The 50 most-cited articles in Journal of Allergy and Clinical Immunology, 2022

The Joint Task Force on Practice Parameters (JTFPP) is committed to ensuring that all guidelines are based on the best scientific evidence at the time of publication, and that such evidence is free of commercial bias to the greatest extent possible. Before confirming the selection of the workgroup chairpersons and members, the JTFPP discusses and resolves all relevant potential conflicts of interest (COI) of each potential workgroup member. The JTFPP recognizes that experts in a field are likely to have interests that could come into conflict with the development of a completely unbiased and objective guideline.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin…

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only…

Allergen immunotherapy (AIT) is an effective treatment for allergic rhinitis, inducing long-term clinical tolerance to the sensitizing allergen. Clinical tolerance induction can be achieved when AIT is administered for at least 3 years. AIT is associated with the modulation of innate and adaptive immune systems. This comprises inhibition of IgE-dependent activation of mast cells and basophils in the local target organ, suppression of T H 2 cells, immune deviation toward T H 1 cells, induction of T and B regulatory cells, and production of allergen-neutralizing antibodies. However, recent developments in their underpinning mechanisms have revealed that AIT, administered subcutaneously or sublingually, induces immune regulation through novel cell targets and molecular mechanisms. This comprehensive review discusses how immune tolerance driven by subcutaneous immunotherapy and sublingual immunotherapy is associated with the induction of a novel regulatory subset of innate lymphoid cells and suppression of proinflammatory T H 2, allergen-specific T H 2 (T H 2A), and T follicular helper…

BACKGROUND: Chronic spontaneous urticaria (CSU) is inadequately controlled in many patients and greatly affects quality of life. Remibrutinib, a highly selective, oral, novel covalent Bruton tyrosine kinase inhibitor, might be effective in CSU. OBJECTIVE: This first-in-patient trial aimed to evaluate the efficacy and safety of remibrutinib in CSU treatment and characterize the dose-response. METHODS: -antihistamines, with at least moderately active CSU, with or without prior anti-IgE treatment (NCT03926611). Patients received remibrutinib 10 mg once daily, 35 mg once daily, 100 mg once daily, 10 mg twice daily, 25 mg twice daily, 100 mg twice daily, or placebo (1:1:1:1:1:1:1 ratio). The main end points were weekly Urticaria Activity Score change from baseline at week 4 and safety. RESULTS: Overall, 311 patients were randomized. Reduced symptom score was observed for all remibrutinib doses from week 1 until week 12, with weekly Urticaria Activity Score change from baseline at week 4: -19.1 (10 mg once daily), -19.1 (35 mg once daily), -14.7 (100 mg once daily), -16.0 (10 mg twice…

Core outcome sets are critically important outcomes that should be measured in clinical trials. Their absence in atopic dermatitis is a form of research waste and impedes combining evidence to inform patient care. Here, we articulate the rationale for core outcome sets in atopic dermatitis and review the work of the international Harmonising Outcome Measures for Eczema group from its inception in Munich, 2010. We describe core domain determination (what should be measured), to instrument selection (how domains should be measured), culminating in the complete core outcome measurement set in Tokyo, 2019. Using a "road map," Harmonising Outcome Measures for Eczema includes diverse research methods including Delphi and nominal group techniques informed by systematic reviews of properties of candidate instruments. The 4 domains and recommended instruments for including in all clinical trials of atopic dermatitis are patient symptoms, measured by Patient-Oriented Eczema Measure and peak Numerical Rating Scale 11 for itch intensity over 24 hours, clinical signs measured using the Eczema…

Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 10 9 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to…

BACKGROUND: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. OBJECTIVE: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). METHODS: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. RESULTS: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts ≥150 or ≥300 cells/μL, respectively). The proportion of patients with greater than or equal to 1-point…

BACKGROUND: Atopic march refers to the sequential development of allergic diseases from infancy through adolescence, typically beginning with atopic dermatitis (AD), followed by food allergy and then airway diseases, later evolving to broader or worsened spectrum of allergic diatheses. No intervention has shown to alter its course. OBJECTIVE: We sought to determine the rate of acquisition of new or worsened allergic events for dupilumab versus placebo in patients with AD. METHODS: Allergy-associated events from 12 clinical trials were grouped into 17 allergy categories, and IgE changes from baseline were defined. A new/worsened event was considered one step of atopic march. Treatment effect was assessed by incidence rate ratios (IRRs), dupilumab versus placebo, by meta-analysis. RESULTS: The duration of pooled AD studies was 4 to 52 weeks (1359 patient-years; n = 2296 dupilumab, n = 1229 placebo, median age 35 years). The median age at AD onset was 2 years. Baseline allergic disease burden was comparable between groups. Dupilumab reduced the risk of new/worsening allergies by 34%…

BACKGROUND: Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. OBJECTIVE: We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD. METHODS: As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias…

Contact dermatitis is a common disease that is caused by repeated skin contact with contact allergens or irritants, resulting in allergic contact dermatitis (ACD) and/or irritant contact dermatitis. Attempts have been made to identify biomarkers to distinguish irritant and allergic patch test reactions, which could aid diagnosis. Some promising candidates have recently been identified, but verification and validation in clinical cases still need to be done. New causes of ACD are constantly being recognized. In this review, 10 new contact allergens from recent years, several relating to anti-aging products, have been identified. Frequent allergens causing considerable morbidity in the population, such as the preservative methylisothiazolinone, have been regulated in the European Union. A significant drop in the number of cases has been seen, whereas high rates are still occurring in other areas such as North America. Other frequent causes are fragrance allergens, especially the widely used terpenes and acrylates found in medical devices for control of diabetes. These represent…

BACKGROUND: Atopic dermatitis (AD) is associated with immune dysregulation, but epidemiologic data on the pattern of autoimmune comorbidity in people with AD are limited. OBJECTIVE: We sought to determine the risk of autoimmune conditions in people newly diagnosed with AD. METHODS: Retrospective cohort analysis (January 2009 to December 2018), using the UK-based Oxford-Royal College of General Practitioners Research and Surveillance Centre primary care database. We compared baseline prevalence and incidence after diagnosis of autoimmune conditions in 173,709 children and adults with new-onset AD and 694,836 age-, sex-, and general practitioner practice-matched controls. Outcomes were a composite of any autoimmune condition (Crohn disease, ulcerative colitis, celiac disease, pernicious anemia, type 1 diabetes, autoimmune hypothyroidism, Graves disease, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, Sjögren syndrome, vitiligo, alopecia areata, and multiple sclerosis) and each individual autoimmune condition. RESULTS: Preexisting…

BACKGROUND: The increased prevalence of many chronic inflammatory diseases linked to gut epithelial barrier leakiness has prompted us to investigate the role of extensive use of dishwasher detergents, among other factors. OBJECTIVE: We sought to investigate the effects of professional and household dishwashers, and rinse agents, on cytotoxicity, barrier function, transcriptome, and protein expression in gastrointestinal epithelial cells. METHODS: Enterocytic liquid-liquid interfaces were established on permeable supports, and direct cellular cytotoxicity, transepithelial electrical resistance, paracellular flux, immunofluorescence staining, RNA-sequencing transcriptome, and targeted proteomics were performed. RESULTS: The observed detergent toxicity was attributed to exposure to rinse aid in a dose-dependent manner up to 1:20,000 v/v dilution. A disrupted epithelial barrier, particularly by rinse aid, was observed in liquid-liquid interface cultures, organoids, and gut-on-a-chip, demonstrating decreased transepithelial electrical resistance, increased paracellular flux, and…

Background Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. Objective We sought to investigate the immune pathways that underlie the pathogenesis of PPP. Methods We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy Results Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several T H 2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4 + T cells of PPP patients were skewed toward a T H 17 phenotype, a phenomenon that was particularly significant among cutaneous…

Background The comparative safety and efficacy of the biologics currently approved for asthma are unclear. Objective We compared the safety and efficacy of mepolizumab, benralizumab, and dupilumab in individuals with severe eosinophilic asthma. Methods We performed a systematic review of peer-reviewed literature published 2000 to 2021. We studied Bayesian network meta-analyses of exacerbation rates, prebronchodilator FEV 1 , the Asthma Control Questionnaire, and serious adverse events in individuals with eosinophilic asthma. Results Eight randomized clinical trials (n = 6461) were identified. We found in individuals with eosinophils ≥300 cells/μL the following: in reducing exacerbation rates compared to placebo: dupilumab (risk ratio [RR], 0.32; 95% credible interval [CI], 0.23 to 0.45), mepolizumab (RR, 0.37; 95% CI, 0.30 to 0.45), and benralizumab (RR, 0.49; 95% CI, 0.43 to 0.55); in improving FEV 1 : dupilumab (mean difference in milliliters [MD] 230; 95% CI, 160 to 300), benralizumab (MD, 150; 95% CI, 100 to 200), and mepolizumab (MD, 150; 95% CI, 66 to 220); and in reducing…

BACKGROUND: The gut-lung axis is generally recognized, but there are few large studies of the gut microbiome and incident respiratory disease in adults. OBJECTIVE: We sought to investigate the association and predictive capacity of the gut microbiome for incident asthma and chronic obstructive pulmonary disease (COPD). METHODS: Shallow metagenomic sequencing was performed for stool samples from a prospective, population-based cohort (FINRISK02; N = 7115 adults) with linked national administrative health register-derived classifications for incident asthma and COPD up to 15 years after baseline. Generalized linear models and Cox regressions were used to assess associations of microbial taxa and diversity with disease occurrence. Predictive models were constructed using machine learning with extreme gradient boosting. Models considered taxa abundances individually and in combination with other risk factors, including sex, age, body mass index, and smoking status. RESULTS: A total of 695 and 392 statistically significant associations were found between baseline taxonomic groups and…

BACKGROUND: Peanut allergy affects 1% to 2% of European children. Early introduction of peanut into the diet reduces allergy in high-risk infants. OBJECTIVE: We aimed to determine the optimal target populations and timing of introduction of peanut products to prevent peanut allergy in the general population. METHODS: Data from the Enquiring About Tolerance (EAT; n = 1303; normal risk; 3-year follow-up; ISRCTN14254740) and Learning Early About Peanut Allergy study (LEAP; n = 640; high risk; 5-year follow-up; NCT00329784) randomized controlled trials plus the Peanut Allergy Sensitization (PAS; n = 194; low and very high risk; 5-year follow-up) observational study were used to model the intervention in a general population. Peanut allergy was defined by blinded peanut challenge or diagnostic skin prick test result. RESULTS: Targeting only the highest-risk infants with severe eczema reduced the population disease burden by only 4.6%. Greatest reductions in peanut allergy were seen when the intervention was targeted only to the larger but lower-risk groups. A 77% reduction in peanut…

BACKGROUND: Upadacitinib is a selective reversible Janus kinase (JAK) inhibitor with established efficacy in moderate-to-severe atopic dermatitis (AD). OBJECTIVE: We evaluated the safety of upadacitinib in patients with moderate-to-severe AD. METHODS: Integrated safety data from the 16-week placebo-controlled periods of 1 phase 2b and 3 ongoing phase 3 studies (16 weeks) and longer-term safety data from patients receiving upadacitinib during the blinded extension periods of the three phase 3 studies were analyzed (all upadacitinib exposure). Treatment-emergent adverse events (TEAEs) were presented as exposure-adjusted rates per 100 patient-years (PY). RESULTS: Safety results were similar between the 16-week and all upadacitinib exposure groups. The latter group included 2485 patients (333 adolescents), receiving upadacitinib 15 mg (n = 1239) or 30 mg (n = 1246) for a mean duration of approximately 1 year. Upadacitinib was well tolerated by both adults and adolescents. TEAEs and discontinuation due to AEs were reported more frequently in patients receiving 30 mg upadacitinib…

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene…