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1.  Birth weight, gestational age, fetal growth and childhood asthma hospitalization 
Childhood asthma may have a fetal origin through fetal growth and development of the immunocompetence or respiratory organs.
We examined to which extent short gestational age, low birth weight and fetal growth restriction were associated with an increased risk of asthma hospitalization in childhood.
We undertook a cohort study based on several national registers in Denmark, Sweden and Finland. We included all live singleton born children in Denmark during 1979-2005 (N = 1,538,093), in Sweden during 1973-2004 (N = 3,067,670), and a 90% random sample of singleton children born in Finland during 1987-2004 (N = 1,050,744). The children were followed from three years of age to first hospitalization for asthma, emigration, death, their 18th birthday, or the end of study (the end of 2008 in Denmark, and the end of 2007 in Sweden or Finland), whichever came first. We computed the pseudo-values for each observation and used them in a generalized estimating equation to estimate relative risks (RR) for asthma hospitalization.
A total of 131,783 children were hospitalized for asthma during follow-up. The risk for asthma hospitalization consistently increased with lower birth weight and shorter gestational age. A 1000-g decrease in birth weight corresponded to a RR of 1.17 (95% confidence interval (CI) 1.15-1.18). A one-week decrease in gestational age corresponded to a RR of 1.05 (95% CI 1.04-1.06). Small for gestational age was associated with an increased risk of asthma hospitalization in term but not in preterm born children.
Fetal growth and gestational age may play a direct or indirect causal role in the development of childhood asthma.
PMCID: PMC3973844  PMID: 24602245
Asthma; Birth weight; Gestational age; Hospitalization; Small for gestational age
2.  Home-based oral immunotherapy (OIT) with an intermittent loading protocol in children unlikely to outgrow egg allergy 
Home based oral immunotherapy (OIT) for food allergy has often been used for young children in Japan, the majority of whom are believed to outgrow the allergy by the school age, therefore the true efficacy of the therapy has been controversial. The aim of this study was to evaluate the efficacy and safety of a newly developed slow- type home-based oral immunotherapy (OIT) regimen in children with hen’s egg (HE) allergy, who had low likelihood of outgrowing the allergy, with treatment involving only elimination diet.
We retrospectively reviewed the medical records of 43 children with egg allergy (30 males; median age 6) who fulfilled Burks et al.’s criteria of being unlikely to outgrow the allergy. Thirty children who agreed to start OIT were assigned to the treatment group, and 13 who did not want to participate immediately were assigned to the untreated group; the patients underwent an elimination diet for 1 year, during which they were monitored. The OIT regimen involved the intake of the maximum tolerated dose 2 to 3 times a week at home, with initial dose introduction followed by dose build-ups with medical supervision. We statistically evaluated the rate of children who changed their threshold up to 32 g of egg – defined as, oral tolerance induction– in both the groups for 1 year and in the OIT group for 2 years, as well as the rate of children who fulfilled Savage et al.’s criteria of clinical tolerance after reaching the abovementioned remission stage.
The rate of children who achieved oral tolerance induction to 32 g of egg after 1 year in the OIT group (9/30) was significantly higher than that in the untreated group (0/13). The total rate within the OIT group was significantly increased from 9/30 at 1 year to 17/30 at two years without any severe adverse reaction; of the above 17 children, we followed 14 children, and noted that 11 of these were able to obtain clinical tolerance.
The home-based OIT with an intermittent loading protocol was very safe and effective in children with a low likelihood of outgrowing egg allergy.
PMCID: PMC3938305  PMID: 24572125
Egg allergy; Home- based oral immunotherapy; Intermittent loading protocol; Unlikely to outgrow
3.  The natural history of IgE mediated wheat allergy in children with dominant gastrointestinal symptoms 
Wheat is one of the most common food allergens in children. The purpose of this study is to define the natural course of wheat allergy in children with dominant gastrointestinal symptoms and identify factors that help predict development of tolerance.
The prospective analysis covered 50 children with positive food challenge results (DBPCFC) and positive wheat IgE test result. Resolution of wheat allergy was determined on the basis of food challenge results (open challenge). The impact of each of the studied factors on the age when tolerance developed was assessed by means of the Cox proportional hazard regression model.
The median age of tolerance development was 69.5 months (37-192 mo.). The rates of resolution were 20% by the age of 4 years, 52% by the age of 8 years, and 66% by 12 years, and 76% by 18 years. The median age of the tolerance development in children with peak wheat IgE level below10 kU/L was 41.4 months, with peak wheat IgE from 10 to 19.9 kU/L was 44.5 months, with peak IgE from 20 to 49.9 kU/L – 84,9 months and with peak IgE ≥ 50 kU/L – 190.5 months. The median of the age when the highest levels of IgE for wheat were reached was 33 months (2-52 mo.) in children with resolved wheat allergy and 67 months (36-178 mo.) in children with persistent allergy (p = .001).
1. The majority of children with wheat allergy can tolerate wheat by adolescence. 2. The age when tolerance to wheat developed depended on the level and the age of reaching the highest levels of specific IgE for wheat. The higher the values of the above parameters, the older a child was when they developed tolerance to wheat.
PMCID: PMC3939402  PMID: 24572171
Food allergy; Food tolerance; Wheat allergy; Specific immunoglobulin E; Children
4.  Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab 
Up to 30% of patients with food allergies have clinical reactivity to more than one food allergen. Although there is currently no cure, oral immunotherapy (OIT) is under investigation. Pilot data have shown that omalizumab may hasten the ability to tolerate over 4 g of food allergen protein.
To evaluate the safety and dose tolerability of a Phase 1 Single Site OIT protocol using omalizumab to allow for a faster and safe desensitization to multiple foods simultaneously.
Participants with multiple food allergies received OIT for up to 5 allergens simultaneously with omalizumab (rush mOIT). Omalizumab was administered for 8 weeks prior to and 8 weeks following the initiation of a rush mOIT schedule. Home reactions were recorded with diaries.
Twenty-five (25) participants were enrolled in the protocol (median age 7 years). For each included food, participants had failed an initial double-blind placebo-controlled food challenge at a protein dose of 100 mg or less. After pre-treatment with omalizumab, 19 participants tolerated all 6 steps of the initial escalation day (up to 1250 mg of combined food proteins), requiring minimal or no rescue therapy. The remaining 6 were started on their highest tolerated dose as their initial daily home doses. Participants reported 401 reactions per 7,530 home doses (5.3%) with a median of 3.2 reactions per 100 doses. Ninety-four percent (94%) of reactions were mild. There was one severe reaction. Participants reached their maintenance dose of 4,000 mg protein per allergen at a median of 18 weeks.
These phase 1 data demonstrate that rush OIT to multiple foods with 16 weeks of treatment with omalizumab could allow for a fast desensitization in subjects with multiple food allergies. Phase 2 randomized controlled trials are needed to better define safety and efficacy parameters of multi OIT experimental treatments with and without omalizumab.
PMCID: PMC3936817  PMID: 24576338
Food allergy; Oral immunotherapy (OIT); Specific Oral Tolerance Induction (SOTI); Multiple food allergy; Safety; Efficacy; Omalizumab; Desensitization
5.  Lung inflammation by fungus, Bjerkandera adusta isolated from Asian sand dust (ASD) aerosol and enhancement of ovalbumin-induced lung eosinophilia by ASD and the fungus in mice 
Bjerkandera adusta (B. adusta) is one of the most important etiological fungi associated with chronic cough. However, precise details of the inflammatory response to exposure are not well understood yet. B. adusta was recently identified in Asian sand dust (ASD) aerosol. Therefore, in the present study the exacerbating effects of ASD on B. adusta-induced lung inflammation and B. adusta + ASD on ovalbumin (OVA)-induced murine lung eosinophilia were investigated using experimental mice.
In order to prepare testing samples, B. adusta obtained from ASD aerosol was inactivated by formalin and ASD collected from the atmosphere was heated to remove toxic organic substances (H-ASD). CD-1 mice were instilled intratracheally with 12 different samples prepared with various combinations of B. adusta, H-ASD, and OVA in a normal saline solution. The lung pathology, cytological profiles in bronchoalveolar lavage fluid (BALF), and the levels of inflammatory cytokines/chemokines in BALF were investigated.
H-ASD aggravated the lung eosinophilia induced by B. adusta alone, which also aggravated the lung eosinophilia induced by OVA. The mixture of OVA, H-ASD, and B. adusta caused serious fibrous thickening of the subepithelial layer, eosinophil infiltration, and proliferation of goblet cells in the airways along with remarkable increases of IL-13, eotaxin, IL-5, and MCP-3 in BALF.
The results of the present study demonstrated that B. adusta isolated from ASD aerosol induces allergic lung diseases. H-ASD enhanced allergic reactions caused by OVA or B. adusta. A mixture of B. adusta, H-ASD, and OVA caused the most remarkable exacerbation to the allergic airway inflammation via remarkable increases of pro-inflammatory mediators.
PMCID: PMC3918174  PMID: 24499133
Asian sand dust; Bjerkandera adusta; Fungus; Lung eosinophilia; Asthma
6.  Invasive group A Streptococcus disease in French-Canadian children is not associated with a defect in MyD88/IRAK4-pathway 
Beta-hemolytic Group A Streptococcus invasive disease (iGASd) has been subject to intense research since its re-emergence in the late 1980s. In Quebec, an increase in the number of severe iGASd cases has recently been observed. Because of the inter-individual variability in the severity of iGASd, a hereditary predisposition to invasive disease can be suspected. Given that iGASd occurs in MyD88- and IRAK4-deficient patients, although rarely, the increasing frequency of iGASd in the population of French-Canadian children may be associated with a deficiency in the host’s innate immune response.
In this report, we assessed the influence of: (i) bacterial genotype and virulence factors, (ii) immune-cellular features, and (iii) Myd88/IRAK4-dependent response to GAS in vitro on the susceptibility to iGASd in a paediatric cohort of 16 children: 11 French-Canadian and 5 from diverse origin.
GAS virulence factors and genotype are not implicated in the susceptibility toward iGASd, and cellular and MyD88/IRAK4 deficiencies are excluded in our patients.
Although it has been shown that the MyD88/IRAK4-dependent signal is involved in the response to invasive GAS, our data indicates that a MyD88/IRAK4-mediated signalling defect is not the main factor responsible for the susceptibility to severe iGASd in a paediatric population from the province of Quebec.
PMCID: PMC3927219  PMID: 24499202
Invasive group A Streptococcus; MyD88/IRAK4-mediated signalling; Innate immunity
7.  Asthma: Gln27Glu and Arg16Gly polymorphisms of the beta2-adrenergic receptor gene as risk factors 
Asthma is caused by both environmental and genetic factors. The ADRB2 gene, which encodes the beta 2-adrenergic receptor, is one of the most extensively studied genes with respect to asthma prevalence and severity. The Arg16Gly (+46A > G) and Gln27Glu (+79C > G) polymorphisms in the ADRB2 gene cause changes in the amino acids flanking the receptor ligand site, altering the response to bronchodilators and the risk of asthma through complex pathways. The ADRB2 polymorphisms affect beta-adrenergic bronchodilator action and are a tool to identify at-risk populations.
To determine the frequency of these two polymorphisms in allergic asthma patients and healthy subjects and to correlate these data with the occurrence and severity of asthma.
Eighty-eight allergic asthma patients and 141 healthy subjects were included in this study. The ADRB2 polymorphisms were analyzed using the amplification-refractory mutation system – polymerase chain reaction (ARMS-PCR) technique. The statistical analysis was performed with the SPSS 21.0 software using the Fisher’s Exact and χ2 tests.
The ADRB2 polymorphisms were associated with asthma occurrence. The Arg16Arg, Gln27Gln and Gln27Glu genotypes were risk factors; the odds ratios were 6.782 (CI = 3.07 to 16.03), 2.120 (CI = 1.22 to 3.71) and 8.096 (CI = 3.90 to 17.77), respectively. For the Gly16Gly and Glu27Glu genotypes, the odds ratios were 0.312 (CI = 0.17 to 0.56) and 0.084 (CI = 0.04 to 0.17), respectively. The haplotype analysis showed that there were associations between the following groups: Arg16Arg-Gln27Gln (OR = 5.108, CI = 1.82 to 16.37), Gly16Gly-Glu27Glu (OR = 2.816, CI = 1.25 to 6.54), Arg16Gly-Gln27Glu (OR = 0.048, CI = 0.01 to 0.14) and Gly16Gly-Gln27Glu (OR = 0.1036, CI = 0.02 to 0.39). The polymorphism Gln27Glu was associated with asthma severity, as the Gln27Gln genotype was a risk factor for severe asthma (OR = 2.798, CI = 1.099 to 6.674) and the Gln27Glu genotype was a protective factor for mild (OR = 3.063, CI = 1.037 to 9.041) and severe (OR = 0.182, CI = 0.048 to 0.691) asthma.
The Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene are associated with asthma presence and severity.
PMCID: PMC3930554  PMID: 24499171
Asthma; ADRB2 gene; Lung disease; Arg16Gly; Gln27Glu
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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