Clin Immunol Research Articles

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83

Genetically engineered cell factories produce glycoengineered vaccines that target antigen-presenting cells and reduce antigen-specific T-cell reactivity

Genetically engineered cell factories produce glycoengineered vaccines that target antigen-presenting cells and reduce antigen-specific T-cell reactivity

Underestimation of house dust mite–specific IgE with extract-based ImmunoCAPs compared with molecular ImmunoCAPs

Underestimation of house dust mite–specific IgE with extract-based ImmunoCAPs compared with molecular ImmunoCAPs

Survey of disease awareness, treatment behavior and treatment satisfaction in patients with atopic dermatitis in Korea: A multicenter study.

In Korea, there is a high dependency on oriental medicine and folk remedies (Korean J Asthma Allergy Clin Immunol, 25, 2005, 110). In addition, inaccurate information available through the Internet is increasing (Korean J Dermatol, 44, 2006, 137). So, there is always a possibility that patients may have difficulty obtaining accurate information about atopic dermatitis (AD). The aim was to determine the awareness, treatment behavior and treatment satisfaction of patients with AD and their caregivers. In October 2017, patients diagnosed with AD at nine hospitals were enrolled in this study. A questionnaire was completed by each patient. A total of 371 subjects were surveyed. In response to the question asking about knowledge of AD, the correct answer rate was 55.4%. Bathing using soap, body scrub and moisturizer showed favorable outcomes. A total of 54.9% patients responded that they were reluctant to use steroid ointment. When asked about their previous treatment, 39.6% reported using oriental medicine and 26.5% had tried folk remedies. The hospital treatment satisfaction score was 6.6. Patients usually applied their knowledge in their daily lives. However, there was a lot of inaccurate knowledge. Therefore, it is important for patients to understand the characteristics of this disease and obtain correct information.

Gastrointestinal Disorders Associated with Primary Immunodeficiency Diseases.

There are now 354 inborn errors of immunity (primary immunodeficiency diseases (PIDDs)) with 344 distinct molecular etiologies reported according to the International Union of Immunological Sciences (IUIS) (Clin Gastroenterol Hepatol 11: p. 1050-63, 2013, Semin Gastrointest Dis 8: p. 22-32, 1997, J Clin Immunol 38: p. 96-128, 2018). Using the IUIS document as a reference and cross-checking PubMed ( www.ncbi.nlm.nih.pubmed.gov ), we found that approximately one third of the 354 diseases of impaired immunity have a gastrointestinal component [J Clin Immunol 38: p. 96-128, 2018]. Often, the gastrointestinal symptomatology and pathology is the heralding sign of a PIDD; therefore, it is important to recognize patterns of disease which may manifest along the gastrointestinal tract as a more global derangement of immune function. As such, holistic consideration of immunity is warranted in patients with clinically significant gastrointestinal disease. Here, we discuss the manifold presentations and GI-specific complications of PIDDs which could lead patients to seek advice from a variety of clinician specialists. Often, patients with these medical problems will engage general pediatricians, surgeons, gastroenterologists, rheumatologists, and clinical immunologists among others. Following delineation of the presenting concern, accurate and often molecular diagnosis is imperative and a multi-disciplinary approach warranted for optimal management. In this review, we will summarize the current state of understanding of PIDD gastrointestinal disease involvement. We will do so by focusing upon gastrointestinal disease categories (i.e., inflammatory, diarrhea, nodular lymphoid hyperplasia, liver/biliary tract, structural disease, and oncologic disease) with an intent to aid the healthcare provider who may encounter a patient with an as-yet undiagnosed PIDD who presents initially with a gastrointestinal symptom, sign, or problem.

Cost\u2013utility analysis of an intervention designed to reduce the critical handling error of insufficient inspiratory effort

ObjectivesUp to 70–80% of patients use inhalers incorrectly. Dry-powder inhalers (DPIs) require forceful inhalation for optimal delivery, and approximately 40% of Global Initiative for Asthma (GINA)-defined Step-3+ patients inhale corticosteroid and long-acting beta-agonist through DPIs. The CRITIKAL study (Price et al. in J Allergy Clin Immunol Pract 5:1071-e9–1081-e9, 2017) found a statistically significant association between ‘insufficient inspiratory effort’ error and increased risk of uncontrolled asthma and hospitalisation-requiring exacerbations. This paper explores the cost-effectiveness of an error-targeted intervention.MethodsA probabilistic Markov cost–utility model simulated patients transitioning between controlled and uncontrolled health states over one year. Odds ratios (ORs, from the CRITIKAL study) of a patient having uncontrolled asthma conditional on making the error were applied to baseline transition probabilities sourced from the literature, both indirectly via an adjustment formula (Zhang et al. in JAMA 280:1690–1691, 1998) and directly by assuming OR approximates relative risk (RR). The analysis explored complete/partial eradication of the error when the intervention was priced to match comparators, as well as impact of indirect costs based on lost/reduced productivity.ResultsThe intervention dominated both DPI comparators over one year, with direct cost savings of £45/£86 with 0.0053/0.0102 additional quality-adjusted life years (QALYs), and had the highest probability of being cost-effective at a £20,000/QALY threshold. Key factors driving variance were weekly utilities per state and RR of moving to an uncontrolled state.ConclusionThe analysis demonstrated the economic and societal costs of ‘insufficient inspiratory effort’ and potential economic benefits of introducing an effective intervention to reduce/eradicate this error. Further research should assess the economic impact of other handling errors.

Screening for Wiskott-Aldrich syndrome by flow cytometry

Screening for Wiskott-Aldrich syndrome by flow cytometry

Intraoperative Anaphylaxis to Chlorhexidine During LVAD and Transplant Surgery

PERIOPERATIVE ANAPHYLAXIS is a condition that can cause complications during surgical procedures, ranging from minor to severe with cardiovascular and/or pulmonary collapse. Some common etiologic agents include antibiotics, neuromuscular blocking agents, latex, and chlorhexidine, 1 Mertes P.M. Alla F. Trechot P. et al. Anaphylaxis during anesthesia in France: An 8-year national survey. J Allergy Clin Immunol. 2011; 128: 366-373 Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar , 2 Tacquard C. Collange O. Gomis P. et al. Anaesthetic hypersensitivity reactions in France between 2011 and 2012: The 10th GERAP epidemiologic survey. Acta Anaesthesiol Scand. 2017; 61: 290-299 Crossref PubMed Scopus (63) Google Scholar , 3 Mertes P.M. Laxenaire M.C. Alla F. et al. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999-2000. Anesthesiology. 2003; 99: 536-545 Crossref PubMed Scopus (475) Google Scholar , 4 Garvey L.H. Roed-Petersen J. Menne T. et al. Danish Anaesthesia Allergy Centre - preliminary results. Acta Anaesthesiol Scand. 2001; 45: 1204-1209 Crossref PubMed Scopus (86) Google Scholar , 5 Meng J. Rotiroti G. Burdett E. et al. Anaphylaxis during general anaesthesia: Experience from a drug allergy centre in the UK. Acta Anaesthesiol Scand. 2017; 61: 281-289 Crossref PubMed Scopus (21) Google Scholar but any medication, blood product, or chemical substance used during the perioperative period has the potential for causing anaphylaxis. Complications from perioperative anaphylaxis can be life-threatening and are associated with a higher mortality rate than anaphylaxis under other circumstances. 6 Simon M.R. Mulla Z.D. A population-based epidemiologic analysis of deaths from anaphylaxis in Florida. Allergy. 2008; 63: 1077-1083 Crossref PubMed Scopus (68) Google Scholar , 7 Gibbs N.M. Sadleir P.H. Clarke R.C. et al. Survival from perioperative anaphylaxis in Western Australia 2000-2009. Br J Anaesth. 2013; 111: 589-593 Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar In this case report, the authors present the clinical course of an end-stage cardiomyopathy patient who experienced two separate episodes of anaphylaxis after exposure to the widely used antiseptic chlorhexidine during two major operations—the first during left ventricular assist device (LVAD) implantation and the second during heart transplantation. Intraoperative Anaphylaxis to Chlorhexidine During LVAD and Transplant SurgeryJournal of Cardiothoracic and Vascular AnesthesiaVol. 33Issue 2Preview“Not many is the good, but in the good, the many” —Aristotle (384-322 BC) Full-Text PDF

Nocturnal movements in children with atopic dermatitis have a timing pattern: A case-control study

Nocturnal movements in children with atopic dermatitis have a timing pattern: A case-control study

Essential role of smooth muscle Rac1 in airway hyperresponsiveness and airway remodelling associated to severe asthma

Introduction Severe asthma is a lung chronic disease characterized by inflammation, airway hyperresponsiveness (AHR), airway remodelling and corticoid resistance. The molecular mechanisms underlying airway smooth muscle cells (aSMC) contraction and proliferation involved in airway hyperresponsiveness (AHR) and airway remodelling are still largely unknown. Small GTPases of the Rho family (RhoA, Rac1 and Cdc42) play a central role in smooth muscle functions. Recently, we demonstrated that Rac1 play a major role in the control of bronchoconstriction by modulating airway SMC contraction (Andre-Gregoire et al., J Allergy Clin Immunol, 2017). The objective of this study was to assess the role of smooth muscle Rac1 in severe asthma. Methods We developed a new model of severe allergic asthma (house dust mite (HDM) sensitized mice) characterized by AHR and strong airway remodelling, including SMC hyperplasia. Interestingly, as in human severe asthma, this model is associated to an altered sensitivity to inhaled corticoids. To assess the role of Rac1 in aSMCs, SMC-Rac1-KO mice were sensitized to HDM. Results Our results demonstrated that deletion of SMC Rac1 totally prevents AHR and smooth muscle mass increase in this murine model. Furthermore, nebulisation of the Rac1 inhibitor NSC23766 prevents AHR and SMC hyperplasia, but also goblet cell hyperplasia and epithelial cell hypertrophy whereas corticoids treatments has no effect on these parameters. In addition, we observed that nebulisation of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from HDM sensitized asthmatic mice. Discussion In this study, we generated a new model of severe allergic asthma that mimic closely the human pathology. We demonstrated that Rac1 plays an essential role in aSMC contraction and hyperplasia, and that its inhibition prevents AHR and airway remodelling associated to severe asthma. Compared to classical bronchodilators, Rac1 inhibition presents the additional advantage to decrease pulmonary inflammation. Conclusion Consistant with these datas, inhibition of Rac1 activity may represent a novel therapeutic approach for patients with severe asthma.

The “efficacy paradox”

The “efficacy paradox” occurs when the efficacy of a treatment in a randomised controlled trial (RCT), or the recommendation in an evidence-based guideline, differs from the treatment benefits seen in clinical practice (1–3). This occurs because in RCT reporting and guidelines, treatment efficacy is judged by the difference in outcome between treatment and placebo (i.e., the specific effect of the treatment). This difference is used to estimate the “strength” or effect size (ES) of a treatment, and only treatments that separate from placebo by a minimum clinically important difference (MCID) may be recommended for use (e.g., by NICE). However, RCT participants who receive placebo often do very well, and in the treatment group the overall treatment ES (which includes both specific and contextual responses) is often in the good-strong range of ES. When a patient receives a treatment in practice it is the overall treatment effect, not just the specific treatment effect that they experience. This difference in focus can cause discordance between guidelines and clinical practice and ignores the impact of contextual response in clinical care (1). An alternative way of reporting RCTs is to firstly highlight the overall treatment effect (as would be expected in practice), and then explain how much of this is attributable to specific treatment effect and how much to placebo/contextual effects (the “proportional contextual effect (PCE)” (2)). This interpretation of all the results would diminish the paradox, alter the hierarchy of “strong treatments” for individual conditions (based on overall treatment rather than just specific treatment effects), and might lead to changes in guideline recommendations. For many chronic painful distressing conditions (e.g., OA, fibromyalgia) the majority of treatment benefit results from contextual effects, and optimising such effects in clinical practice could lead to substantial improvements in patient-centred outcomes. 1. Walach H. J Altern Complement Med 2001;7(3):213–218. 2. Zhang et al. Ann Intern Med 2015;163:392–393. 3. Zhang W, Doherty M. Clin Immunol 2017. https://doi.org/10.1016/j.clim.2017.07.018.

Association between (CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations

Association between (CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Biphasic activation of complement and fibrinolysis during the human nasal allergic response

Biphasic activation of complement and fibrinolysis during the human nasal allergic response

Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion

Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion

P845 Compound heterozygous mutations in IL10RA combined with a hemizygous CFP mutation acting as a potential modifier in infantile-onset inflammatory bowel disease

Inflammatory bowel diseases (IBDs) result from a complex interaction of host genetic factors, gut microbiome, and environmental stimuli.1 Although many genome-wide association studies have identified host genetic factors associated with IBD, rare Mendelian forms of IBD have been reported in patients with very early onset forms.2,3 Therefore, this study aimed to identify genetic variants associated with infantile-onset IBD. Genomic DNAs were obtained from whole blood of a male patient with infantile-onset IBD and non-consanguineous Korean parents. Pedigree of the patient. The patient’s older brother died due to complications of severe colitis. His brother also had multiple oral ulcers. The patient’s cousin had adolescent onset ulcerative colitis (UC). The sequenced trio are marked in blue. We performed whole-exome sequencing using trio samples. Then, we analysed the data using susceptibility genes for monogenic forms of IBD4,5,6 and various immunodeficiencies.7–10 Variants filtered for rare (minor allele frequency < 5% in the 1000 Genomes Project data) and nonsynonymous variants. The patient who presented with oral aphthous ulcers at the age of 14 days suffered from severe colitis and was refractory to medical treatment. Colonoscopy images from the patient. (A) A large ulceration (arrow) was noted in the sigmoid colon. (B) Colonic mucosa was friable and easy touch bled. After filtering out among more than 51000 genetic variants, compound-heterozygous mutations in IL10RA (p.R101W; p.T179T) were found in the patient. In addition, a hemizygous mutation in Complement Factor Properdin (CFP) (p.L456V) located on the X-chromosome was detected, inherited from the patient’s mother. het: heterozygous, hemi: hemizygous; dann: functional prediction score generated by deep learning; dbscSNV: for splice site prediction by AdaBoost and Random Forest het: heterozygous, hemi: hemizygous; dann: functional prediction score generated by deep learning; dbscSNV: for splice site prediction by AdaBoost and Random Forest The variant in CFP is predicted as “pathogenic” with a DANN score of 1, the highest possible score. Therefore, CFP mutation may also contribute to the phenotype of the patient as a genetic modifier. This study identified compound-heterozygous mutations in IL10RA combined with a hemizygous mutation in CFP acting as a potential modifier using whole-exome sequencing. 1. Ellinghaus D, Zhang H, Zeissig S, et al. Association between variants of PRDM1 and NDP52 and Crohn’s disease, based on exome sequencing and functional studies. Gastroenterology, 2013;2:339–47. 2. Glocker E-O, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med, 2009;21:2033–45. 3. Zeissig Y, Petersen B-S, Milutinovic S, et al. XIAP variants in male Crohn’s disease. Gut, 2015;1:66–76. 4. Al-Herz W, Bousfiha A, Casanova J-L, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol, 2011;2:54. 5. Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency 2015. J Clin Immunol, 2015. 6. Notarangelo LD, Fischer A, Geha RS, et al. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol, 2009;6:1161–78. 7. Uhlig HH, Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut, 2013;12:1795–805. 8. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease,. Gastroenterology, 2014;5:990–1007. 9. Bianco AM, Girardelli M, Tommasini A. Genetics of inflammatory bowel disease from multifactorial to monogenic forms. World J Gastroenterol, 2015;43:12296–310. 10. Uhlig HH, Schwerd T, From genes to mechanisms: the expanding spectrum of monogenic disorders associated with inflammatory bowel disease. Inflamm Bowel Dis, 2016;1:202–12.

Nasal IL-25 predicts the response to oral corticosteroids in chronic rhinosinusitis with nasal polyps

Nasal IL-25 predicts the response to oral corticosteroids in chronic rhinosinusitis with nasal polyps

A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle

Chromosome 17q12–21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12–21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus. (J Allergy Clin Immunol 2018;142:749–64.)

Rapid and comprehensive discovery of unreported shellfish allergens using large-scale transcriptomic and proteomic resources

[Extract] Discovery of allergens in various food and inhalant sources is central to our understanding of the molecular mechanisms of allergic reactions. Allergen characterization is the most important underlying factor for better patient management and the design and development of novel immunotherapeutics.1 Of the "Big eight" allergen food groups, shellfish presents a unique challenge in terms of allergen discovery due to the large number and diversity of consumed species, leading to heterogeneity of allergen structure and cross-reactivity among various sources. At present, 31 crustacean allergens have been officially registered in the World Health Organization and International Union of Immunological Societies Allergen Nomenclature Database as compared with 4 mollusk allergens due to pitfalls in current allergy discovery approaches. Cosensitization of patients with crustacean and mollusk allergy is often described; however, the current diagnostic approaches to manage these patients are not based on sufficient molecular knowledge of these shellfish allergens.