An Ethical Framework for Allergy and Immunology.

Ethical dilemmas routinely occur in the clinical practice of allergy and immunology. These ethical questions stem from the range of conditions and the different populations cared for by Allergists/Immunologists. Hence, medical ethics is not an esoteric concept, but a practical skill physicians exercise regularly. Moreover, an ethics-centered approach may improve patient safety and outcomes. This article describes key principles of bioethics and illustrates an ethical framework that physicians can use in their conversations with patients. Utilization of this ethical framework is demonstrated through applying it to 4 unique clinical scenarios encountered by Allergists/Immunologists from different practice settings. The ethical framework for allergy and immunology is a technique to navigate ethically complex decisions that arise in routine clinical practice.

Safety and outcomes of penicillin allergy evaluation in pregnant women.

BACKGROUND: Penicillin allergy in pregnancy is associated with increased morbidity and the use of less effective antibiotics. Penicillin allergy evaluation in pregnancy is now recommended as per obstetrical guidelines but remains infrequent. OBJECTIVE: We studied pregnant women who underwent penicillin allergy evaluation in an allergy clinic to assess the effectiveness and safety of penicillin skin testing (PST) and incremental drug challenge (IDC) in pregnancy. METHODS: Index drug reactions, PST, and IDC results were reviewed. Antibiotic use, pregnancy outcomes, and pregnancy complications were compared with a control cohort of pregnant women with penicillin allergy who did not undergo allergy evaluation before delivery. RESULTS: Penicillin allergy was evaluated in 136 women. Culprit drugs included penicillin (37%), amoxicillin (30%), and unknown (20%). Index reactions occurred greater than 5 years ago in 91%, and these reactions were cutaneous or unknown in 92%. Of the 133 patients who underwent skin testing, 131 (99%) had negative or equivocal results and proceeded to incremental challenge. All 131 women passed penicillin IDC. Of the 69 women who ultimately used intrapartum beta-lactam antibiotics, all but 1 patient tolerated them. Women who underwent penicillin allergy evaluation did not have an increased risk of cesarean delivery or other pregnancy complications when compared with women without penicillin allergy evaluation. CONCLUSION: PST and IDC can be safely conducted in pregnant women. When evaluated as low risk, most women tolerate IDC and can receive penicillin intrapartum without adverse reactions or negative pregnancy outcomes.

Diagnosis of GATA2 Deficiency in a Young Woman with Hemophagocytic Lymphohistiocytosis Triggered by Acute Systemic Cytomegalovirus Infection.

BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by an intense immunologic response that results in multiorgan dysfunction. It typically manifests as a result of a familial genetic immunodeficiency disorder or secondary to a trigger such as an infection, malignancy, or autoimmune disease. The major factors involved in the development of the disease are an individual's genetic propensity to develop HLH, such as rare associated mutations, or inflammatory processes that trigger the immune system to go haywire. CASE REPORT Before the COVID-19 pandemic, a 22-year-old woman with a history of congenital absence of the right kidney, right-sided hearing loss, and leukopenia presented with a 3-week history of generalized malaise, fever, chest pain, cough, and shortness of breath. She developed an acute systemic cytomegalovirus infection further complicated by HLH. Based on her history and clinical course, an underlying primary immunodeficiency was suspected. An immunodeficiency gene panel revealed a monoallelic mutation in GATA2, a gene that encodes zinc-transcription factors responsible for the regulation of hematopoiesis. CONCLUSIONS GATA2 deficiency encompasses a large variety of mutations in the GATA2 gene and leads to disorders associated with hematologic and immunologic manifestations of monocytopenia and B-, and natural killer-cell deficiency. Over time, affected individuals are at high risk of developing life-threatening infections and serious hematologic complications, such as myelodysplastic syndromes and/or leukemias. We aimed to illustrate the importance of identifying an underlying genetic disorder associated with secondary HLH to help guide acute and long-term management.

Controller Inhalers: Overview of Devices, Instructions for Use, Errors, and Interventions to Improve Technique.

Inadequate inhaler technique in persistent asthma is frequently reported. However, there is little consensus on inhaler checklists, and critical elements of technique are not uniformly described. In addition, inhaler error rates and risk factors for poor technique are variable across studies. This Clinical Commentary Review summarizes the literature on inhaler design, use, and interventions to improve technique. Our aim is to help clinicians identify patients with poor inhaler technique, recognize the most important errors, and correct technique using evidence-based interventions.

Common variable immunodeficiency-associated endotoxemia promotes early commitment to the T follicular lineage.

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

Advances in asthma in 2017: Mechanisms, biologics, and genetics.

This review summarizes some of the most significant advances in asthma research over the past year. We first focus on novel discoveries in the mechanism of asthma development and exacerbation. This is followed by a discussion of potential new biomarkers, including the use of radiographic markers of disease. Several new biologics have become available to the clinician in the past year, and we summarize these advances and how they can influence the clinical delivery of asthma care. After this, important findings in the genetics of asthma and heterogeneity in phenotypes of the disease are explored, as is the role the environment plays in shaping the development and exacerbation of asthma. Finally, we conclude with a discussion of advances in health literacy and how they will affect asthma care.

53BP1 Contributes to Igh Locus Chromatin Topology during Class Switch Recombination.

In B lymphocytes, Ig class switch recombination (CSR) is induced by activation-induced cytidine deaminase, which initiates a cascade of events leading to DNA double-strand break formation in switch (S) regions. Resolution of DNA double-strand breaks proceeds through formation of S-S synaptic complexes. S-S synapsis is mediated by a chromatin loop that spans the C region domain of the Igh locus. S-S junctions are joined via a nonhomologous end joining DNA repair process. CSR occurs via an intrachromosomal looping out and deletion mechanism that is 53BP1 dependent. However, the mechanism by which 53BP1 facilitates deletional CSR and inhibits inversional switching events remains unknown. We report a novel architectural role for 53BP1 in Igh chromatin looping in mouse B cells. Long-range interactions between the Eµ and 3'Eα enhancers are significantly diminished in the absence of 53BP1. In contrast, germline transcript promoter:3'Eα looping interactions are unaffected by 53BP1 deficiency. Furthermore, 53BP1 chromatin occupancy at sites in the Igh locus is B cell specific, is correlated with histone H4 lysine 20 marks, and is subject to chromatin spreading. Thus, 53BP1 is required for three-dimensional organization of the Igh locus and provides a plausible explanation for the link with 53BP1 enforcement of deletional CSR.

Constraints contributed by chromatin looping limit recombination targeting during Ig class switch recombination.

Engagement of promoters with distal elements in long-range looping interactions has been implicated in regulation of Ig class switch recombination (CSR). The principles determining the spatial and regulatory relationships among Igh transcriptional elements remain poorly defined. We examined the chromosome conformation of C region (CH) loci that are targeted for CSR in a cytokine-dependent fashion in mature B lymphocytes. Germline transcription (GLT) of the γ1 and ε CH loci is controlled by two transcription factors, IL-4-inducible STAT6 and LPS-activated NF-κB. We showed that although STAT6 deficiency triggered loss of GLT, deletion of NF-κB p50 abolished both GLT and γ1 locus:enhancer looping. Thus, chromatin looping between CH loci and Igh enhancers is independent of GLT production and STAT6, whereas the establishment and maintenance of these chromatin contacts requires NF-κB p50. Comparative analysis of the endogenous γ1 locus and a knock-in heterologous promoter in mice identified the promoter per se as the interactive looping element and showed that transcription elongation is dispensable for promoter/enhancer interactions. Interposition of the LPS-responsive heterologous promoter between the LPS-inducible γ3 and γ2b loci altered GLT expression and essentially abolished direct IgG2b switching while maintaining a sequential µâ†’γ3→γ2b format. Our study provides evidence that promoter/enhancer looping interactions can introduce negative constraints on distal promoters and affect their ability to engage in germline transcription and determine CSR targeting.

Increasing use of non-traditional vehicles for psoriasis and other inflammatory skin conditions.

BACKGROUND: Although topical corticosteroid ointments were once viewed as the best vehicle for treating inflammatory skin diseases, the recognition of the problem of poor compliance and patients' preferences for other vehicles has led to the development of corticosteroid products in alternative formulations. OBJECTIVE: To describe patterns of use of newer vehicle formulations including foams, shampoos, sprays, and lotions for the treatment of psoriasis and other dermatoses. METHODS: The use of non-traditional vehicles was identified using visit with diagnoses for psoriasis and other dermatoses from the National Ambulatory Medical Care Survey 2000-2010 data. Trends in corticosteroid vehicles mentions were evaluated over the study period to determine how the use of non-traditional vehicles has changed. The odds ratios of being prescribed a nontraditional vehicle were reported for patient and office-based characteristics of visits. RESULTS: Approximately 2.3% and 1.9% of visits mentioned foam and other non-traditional vehicles (shampoo, lotion, spray), respectively. The use of corticosteroids in shampoo, lotion, or spray preparations increased by 0.5% annually (p=0.008) but did not significantly change for corticosteroids in a foam preparation (p=0.10). Psoriasis and seborrheic dermatitis were the leading diagnoses at visits prescribed corticosteroids in nontraditional vehicles. Dermatologists were more likely than non-dermatologists to prescribe foam products [OR: 8.4 (3.6, 19.9)] or clobetasol in another non-traditional vehicle [OR: 49.7 (10.3, 240.5)]. LIMITATIONS: Product vehicle was not specified for all corticosteroids. CONCLUSION: Although there was increasing use of non-traditional vehicles, the rate of use has remained low. Dermatologists appear to have greater familiarity with the use of these newer vehicle formulations than do physicians in other specialties.

Are topical keratolytic agents needed in the treatment of scalp psoriasis?

BACKGROUND: Topical corticosteroids are the primary treatment for scalp psoriasis. Keratolytic agents are promoted as adjunctive treatments. However, complex treatment regimens may result in poor adherence and outcomes. OBJECTIVE: To evaluate the evidence for the need for use of topical keratolytic agents as opposed to topical corticosteroid monotherapy in the treatment of scalp psoriasis. METHODS: A review of the literature was performed seeking clinical trials using topical keratolytics, topical corticosteroids or the combination for treatment of scalp psoriasis. RESULTS: Complete clearance of scalp psoriasis can be achieved in 10-78% of patients using topical corticosteroids alone, in 3% of patients using topical keratolytics alone, and in up to 84% using a combination of topical keratolytics and topical steroids. Clinical trials comparing the combination of keratolytics and topical corticosteroids versus topical corticosteroids alone found marginally more efficacy using combination regimens. LIMITATIONS: We could not find any long term study evaluating the efficacy of combination therapy in scalp psoriasis and its effect on the patients' adherence. CONCLUSION: High potency topical corticosteroids are usually effective in treating scalp psoriasis in clinical trials. Poor efficacy in clinical practice may be owing to poor adherence to the treatment regimen. Using a keratolytic agent in conjunction with a topical corticosteroid may provide marginal additional benefit in clinical trials, but that benefit is likely outweighed by the downside of complicating treatment and reducing adherence in the clinical setting, unless a single product containing both medications were used.

Three-dimensional architecture of the IgH locus facilitates class switch recombination.

Immunoglobulin (Ig) class switch recombination (CSR) is responsible for diversification of antibody effector function during an immune response. This region-specific recombination event, between repetitive switch (S) DNA elements, is unique to B lymphocytes and is induced by activationinduced deaminase (AID). CSR is critically dependent on transcription of noncoding RNAs across S regions. However, mechanistic insight regarding this process has remained unclear. New studies indicate that long-range intrachromosomal interactions among IgH transcriptional elements organize the formation of the S/S synaptosome, as a prerequisite for CSR. This three-dimensional chromatin architecture simultaneously brings promoters and enhancers into close proximity to facilitate transcription. Here, we recount how transcription across S DNA promotes accumulation of RNA polymerase II, leading to the introduction of activating chromatin modifications and hyperaccessible chromatin that is amenable to AID activity.

S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination.

Immunoglobulin class switch recombination is governed by long-range interactions between enhancers and germline transcript promoters to activate transcription and modulate chromatin accessibility to activation-induced cytidine deaminase (AID). However, mechanisms leading to the differential targeting of AID to switch (S) regions but not to constant (C(H)) regions remain unclear. We show that S and C(H) regions are dynamically modified with histone marks that are associated with active and repressed chromatin states, respectively. Chromatin accessibility is superimposable with the activating histone modifications, which extend throughout S regions irrespective of length. High density elongating RNA polymerase II (RNAP II) is detected in S regions, suggesting that the transcription machinery has paused and stalling is abolished by deletion of the S region. We propose that RNAP II enrichment facilitates recruitment of histone modifiers to generate accessibility. Thus, the histone methylation pattern produced by transcription localizes accessible chromatin to S regions, thereby focusing AID attack.