Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

Global warming and implications for epithelial barrier disruption and respiratory and dermatologic allergic diseases.

Global warming has direct and indirect effects, as well as short- and long-term impacts on the respiratory and skin barriers. Extreme temperature directly affects the airway epithelial barrier by disrupting the structural proteins and by triggering airway inflammation and hyperreactivity. It enhances tidal volume and respiratory rate by affecting the thermoregulatory system, causing specific airway resistance and reflex bronchoconstriction via activation of bronchopulmonary vagal C fibers and upregulation of transient receptor potential vanilloid (TRPV) 1 and TRPV4. Heat shock proteins are activated under heat stress and contribute to both epithelial barrier dysfunction and airway inflammation. Accordingly, the frequency and severity of allergic rhinitis and asthma have been increasing. Heat activates TRPV3 in keratinocytes, causing the secretion of inflammatory mediators and eventually pruritus. Exposure to air pollutants alters the expression of genes that control skin barrier integrity and triggers an immune response, increasing the incidence and prevalence of atopic dermatitis. There is evidence that extreme temperature, heavy rains and floods, air pollution, and wildfires increase atopic dermatitis flares. In this narrative review, focused on the last 3 years of literature, we explore the effects of global warming on respiratory and skin barrier and their clinical consequences.

Mental health interventions for atopic dermatitis: knowledge gaps, pilot programmes and future directions.

Atopic dermatitis (AD) is associated with high levels of psychosocial burden, often resulting in poor mental health outcomes. Despite this association, few studies have evaluated the efficacy of mental health interventions within this population. Utilization of multidisciplinary and peer-led support, in addition to equipping patients with psychological tools, may be beneficial in improving mental health outcomes. Future research is needed to determine which interventions and formats are desired by, effective in and accessible to patients and caregivers with AD.

History of S. aureus Skin Infection Significantly Associates with History of Eczema Herpeticum in Patients with Atopic Dermatitis.

INTRODUCTION: Patients with atopic dermatitis (AD) are uniquely susceptible to a number of serious viral skin complications, including eczema herpeticum (EH), caused by herpes simplex virus. This study explored the associations between biomarkers of epithelial barrier dysfunction, type 2 immunity, Staphylococcus aureus infection, and S. aureus-specific immunoglobulin responses in a cohort of AD subjects with and without a history of EH (EH+ and EH-, respectively). METHODS: A total of 112 subjects with AD (56 EH+, 56 EH-), matched by age and AD severity, were selected from a registry of over 3000 AD subjects. Logistic regression was used to test the association between history of S. aureus skin infection and history of EH, while controlling for a number of confounders. RESULTS: Compared to those without a history of S. aureus skin infection, subjects with a history of S. aureus skin infection were found to have more than sixfold increased odds of having a history of EH (6.60, 95% confidence interval [CI]: 2.00-21.83), after adjusting for history of other viral skin infections (molluscum contagiosum virus, human papillomavirus), serum total IgE, and IgG against the S. aureus virulence factor SElX. CONCLUSIONS: These findings indicate an important relationship between S. aureus skin infections and EH.

Rethinking Immunological Risk: A Retrospective Cohort Study of Severe SARS-Cov-2 Infections in Individuals With Congenital Immunodeficiencies.

BACKGROUND: Debates on the allocation of medical resources during the coronavirus disease 2019 (COVID-19) pandemic revealed the need for a better understanding of immunological risk. Studies highlighted variable clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. OBJECTIVE: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. METHODS: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged 2 months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020, through March 31, 2022. Risks of hospitalization were assessed using a multivariable logistic regression analysis. RESULTS: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 4.50; 95% confidence interval [95% CI] 1.57-13.4), a diagnosis of any genetically defined immunodeficiency (OR 3.32; 95% CI 1.24-9.43), obesity (OR 4.24; 95% CI 1.38-13.3), and neurological disease (OR 4.47; 95% CI 1.44-14.3). The COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; 95% CI 0.31-0.81). Defects in T cell and innate immune function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. CONCLUSIONS: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunological risk factors for individuals with inborn errors of immunity.

Rethinking immunologic risk: a retrospective cohort study of severe SARS-CoV-2 infections in individuals with congenital immunodeficiencies.

Background: Debates on the allocation of medical resources during the COVID-19 pandemic revealed the need for a better understanding of immunologic risk. Studies highlighted variable clinical outcomes of SARS-CoV-2 infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. Objective: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. Methods: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged two months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020 through March 31, 2022. Risks of hospitalization was assessed using a multivariable logistic regression analysis. Results: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 5.29; confidence interval [CI], 1.76-17.0), a diagnosis of any genetically-defined immunodeficiency (OR 4.62; CI, 1.60-14.8), use of B cell depleting therapy within one year of infection (OR 6.1; CI, 1.05-38.5), obesity (OR 3.74; CI, 1.17-12.5), and neurologic disease (OR 5.38; CI, 1.61-17.8). COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; CI, 0.31-0.81). Defective T cell function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. Conclusions: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunologic risk factors for individuals with inborn errors of immunity. Highlights: What is already known about this topic? Outcomes of SARS-CoV-2 infections in individuals with inborn errors of immunity (IEI) are highly variable. Prior studies of patients with IEI have not controlled for race or social vulnerability. What does this article add to our knowledge ? For individuals with IEI, hospitalizations for SARS-CoV-2 were associated with race, ethnicity, obesity, and neurologic disease. Specific types of immunodeficiency, organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization. How does this study impact current management guidelines? Current guidelines for the management of IEIs focus on risk conferred by genetic and cellular mechanisms. This study highlights the importance of considering variables linked with social determinants of health and common comorbidities as immunologic risk factors.

Phenotypic and Endotypic Determinants of Atopic Dermatitis Severity From the Atopic Dermatitis Research Network (ADRN) Registry.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin condition with a highly variable clinical phenotype. OBJECTIVE: This study aimed to identify historical and clinical features and biomarkers associated with AD severity. METHODS: A US registry of extensively phenotyped AD participants (aged 0.73-80 years) were enrolled at 9 academic centers. Information on family and personal medical history, examination, skin swabs (culture), and serum biomarkers was collected to evaluate their association with AD severity. RESULTS: Participants with AD (N = 2862) whose disease was categorized as mild (11.6%), moderate (58.0%), or severe (30.4%) based on Rajka-Langeland scoring were enrolled. The trend test, when adjusting for gender, race, and age, demonstrated that severity was strongly (P ≤ .04) associated with a personal/family history of allergic disorders, history of alopecia, exposure to passive smoke, ocular herpes infection, skin bacterial and viral infections, and history of arrhythmia. Features observed more frequently (P ≤ .002), as a function of severity, included skin infections (impetigo, human papillomavirus, and molluscum contagiosum virus), Staphylococcus aureus colonization, excoriations, hyperlinear palms, ichthyosis, blepharitis, conjunctivitis, ectropion, and wheezing. Serum IgE, allergen and food (≤6 years) Phadiatop, and eosinophilia were strongly linked to severity (P < .001). CONCLUSIONS: In a diverse US AD population, severity was associated with a history of atopic disorders, skin and extracutaneous bacterial and viral infections (by history and physical examination), higher IgE, eosinophilia and allergen sensitization, atopic skin manifestations (ie, excoriation, hyperlinear palms, and ichthyosis), and atopic ocular features (ie, blepharitis, conjunctivitis, and ectropion) as well as asthma findings (ie, wheezing). Data from our prospective registry significantly advance our understanding of AD phenotypes and endotypes, which is critical to achieve optimal management.

Values and Preferences of Patients and Caregivers Regarding Treatment of Atopic Dermatitis (Eczema): A Systematic Review.

Importance: Patient values and preferences can inform atopic dermatitis (AD) care. Systematic summaries of evidence addressing patient values and preferences have not previously been available. Objective: To inform American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma and Immunology (ACAAI) Joint Task Force on Practice Parameters AD guideline development, patient and caregiver values and preferences in the management of AD were systematically synthesized. Evidence Review: Paired reviewers independently screened MEDLINE, Embase, PsycINFO, and CINAHL databases from inception until March 20, 2022, for studies of patients with AD or their caregivers, eliciting values and preferences about treatment, rated risk of bias, and extracted data. Thematic and inductive content analysis to qualitatively synthesize the findings was used. Patients, caregivers, and clinical experts provided triangulation. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research) informed rating of the quality of evidence. Findings: A total of 7780 studies were identified, of which 62 proved eligible (n = 19 442; median age across studies [range], 15 years [3-44]; 59% female participants). High certainty evidence showed that patients and caregivers preferred to start with nonmedical treatments and to step up therapy with increasing AD severity. Moderate certainty evidence showed that adverse effects from treatment were a substantial concern. Low certainty evidence showed that patients and caregivers preferred odorless treatments that are not visible and have a minimal effect on daily life. Patients valued treatments capable of relieving itching and burning skin and preferred to apply topical corticosteroids sparingly. Patients valued a strong patient-clinician relationship. Some studies presented varied perspectives and 18 were at high risk for industry sponsorship bias. Conclusions and Relevance: In the first systematic review to address patient values and preferences in management of AD to our knowledge, 6 key themes that may inform optimal clinical care, practice guidelines, and future research have been identified.

Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434. FINDINGS: Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation. INTERPRETATION: Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Safely Reducing Hospitalizations for Anaphylaxis in Children Through an Evidence-Based Guideline.

BACKGROUND: Emergency department visits for anaphylaxis have increased considerably over the past few decades, especially among children. Despite this, anaphylaxis management remains highly variable and contributes to significant health care spending. On the basis of emerging evidence, in this quality improvement project we aimed to safely decrease hospitalization rates, increase the use of cetirizine, and decrease use of corticosteroids for children with anaphylaxis by December 31, 2019. METHODS: A multipronged intervention strategy including a revised evidence-based guideline was implemented at a tertiary children's teaching hospital by using the Model for Improvement. Statistical process control was used to evaluate for changes in key measures. Length of stay and unplanned return visits within 72 hours were monitored as process and balancing measures, respectively. As a national comparison, hospitalization rates were compared with other hospitals' data from the Pediatric Health Information System. RESULTS: Hospitalizations decreased significantly from 28.5% to 11.2% from preimplementation to implementation, and the balancing measure of 72-hour revisits was stable. The proportion of patients receiving cetirizine increased significantly from 4.2% to 59.7% and use of corticosteroids decreased significantly from 72.6% to 32.4% in patients without asthma. The proportion of patients meeting length of stay criteria increased from 53.3% to 59.9%. Hospitalization rates decreased nationally over time. CONCLUSIONS: We reduced hospitalizations for anaphylaxis by 17.3% without concomitant increases in revisits, demonstrating that unnecessary hospitalizations can be safely avoided. The use of a local evidence-based guideline paired with close outcome monitoring and sustained messaging and feedback to clinicians can effectively improve anaphylaxis management.

Safety of Epicutaneous Immunotherapy in Peanut-Allergic Children: REALISE Randomized Clinical Trial Results.

BACKGROUND: Treatment options for peanut allergy are limited. In previous clinical trials, epicutaneous immunotherapy with a patch containing 250-µg peanut protein (Viaskin Peanut 250 µg [VP250]) was well tolerated and statistically superior to placebo in desensitizing peanut-allergic children. OBJECTIVE: To examine the safety of VP250 in children, using a study design approximating potential real-world use. METHODS: REAL LIfe Use and Safety of EPIT (REALISE) is a phase 3 multicenter study consisting of a 6-month, randomized, double-blind, placebo-controlled period followed by open-label active treatment. Children aged 4 to 11 years with physician diagnosis of peanut allergy received daily treatment with placebo (6 months) or VP250 (up to 36 months). Data from the 6-month, randomized, controlled phase of REALISE are reported. RESULTS: Three hundred ninety-three children were randomized 3:1 to receive VP250 (n = 294) or placebo (n = 99) for 6 months; 284 (72.3%) children had a history of peanut anaphylaxis. According to parent diary, all participants receiving VP250 and 83.8% receiving placebo reported at least 1 episode of local skin reaction, with frequency decreasing over time. Only 4 participants (1.4%) receiving VP250 discontinued because of adverse events (AEs). Epinephrine was administered for allergic reactions attributed to VP250 in 7 children (2.4%), of whom 5 remained in the study; none involved severe anaphylaxis. Overall, AE rates were similar among participants with and without a history of peanut anaphylaxis. CONCLUSIONS: In a study designed to mirror real-world use, VP250 was observed to be well tolerated in peanut-allergic children, consistent with previous phase 2b and 3 studies.

Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors.

BACKGROUND: While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. OBJECTIVES: This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. METHODS: AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. RESULTS: Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36). CONCLUSIONS: This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

Anaphylaxis knowledge gaps and future research priorities: A consensus report.

BACKGROUND: Despite a better understanding of the epidemiology, pathogenesis, and management of patients with anaphylaxis, there remain knowledge gaps. Enumerating and prioritizing these gaps would allow limited scientific resources to be directed more effectively. OBJECTIVE: We sought to systematically describe and appraise anaphylaxis knowledge gaps and future research priorities based on their potential impact and feasibility. METHODS: We convened a 25-member multidisciplinary panel of anaphylaxis experts. Panelists formulated knowledge gaps/research priority statements in an anonymous electronic survey. Four anaphylaxis themed writing groups were formed to refine statements: (1) Population Science, (2) Basic and Translational Sciences, (3) Emergency Department Care/Acute Management, and (4) Long-Term Management Strategies and Prevention. Revised statements were incorporated into an anonymous electronic survey, and panelists were asked to rate the impact and feasibility of addressing statements on a continuous 0 to 100 scale. RESULTS: The panel generated 98 statements across the 4 anaphylaxis themes: Population Science (29), Basic and Translational Sciences (27), Emergency Department Care/Acute Management (24), and Long-Term Management Strategies and Prevention (18). Median scores for impact and feasibility ranged from 50.0 to 95.0 and from 40.0 to 90.0, respectively. Key statements based on median rating for impact/feasibility included the need to refine anaphylaxis diagnostic criteria, identify reliable diagnostic, predictive, and prognostic anaphylaxis bioassays, develop clinical prediction models to standardize postanaphylaxis observation periods and hospitalization criteria, and determine immunotherapy best practices. CONCLUSIONS: We identified and systematically appraised anaphylaxis knowledge gaps and future research priorities. This study reinforces the need to harmonize scientific pursuits to optimize the outcomes of patients with and at risk of anaphylaxis.

Multiethnic genome-wide and HLA association study of total serum IgE level.

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. RESULTS: We identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8). CONCLUSION: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized, Placebo-Controlled, Phase 3 Clinical Trial.

BACKGROUND: Laboratory testing is typically required for patients with atopic dermatitis (AD) treated with systemic immunosuppressants. A previous analysis of laboratory outcomes in randomized, double-blinded, placebo-controlled clinical trials of dupilumab in adults with moderate-to-severe AD found no clinically important changes in hematologic, serum chemistry, and urinalysis parameters, supporting the use of dupilumab without routine laboratory monitoring. OBJECTIVE: The aim was to assess laboratory results in adolescents with moderate-to-severe AD treated with dupilumab in a phase 3, randomized, double-blind, placebo-controlled trial. METHODS: Adolescents aged ≥ 12 to < 18 years with moderate-to-severe AD were randomized 1:1:1 to subcutaneous dupilumab 200/300 mg every 2 weeks (q2w) (200 mg for patients < 60 kg at baseline; 300 mg for patients ≥ 60 kg at baseline); dupilumab 300 mg every 4 weeks (q4w); or placebo for 16 weeks. Laboratory evaluations included hematology, serum chemistry, and urinalysis parameters. RESULTS: Of 251 patients enrolled in the study, 250 received treatment and were included in the analysis. 4.7%, 2.4%, and 4.8% of patients receiving placebo, dupilumab 200/300 mg q2w, and dupilumab 300 mg q4w, respectively, had laboratory abnormalities reported as treatment-emergent adverse events, none of which prompted discontinuation of study treatment or study withdrawal. Mean eosinophil counts were elevated at baseline in all treatment groups. Patients in both dupilumab regimens, but not the placebo group, showed mild transient increases in mean eosinophil counts above baseline that returned to near-baseline values by week 16. Mean levels of lactate dehydrogenase trended towards the upper limit of normal at baseline and decreased with treatment; greater decreases were seen in dupilumab-treated patients than placebo-treated patients. There were no meaningful changes in other laboratory parameters, and none of the laboratory abnormalities were clinically significant. CONCLUSION: No clinically meaningful changes in laboratory parameters were seen in adolescents, similar to that observed in adults. The findings of this study indicate no routine laboratory monitoring is required in this population prior to or during dupilumab treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03054428. Video abstract: Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized Placebo-Controlled Phase 3 Clinical Trial (MP4 175137 KB).

Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum.

BACKGROUND: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+). METHODS: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation. RESULTS: Eight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR). CONCLUSION: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.

Severity grading system for acute allergic reactions: A multidisciplinary Delphi study.

BACKGROUND: There is no widely adopted severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions, thus limiting the ability to optimize and standardize management practices and advance research. OBJECTIVE: The aim of this study was to develop a severity grading system for acute allergic reactions for use in clinical care and research. METHODS: From May to September 2020, we convened a 21-member multidisciplinary panel of allergy and emergency care experts; 9 members formed a writing group to critically appraise and assess the strengths and limitations of prior severity grading systems and develop the structure and content for an optimal severity grading system. The entire study panel then revised the grading system and sought consensus by utilizing Delphi methodology. RESULTS: The writing group recommended that an optimal grading system encompass the severity of acute allergic reactions on a continuum from mild allergic reactions to anaphylactic shock. Additionally, the severity grading system must be able to discriminate between clinically important differences in reaction severity to be relevant in research while also being intuitive and straightforward to apply in clinical care. Consensus was reached for all elements of the proposed severity grading system. CONCLUSION: We developed a consensus severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions. Successful international validation, refinement, dissemination, and application of the grading system will improve communication among providers and patients about the severity of allergic reactions and will help advance future research.

Improving patient education for atopic dermatitis: A randomized controlled trial of a caregiver handbook.

BACKGROUND/OBJECTIVES: Patient education is important to families' ability to manage and cope with pediatric atopic dermatitis (AD). We evaluated whether an educational handbook could improve AD symptoms, caregiver confidence in AD management skills, and AD-related quality of life. METHODS: Caregivers of children with AD ages 1 month to 16 years were randomly assigned to the intervention arm (handbook in addition to standard AD management) or the control arm (standard management alone). Caregivers completed self-report outcome questionnaires prior to a clinical visit for AD and at 3-month follow-up. RESULTS: 175 caregivers completed questionnaires at baseline and follow-up. AD symptoms measured by the Patient-Oriented Eczema Measure (POEM) improved in both the handbook and control arms. However, the decrease in the mean POEM score in the handbook arm (-4.4, 95% CI [-5.8, -3.0]) did not differ from that in the control arm (-3.4, 95% CI [-4.8, -2.03]; P = .343). Change in quality of life did not differ between study arms. Among caregivers attending a new patient visit for AD, mean confidence scores (measured from 0 to 100) increased more in the handbook arm (67 [95% CI {60, 74}] to 83 [95% CI {77, 88}]) relative to the control arm (74 [95% CI {65, 82}] to 75 [95% CI {67, 83}]; P = .012). The majority of caregivers rated the handbook as helpful in managing the child's AD. CONCLUSIONS: Despite an adequate sample size, the handbook did not improve AD symptoms more than standard management alone. The handbook improved confidence in management skills for families attending new patient visits for AD.

Persistent, refractory, and biphasic anaphylaxis: A multidisciplinary Delphi study.

BACKGROUND: The use of inconsistent definitions for anaphylaxis outcomes limits our understanding of the natural history and epidemiology of anaphylaxis, hindering clinical practice and research efforts. OBJECTIVE: Our aim was to develop consensus definitions for clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis. METHODS: Using Delphi methodology, we developed agenda topics and drafted questions to review during monthly conference calls. Through online surveys, a 19-member panel consisting of experts in allergy and/or immunology and emergency medicine rated their level of agreement with the appropriateness of statements on a scale of 1 to 9. A median value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate. A disagreement index was then calculated, with values less than 1.0 categorized as "consensus reached." If consensus was not reached after the initial survey, subsequent surveys incorporating the aggregate de-identified responses from prior surveys were sent to panel members. This process was repeated until consensus was reached or 4 survey rounds had been completed, after which the question was categorized as "no consensus reached." RESULTS: The panel developed outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. There was also consensus among panel members regarding the need to develop an anaphylaxis severity grading system. CONCLUSION: Dissemination and application of these definitions in clinical care and research will help standardize the terminology used to describe anaphylaxis outcomes and serve as the foundation for future research, including research aimed at development of an anaphylaxis severity grading system.