene regions when compared with non stimulated tissue. Data enrichment analysis highlighted two genes: the IKBKB and STAT-5B, both playing a crucial role in T- cell maturation/activation and immune response.
PMCID: PMC3867657  PMID: 24341752
Staphylococcus aureus enterotoxin B; Chronic rhinosinusitis and nasal polyps; DNA methylation; MBD2; Whole genome methylation analysis; Hypermethylation
35.  Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting 
Oral corticosteroids (OCS) are commonly administered in patients with severe persistent allergic asthma. Despite their efficacy, they are associated with a wide variety of adverse events. The eXpeRience registry was set up to investigate real-world outcomes among patients receiving omalizumab for the treatment of uncontrolled allergic asthma. Here, we present the effect of omalizumab treatment on OCS use.
eXpeRience was a 2-year, multinational, non-interventional, observational registry of patients receiving omalizumab for uncontrolled allergic asthma. OCS use (proportion of patients on maintenance OCS, mean total daily OCS dose and change in status of OCS therapy) was assessed at baseline, 16 weeks, and 8, 12, 18, and 24 months after the initiation of omalizumab. Response to omalizumab was assessed using the physician’s Global Evaluation of Treatment Effectiveness (GETE) at approximately Week 16. Safety data were also recorded.
A total of 943 patients (mean age, 45 years; female, 64.9%) were enrolled in the registry, 263 of whom were receiving maintenance OCS at baseline. The proportion of patients taking maintenance OCS was markedly lower at Months 12 (16.1%) and 24 (14.2%) than at baseline (28.6%; intent-to-treat population). GETE status was determined in 915 patients receiving omalizumab: 64.2% were responders (excellent or good response), 30.7% were non-responders (moderate, poor or worsening response); 5.1% had no assessment. The frequency of serious adverse events was comparable to that seen in controlled trials of omalizumab.
Omalizumab use is associated with an OCS-sparing effect in patients with uncontrolled persistent allergic asthma in the real-world setting.
PMCID: PMC3879326  PMID: 24305549
Anti-immunoglobulin E; Oral corticosteroid use; Omalizumab; Registry; Uncontrolled persistent allergic asthma
36.  Vitamin C and common cold-induced asthma: a systematic review and statistical analysis 
Asthma exacerbations are often induced by the common cold, which, in turn, can be alleviated by vitamin C.
To investigate whether vitamin C administration influences common cold-induced asthma.
Systematic review and statistical analysis of the identified trials. Medline, Scopus and Cochrane Central were searched for studies that give information on the effects of vitamin C on common cold-induced asthma. All clinically relevant outcomes related to asthma were included in this review. The estimates of vitamin C effect and their confidence intervals [CI] were calculated for the included studies.
Three studies that were relevant for examining the role of vitamin C on common cold-induced asthma were identified. The three studies had a total of 79 participants. Two studies were randomized double-blind placebo-controlled trials. A study in Nigeria on asthmatics whose asthma attacks were precipitated by respiratory infections found that 1 g/day vitamin C decreased the occurrence of asthma attacks by 78% (95% CI: 19% to 94%). A cross-over study in former East-Germany on patients who had infection-related asthma found that 5 g/day vitamin C decreased the proportion of participants who had bronchial hypersensitivity to histamine by 52 percentage points (95% CI: 25 to 71). The third study did not use a placebo. Administration of a single dose of 1 gram of vitamin C to Italian non-asthmatic common cold patients increased the provocative concentration of histamine (PC20) 3.2-fold (95% CI: 2.0 to 5.1), but the vitamin C effect was significantly less when the same participants did not suffer from the common cold.
The three reviewed studies differed substantially in their methods, settings and outcomes. Each of them found benefits from the administration of vitamin C; either against asthma attacks or against bronchial hypersensitivity, the latter of which is a characteristic of asthma. Given the evidence suggesting that vitamin C alleviates common cold symptoms and the findings of this systematic review, it may be reasonable for asthmatic patients to test vitamin C on an individual basis, if they have exacerbations of asthma caused by respiratory infections. More research on the role of vitamin C on common cold-induced asthma is needed.
PMCID: PMC4018579  PMID: 24279478
Anti-asthmatic agents; Ascorbic acid; Asthma; Bronchial provocation tests; Bronchoconstriction; Common cold; Forced expiratory flow rates; Histamine; Rhinovirus; Upper respiratory tract infections
37.  Encasing bedding in covers made of microfine fibers reduces exposure to house mite allergens and improves disease management in adult atopic asthmatics 
Studies of avoidance of exposure to group 1 allergens of the Dermatophagoides group (Der p 1) have not yielded consistent improvements in adult asthma through avoidance. We explored whether the use of pillow and bed covers and allergen-avoidance counseling resulted in Der 1-level reduction, as measured by enzyme-linked immunosorbent assay, and thus improved asthma symptoms in adult patients.
Twenty-five adult patients with moderate or severe atopic asthma were randomized into intervention and control groups. Intervention patients slept on pillows and mattresses or futons encased in microfine-fiber covers and were counseled in allergen avoidance through bedroom cleaning. Control patients received neither special covers nor counseling. In the period August to October in 2009 (pre-intervention) and 2010 (post-intervention), dust samples were collected in open Petri dishes placed in bedrooms for 2 weeks and by rapid lifting of dust from bedding and skin using adhesive tape on the morning of 1 day of Petri dish placement. We examined the associations between changes in Der 1 level (as measured by enzyme-linked immunosorbent assay) and clinical symptom score, minimum % peak expiratory flow, and fraction of exhaled nitric oxide.
Der 1 allergen levels on the mattress/futon covers and near the floor of the bedrooms of intervention patients, but not controls, were lower in 2010 than in 2009. From 2009 to 2010, asthma symptom scores decreased significantly, and minimum % peak expiratory flow increased significantly, in intervention patients. The fall in Der p 1 concentration was correlated with a reduction in the fraction of exhaled nitric oxide.
Minimization of Der 1 allergen exposure by encasing pillows and mattresses or futons and receiving counseling on avoiding exposure to indoor allergens improved asthma control in adult patients.
PMCID: PMC3829998  PMID: 24499343
Adult intervention; Allergen; Atopic asthma; Bed cover; Dermatophagoides; Group 1 mite antigen
38.  Exploring the impact of elevated depressive symptoms on the ability of a tailored asthma intervention to improve medication adherence among urban adolescents with asthma 
In patients with asthma, medication adherence is a voluntary behavior that can be affected by numerous factors. Depression is an important co-morbidity in adolescents with asthma that may significantly impact their controller medication adherence and other asthma-related outcomes. The modifying effect of depressive symptoms on an asthma intervention’s ability to improve asthma controller medication adherence among urban adolescents with asthma has not yet been reported.
To assess self-reported symptoms of depression as an effect modifier of the relationship between randomization group and controller medication adherence at 6-month follow-up.
These analyses use data from a randomized controlled trial (RCT) conducted in Detroit high schools to evaluate a tailored asthma management program. The intervention included referrals to school or community resources for students reporting symptoms of depression and other issues. “Elevated depressive symptoms” was defined as a positive answer to ≥ 5 of 7 questions from a validated tool included on the baseline questionnaire. Self-reported adherence to controller medication was collected at intervention onset (session 1) and at 6-month follow up. Analyses were restricted to students with report of a controller medication at baseline. Logistic regression was used to assess elevated depressive symptoms as an effect modifier of the relationship between randomization group and 6-month adherence.
Of the 422 students enrolled in the RCT, a controller medication was reported at intervention onset by n = 123 adolescents (29%). Analyzing this group, we observed an interaction between elevated depressive symptoms and adherence (p = 0.073). Stratified analysis showed better adherence in treatment group adolescents meeting criteria for elevated depressive symptoms at baseline as compared to the control group (adjusted Odds Ratio [aOR] = 9.50; p = 0.024). For adolescents without elevated depressive symptoms at baseline, differences in adherence by group assignment did not reach statistical significance (aOR 1.40, p = 0.49).
In this sample of students reporting controller medications at baseline, report of elevated depressive symptoms at baseline and randomization to the intervention group was associated with significantly better adherence at 6-month follow up when compared to that of a control group. Larger studies are needed to evaluate the impact of depression on the relationship between adherence and asthma intervention effectiveness.
PMCID: PMC3832221  PMID: 24479403
Asthma; Depression; Medication adherence; Randomized controlled trial; Self-management; Adolescents; Urban
39.  Evaluation of nasal symptoms induced by platelet activating factor, after nasal challenge in both healthy and allergic rhinitis subjects pretreated with rupatadine, levocetirizine or placebo in a cross-over study design 
Platelet-activating factor (PAF) is produced by most inflammatory cells and it is involved in inflammatory and allergic reactions. We aimed to assess the anti-PAF effects of rupatadine and levocetirizine in the upper airways.
Healthy volunteers (HV, N = 10) and seasonal allergic rhinitis (SAR, N = 10) asymptomatic patients were treated out of the pollen season with either rupatadine 20 mg, levocetirizine 10 mg, or placebo once a day during 5 days prior to the PAF nasal challenge. Total 4-nasal symptom score (T4SS) and nasal patency (Vol2-5, by acoustic rhinometry) were assessed from 0 to 240 minutes after a repeated PAF challenge. In SAR patients but not in HV, both rupatadine and levocetirizine showed a trend to decrease PAF-induced T4SS from 60 to 120 minutes. Rupatadine but not levocetirizine caused a significant reduction (p < 0.05) of T4SS area under the curve compared to placebo. Rupatadine and levocetirizine caused no significant changes on nasal patency compared to placebo.
These results suggest that both rupatadine and levocetirizine showed a tendency decrease toward nasal symptoms, but only rupatadine significally reduces the overall nasal symptoms (AUC) induced by PAF in SAR patients.
PMCID: PMC4029526  PMID: 24499312
Allergic rhinitis; Antihistamines; Healthy volunteers; Levocetirizine; Platelet activating factor; Rupatadine
40.  Threshold for basophil activation test positivity in neuromuscular blocking agents hypersensitivity reactions 
Several different criteria for the positivity of the flow-assisted Basophil Activation Test (BAT) for the diagnosis of Neuromuscular Blocking Agents (NMBA) hypersensitivity reactions have been used in past studies. Our aims were to determine the threshold for BAT positivity expressed as the stimulation index (SI, calculated as the percentage of activated basophils after stimulation with NMBA divided by the number of basophils with no NMBA stimulation) and as the percentage of activated basophils, and to determine the sensitivity and specificity of BAT for NMBAs.
22 consenting adult patients with previous intraanaesthetic NMBAs-related hypersensitivity reactions were tested for the culprit drug. 34 controls who tolerated NMBAs were similarly tested. BAT was performed using Flow2Cast technique and the up-regulation of the CD63 marker on the basophils was measured using Cell Quest programme (FACSCalibur Becton Dickinson, USA). Receiver operating characteristics curve (ROC) analysis was performed.
ROC curve analysis for BAT results versus history yields a stimulation index of 1.76 as the optimal threshold, with an AUC of 0.81 (CI 95% 0.69-0.93, p < 0.01) and a percentage of activated basophils > 5.01%, with an AUC of 0.84 (CI 95% 0.72-0.95, p < 0.01). Considering both thresholds (the SI ≥ 1.76 together with the percentage of activated basophils > 5%) as diagnostic criteria, 15 patients had positive BAT, the overall BAT sensitivity being 68.18% (CI 95% 45.11-82.26%). None of the controls fulfilled both criteria and the specificity of the test was 100% (CI 95% 87.35-100%).
With a stimulation index ≥ 1.76 and a percentage of activated basophils > 5.01% as threshold, the performance of BAT for NMBAs yields 68.18% sensitivity and 100% specificity.
PMCID: PMC4029498  PMID: 24499278
Basophils; Drug hypersensitivity; Flow cytometry; Neuromuscular blocking agents
41.  IgE induces proliferation in human airway smooth muscle cells: role of MAPK and STAT3 pathways 
Airway remodeling is not specifically targeted by current asthma medications, partly owing to the lack of understanding of remodeling mechanisms, altogether posing great challenges in asthma treatment. Increased airway smooth muscle (ASM) mass due to hyperplasia/hypertrophy contributes significantly to overall airway remodeling and correlates with decline in lung function. Recent evidence suggests that IgE sensitization can enhance the survival and mediator release in inflammatory cells. Human ASM (HASM) cells express both low affinity (FcεRII/CD23) and high affinity IgE Fc receptors (FcεRI), and IgE can modulate the contractile and synthetic function of HASM cells. IgE was recently shown to induce HASM cell proliferation but the detailed mechanisms remain unknown. We report here that IgE sensitization induces HASM cell proliferation, as measured by 3H-thymidine, EdU incorporation, and manual cell counting. As an upstream signature component of FcεRI signaling, inhibition of spleen tyrosine kinase (Syk) abrogated the IgE-induced HASM proliferation. Further analysis of IgE-induced signaling depicted an IgE-mediated activation of Erk 1/2, p38, JNK MAPK, and Akt kinases. Lastly, lentiviral-shRNA-mediated STAT3 silencing completely abolished the IgE-mediated HASM cell proliferation. Collectively, our data provide mechanisms of a novel function of IgE which may contribute, at least in part, to airway remodeling observed in allergic asthma by directly inducing HASM cell proliferation.
PMCID: PMC3842672  PMID: 24499258
Human; Airway remodeling; EdU incorporation; Airway smooth muscle; Syk; MAPK; STAT3
42.  Impact of allergic rhinitis and specific subcutaneous immunotherapy on peripheral blood basophils of patients sensitized to Dermatophagoides pteronyssinus 
Basophils are important effectors cells in allergic rhinitis (AR) since they are involved in immunoglobulin (Ig) E – mediated inflammation and in the release of pro-inflammatory mediators. Specific subcutaneous immunotherapy (SCIT) provides clear immunologic modulation in some immune cells, however its systemic effects on basophils are not well known.
Peripheral blood (PB) samples from 43 patients with allergic rhinitis mono-sensitized to Dermatophagoides pteronyssinus (Dpt) [33 of them under SCIT with allergoid Dpt extract, in maintenance dose (SCIT), with evaluation just before SCIT injection (SCIT-T0) and 4 hours later (SCIT-T4) and the other 10 Dpt allergic patients never having, in the past, undergone specific immunotherapy treatment (NSIT)], and 15 healthy age- and gender-matched controls (HG), were analyzed. For each sample, the total (t-IgE) and specific IgE (s-IgE) was performed, as well as, the relative frequency and absolute number of PB basophils and receptor-bound IgE and IgG expression were evaluated by flow cytometry and the Histamine N-methyltransferase (HNMT) and tryptase α/β1 (TPSAB1) gene expression was assessed by real-time PCR.
Higher levels of receptor-bound IgE were observed in SCIT patients, which are correlated with the levels of serum t-IgE and s-IgE, whereas no significant differences were observed for receptor-bound IgG. Regarding HNMT mRNA expression, significantly lower expression levels were detected in AR patients compared to HG, independently of type of therapy. Moreover a negative correlation was found between HNMT gene expression and time under SCIT. Conversely, tryptase gene expression was significantly up-regulated in NSIT when compared to HG; however in SCIT patients, tryptase gene expression was significantly decreased than in NSIT patients. No differences were found for any parameter between SCIT-T0 and SCIT-T4 with exception of a transient increased expression of tryptase in SCIT-T4.
PB basophils from patients with AR show altered functional features, which seems to be influenced by SCIT, suggesting that these cells could be useful to clarify the SCIT triggered mechanisms at a systemic level.
PMCID: PMC3852786  PMID: 24484850
Allergic rhinitis; Dermatophagoides pteronyssinus; Basophils; Histamine N-methyltransferase; Tryptase; Specific subcutaneous immunotherapy
43.  The effects of rituximab on serum IgE and BAFF 
There are few treatment options for patients with severe atopic asthma. Antagonism of IgE is an effective strategy. We investigated, by utilizing serum samples from a clinical trial of Rituximab in patients with Idiopathic Thrombocytopenic Purpura, if B cell depletion would decrease serum IgE and therefore be a potential therapeutic option.
In a placebo-controlled randomized clinical trial of Rituximab, an anti-CD20 molecule, there were no significant differences in serum levels of IgE or BAFF levels between the two treatment groups at 3 or 6 months irrespective of the baseline serum IgE levels.
Since Rituximab did not significantly decrease serum IgE levels, this proof of concept study suggests that Rituximab may not be a useful treatment strategy for patients with severe IgE mediated disease.
PMCID: PMC3850905  PMID: 24219860
Anti-CD20; Rituximab; Immunoglobulin E; BAFF; Asthma
44.  The utility of using fiberoptic rhinoscopy in the diagnosis of nasal polyps 
Symtomatology of nasal polyps (NP) is relatively non-specific and other nasal conditions that cause nasal may be mistaken for NP. The purpose of this study was to evaluate the accuracy otoscopic (OT) examination in detecting presence of NP by using fiberoptic rhinoscopy (FR) as the gold standard to confirm diagnosis of NP.
Charts from a single allergy clinic were reviewed for any patient having NP diagnosed by FR. Data collected included gender, age, allergy skin test results, and presence of asthma, aspirin allergy, previous nasal surgeries, intranasal corticosteroid use and leukotriene receptor antagonist use.
The OT examination had 44% sensitivity. In this study, more than half (56%) of patients with NP would have had their NP missed if FR had not been performed in addition to the OT examination.
The standard physical examination procedure is often not sufficient to confirm a diagnosis of NP. FR should be considered in the investigation of patients with rhinitis symptoms.
PMCID: PMC3852625  PMID: 24274928
45.  A detailed phenotypic analysis of immune cell populations in the bronchoalveolar lavage fluid of atopic asthmatics after segmental allergen challenge 
Atopic asthma is characterized by intermittent exacerbations triggered by exposure to allergen. Exacerbations are characterized by an acute inflammatory reaction in the airways, with recruitment of both innate and adaptive immune cells. These cell populations as well as soluble factors are critical for initiating and controlling the inflammatory processes in allergic asthma. Detailed data on the numbers and types of cells recruited following allergen challenge is lacking. In this paper we present an extensive phenotypic analysis of the inflammatory cell infiltrate present in the bronchoalveolar lavage (BAL) fluid following bronchoscopically directed allergen challenge in mild atopic asthmatics.
A re-analysis of pooled data obtained prior to intervention in our randomized, placebo controlled, double blinded study (costimulation inhibition in asthma trial [CIA]) was performed. Twenty-four subjects underwent bronchoscopically directed segmental allergen challenge followed by BAL collection 48 hours later. The BAL fluid was analyzed by multi-color flow cytometry for immune cell populations and multi-plex ELISA for cytokine detection.
Allergen instillation induced pro-inflammatory cytokines (IL-6) and immune modulating cytokines (IL-2, IFN-γ, and IL-10) along with an increase in lymphocytes and suppressor cells (Tregs and MDSC). Interestingly, membrane expression of CD30 was identified on lymphocytes, especially Tregs, but not eosinophils. Soluble CD30 was also detected in the BAL fluid after allergen challenge in adult atopic asthmatics.
After segmental allergen challenge of adult atopic asthmatics, cell types associated with a pro-inflammatory as well as an anti-inflammatory response are detected within the BAL fluid of the lung.
PMCID: PMC3848528  PMID: 24330650
T lymphocyte; CD30 expression; Segmental allergen challenge; Asthma
46.  Hypogammaglobulinemia factitia- Munchausen syndrome masquerading as common variable immune deficiency 
We describe the first case of a patient with factitious disorder who closely simulated a primary immune deficiency disorder – Common Variable Immune Deficiency (CVID), by surreptitiously ingesting non-steroidal anti-inflammatory agents.
Case description
He was treated with several expensive and potentially dangerous drugs before the diagnosis was established through collateral information. In retrospect he did not meet the proposed new criteria for CVID. These criteria may prove useful in distinguishing cases of CVID from secondary hypogammaglobulinemia.
It is imperative clinicians recognise patients with factitious disorder at the earliest opportunity to prevent iatrogenic morbidity and mortality.
PMCID: PMC3848570  PMID: 24341706
Factitious disorder; NSAID; CVID; Hypogammaglobulinemia factitia; Munchausen syndrome
47.  Peanut Allergen Threshold Study (PATS): validation of eliciting doses using a novel single-dose challenge protocol 
The eliciting dose (ED) for a peanut allergic reaction in 5% of the peanut allergic population, the ED05, is 1.5 mg of peanut protein. This ED05 was derived from oral food challenges (OFC) that use graded, incremental doses administered at fixed time intervals. Individual patients’ threshold doses were used to generate population dose-distribution curves using probability distributions from which the ED05 was then determined. It is important to clinically validate that this dose is predictive of the allergenic response in a further unselected group of peanut-allergic individuals.
This is a multi-centre study involving three national level referral and teaching centres. (Cork University Hospital, Ireland, Royal Children’s Hospital Melbourne, Australia and Massachusetts General Hospital, Boston, U.S.A.) The study is now in process and will continue to run until all centres have recruited 125 participates in each respective centre.
A total of 375 participants, aged 1–18 years will be recruited during routine Allergy appointments in the centres. The aim is to assess the precision of the predicted ED05 using a single dose (6 mg peanut = 1.5 mg of peanut protein) in the form of a cookie. Validated Food Allergy related Quality of Life Questionnaires-(FAQLQ) will be self-administered prior to OFC and 1 month after challenge to assess the impact of a single dose OFC on FAQL. Serological and cell based in vitro studies will be performed.
The validation of the ED05 threshold for allergic reactions in peanut allergic subjects has potential value for public health measures. The single dose OFC, based upon the statistical dose-distribution analysis of past challenge trials, promises an efficient approach to identify the most highly sensitive patients within any given food-allergic population.
PMCID: PMC3850217  PMID: 24028324
Eliciting dose (ED); Food Allergy related Quality of Life Questionnaires-(FAQLQ); Single dose; Peanut thresholds; Oral Food Challenges (OFC); Voluntary Incidental Trace Allergen Labelling (VITAL); Peanut Allergen Threshold Study (PATS)
49.  Single venom-based immunotherapy effectively protects patients with double positive tests to honey bee and Vespula venom 
Referring to individuals with reactivity to honey bee and Vespula venom in diagnostic tests, the umbrella terms “double sensitization” or “double positivity” cover patients with true clinical double allergy and those allergic to a single venom with asymptomatic sensitization to the other. There is no international consensus on whether immunotherapy regimens should generally include both venoms in double sensitized patients.
We investigated the long-term outcome of single venom-based immunotherapy with regard to potential risk factors for treatment failure and specifically compared the risk of relapse in mono sensitized and double sensitized patients.
Re-sting data were obtained from 635 patients who had completed at least 3 years of immunotherapy between 1988 and 2008. The adequate venom for immunotherapy was selected using an algorithm based on clinical details and the results of diagnostic tests.
Of 635 patients, 351 (55.3%) were double sensitized to both venoms. The overall re-exposure rate to Hymenoptera stings during and after immunotherapy was 62.4%; the relapse rate was 7.1% (6.0% in mono sensitized, 7.8% in double sensitized patients). Recurring anaphylaxis was statistically less severe than the index sting reaction (P = 0.004). Double sensitization was not significantly related to relapsing anaphylaxis (P = 0.56), but there was a tendency towards an increased risk of relapse in a subgroup of patients with equal reactivity to both venoms in diagnostic tests (P = 0.15).
Single venom-based immunotherapy over 3 to 5 years effectively and long-lastingly protects the vast majority of both mono sensitized and double sensitized Hymenoptera venom allergic patients. Double venom immunotherapy is indicated in clinically double allergic patients reporting systemic reactions to stings of both Hymenoptera and in those with equal reactivity to both venoms in diagnostic tests who have not reliably identified the culprit stinging insect.
PMCID: PMC3846485  PMID: 24004607
Anaphylaxis; Double sensitization; Field sting; Honey bee; Hymenoptera venom; Immunotherapy; Relapse; Risk factor; Treatment failure; Vespula
50.  A topical microemulsion for the prevention of allergic rhinitis symptoms: results of a randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial (Nares study) 
Since barrier protection measures to avoid contact with allergens are being increasingly developed, we assessed the clinical efficacy and tolerability of a topical nasal microemulsion made of glycerol esters in patients with allergic rhinitis.
Randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial in which adult patients with allergic rhinitis or rhinoconjunctivitis due to sensitization to birch, grass or olive tree pollens received treatment with topical microemulsion or placebo during the pollen seasons. Efficacy variables included scores in the mini-RQLQ questionnaire, number and severity of nasal, ocular and lung signs and symptoms, need for symptomatic medications and patients’ satisfaction with treatment. Adverse events were also recorded.
Demographic characteristics were homogeneous between groups and mini-RQLQ scores did not differ significantly at baseline (visit 1). From symptoms recorded in the diary cards, the ME group showed statistically significant better scores for nasal congestion (0.72 vs. 1.01; p = 0.017) and mean total nasal symptoms (0.7 vs. 0.9; p = 0.045). At visit 2 (pollen season), lower values were observed in the mini-RQLQ in the ME group, although there were no statistically significant differences between groups in both full analysis set (FAS) and patients completing treatment (PPS) populations. The results obtained in the nasal symptoms domain of the mini-RQLQ at visit 2 showed the highest difference (−0.43; 95% CI: -0.88 to 0.02) for the ME group in the FAS population. The topical microemulsion was safe and well tolerated and no major discomforts were observed. Satisfaction rating with the treatment was similar between the groups.
The topical application of the microemulsion is a feasible and safe therapy in the prevention of allergic symptoms, particularly nasal congestion.
Trial registration Identifier: NCT01478425
PMCID: PMC3766093  PMID: 23981504
Allergic rhinitis; Rhinoconjunctivitis; Allergen avoidance; Barrier measures; Corticosteroids use; Nasal symptoms; Natural pollen exposure; Quality of life; Efficacy; Safety

Results 26-50 (438)