Leukotriene receptor antagonists as add-on therapy to antihistamines for urticaria: Systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The benefits and harms of adding antileukotrienes to H1 antihistamines (AHs) for the management of urticaria (hives, itch, and/or angioedema) remain unclear. OBJECTIVE: We sought to systematically synthesize the treatment outcomes of antileukotrienes in combination with AHs versus AHs alone for acute and chronic urticaria. METHODS: As part of updating American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters urticaria guidelines, we searched Medline, Embase, Central, LILACS, WPRIM, IBECS, ICTRP, CBM, CNKI, VIP, Wanfang, US Food and Drug Administration, and European Medicines Agency databases from inception to December 18, 2023, for randomized controlled trials (RCTs) evaluating antileukotrienes and AHs versus AHs alone in patients with urticaria. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random effects models pooled effect estimates for urticaria activity, itch, wheal, sleep, quality of life, and harms. The GRADE approach informed certainty of evidence ratings. The study was registered at the Open Science Framework (osf.io/h2bfx/). RESULTS: Thirty-four RCTs enrolled 3324 children and adults. Compared to AHs alone, the combination of a leukotriene receptor antagonist with AHs probably modestly reduces urticaria activity (mean difference, -5.04; 95% confidence interval, -6.36 to -3.71; 7-day urticaria activity score) with moderate certainty. We made similar findings for itch and wheal severity as well as quality of life. Adverse events were probably not different between groups (moderate certainty); however, no RCT reported on neuropsychiatric adverse events. CONCLUSION: Among patients with urticaria, adding leukotriene receptor antagonists to AHs probably modestly improves urticaria activity with little to no increase in overall adverse events. The added risk of neuropsychiatric adverse events in this population with leukotriene receptor antagonists is small and uncertain.

A systematic review and expert Delphi Consensus recommendation on the use of vaccines in patients receiving dupilumab: A position paper of the American College of Allergy, Asthma and Immunology.

BACKGROUND: Dupilumab is a monoclonal antibody that targets the interleukin (IL)-4 receptor alpha subunit, thus blocking the effects of IL-4 and IL-13, and has shown efficacy in treating various conditions including asthma, atopic dermatitis, eosinophilic esophagitis, and others. Because of its immune modulatory effects, clinical trials that studied dupilumab did not allow patients to receive live vaccines during the clinical trials because of an abundance of caution, and thus package inserts recommend that patients who are being treated with dupilumab should avoid live vaccines. Because dupilumab is now approved for use in patients from 6 months of age for the treatment of atopic dermatitis, this reported contraindication is now posing a clinical dilemma for patients and clinicians. OBJECTIVE: To perform a systematic review of literature on the safety and efficacy of vaccinations in patients who are receiving dupilumab and to provide expert guidance on the use of vaccines in patients who are receiving dupilumab. METHODS: A systematic review of the literature was performed, and an expert Delphi Panel was assembled. RESULTS: The available literature on patients who received vaccinations while using dupilumab overall suggests that live vaccines are safe and that the vaccine efficacy, in general, is not affected by dupilumab. The expert Delphi panel agreed that the use of vaccines in patients receiving dupilumab was likely safe and effective. CONCLUSION: Vaccines (including live vaccines) can be administered to patients receiving dupilumab in a shared decision-making capacity.

Topical corticosteroids for hives and itch (urticaria): systematic review and Bayesian meta-analysis of randomized trials.

BACKGROUND: Topical corticosteroids are widely used as a treatment for itch and wheals (urticaria), but their benefits and harms are unclear. OBJECTIVE: To systematically synthesize the benefits and harms of topical corticosteroids for the treatment of urticaria. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from database inception to March 23, 2024, for randomized trials addressing comparing topical corticosteroid to placebo for patients with urticaria (either chronic spontaneous or inducible urticaria or acute urticaria elicited from skin/intradermal allergy testing). Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects meta-analyses addressed urticaria severity, itch severity (numeric rating scale; range 0-10; higher is worse), and adverse events. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed certainty of evidence ratings. PROSPERO registration: CRD42023455182. RESULTS: Nineteen RCTs enrolled 379 participants with a median of mean age of 30.1 years (range 21.1 to 44.0). Compared to placebo, topical corticosteroids may reduce wheal size (ratio of means 0.47, 95%CI 0.38 to 0.59; low certainty) and itch severity (mean difference -1.30, 95%CI -5.07 to 2.46; very low certainty). Topical corticosteroids result in little to no difference in overall adverse events (94 fewer patients per 1000, 95%CrI 172 fewer to 12 more; high certainty). CONCLUSION: Compared to placebo, topical corticosteroids may result in a reduction of wheal size, and result in little to no difference in overall adverse events. Topical corticosteroids may reduce itch severity, but the evidence is very uncertain. Future large, randomized trials addressing the use of topical corticosteroids would further support optimal urticaria management.

Chronic Spontaneous Urticaria: An Update on the Evaluation and Management.

Chronic spontaneous urticaria (CSU) affects 0.5% to 1% of the general population and is often managed by allergy and immunology specialists. Guidelines have evolved over the past several decades with an emphasis on decreasing extensive screening laboratory testing as they are of low-yield and cost-ineffective. The utility of biomarkers remains under investigation but total immunoglobulin E may be helpful in determining specific endotypes and response to omalizumab. Antihistamines and omalizumab remain the primary therapeutic options for CSU, but an expanding body of evidence supports the use of immunosuppressants and anti-inflammatory medications in refractory cases.

The Impact of Prior Authorization on Clinical Practice and Patient Care Outcomes: A Work Group Report of the AAAAI Prior Authorization Task Force.

The Prior Authorization Task Force of the American Academy of Allergy, Asthma & Immunology (AAAAI), a presidential initiative of David Khan, MD, FAAAI, was established to develop an AAAAI position statement outlining ways to improve health care for our patients, to support legislation that advocates for prior authorization (PA) reform and identify the impact PA has on its membership using a questionnaire survey. This article describes the results of this survey. An electronic anonymous survey questionnaire was developed to assess the impact and burden of PA on AAAAI members and their staff and patients. Surveys were sent to randomly selected members and fellows of the AAAAI in the United States. Descriptive statistics were used to analyze the results by the Information Services team of the AAAAI and the authors of this work group report. The questionnaire responses from allergy immunology specialists demographically reflected the AAAAI membership and indicate that PAs can significantly affect patient care delivery and increase administrative burden to clinical practices, leading to serious adverse events in some circumstances. Differential responses regarding PAs for various medication classes likely reflect the physician's patient population, which can shift prescribing patterns. Prior authorization is a serious health care problem that is wasting financial resources and needlessly placing patients in danger when they are unable to access medications or medical services required for clinical management. The results of this questionnaire study support the recommendations made in the recent AAAAI position statement on PA.

Patient-Reported Outcome Measures in Food and Drug Allergy.

A patient-reported outcome is directly reported by the patient without interpretation of the patient's response by anyone else. It refers to the patient's health (symptoms and feelings), quality of life, or functional status associated with health care or treatment. Patient-reported outcome measures (PROMs) are defined as the tools or instruments that are used to measure patient-reported outcomes. Health-related quality of life has been the most studied psychosocial PROM in food allergy, using validated questionnaires. In drug allergy, PROMs are useful in capturing patients' experiences of potential allergic reactions, including subjective symptoms such as headache, dizziness, or fatigue. Patient-reported outcome measures can also help differentiate true allergies from side effects or other nonallergic reactions and inform decisions about drug challenges and de-labeling strategies. Ensuring the chosen tool is validated for the specific allergy context is crucial for accurate data collection. Integrating patient-reported experiences alongside traditional methods can lead to more accurate assessments and personalized care.

Contribution of caregiver and child anxiety and depressive symptoms to child asthma-related quality of life.

BACKGROUND: Depression and anxiety negatively affect asthma-related quality of life (QoL). Yet, little is known regarding mood and asthma-related factors that best uniquely explain asthma-related QoL in children. OBJECTIVE: This cross-sectional study evaluated the unique variance explained by caregiver and child depressive and anxiety symptom severity in child asthma-related QoL, apart from that explained by demographics and asthma control. METHODS: Children aged 7 to 17 years with asthma (n = 205) and their caregivers with major depressive disorder were included. A 3-stage hierarchical linear regression analysis was conducted with the Pediatric Asthma Quality of Life Questionnaire total scores considered as the outcome. Predictors included demographic characteristics (stage 1); asthma control assessed by the Asthma Control Test (stage 2); and caregiver depression and anxiety (Hamilton Rating Scale for Depression and the Spielberger State/Trait Anxiety Scale) and child depression and anxiety (Children's Depression Inventory and the Screen for Child Anxiety-Related Disorders) (stage 3). RESULTS: Demographic characteristics accounted for only 5.5% of the Pediatric Asthma Quality of Life Questionnaire scores. Asthma control significantly increased variance explained in QoL to 32.6%, whereas caregiver and child depression and anxiety symptoms significantly increased variance explained to 42.6%. Child anxiety was found to uniquely explain the largest proportion of variance in QoL (rs2 = 0.584). CONCLUSION: After adjusting variance in QoL for demographic characteristics and asthma control, caregiver and child depression and anxiety measures significantly increased the proportion of variance explained in a child's asthma-related QoL. In addition to better asthma control, child and caregiver depression and anxiety should be addressed to increase child asthma-related QoL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02809677.

fMRI BOLD responses to film stimuli and their association with exhaled nitric oxide in asthma and health.

Little is known about central nervous system (CNS) responses to emotional stimuli in asthma. Nitric oxide in exhaled breath (FENO) is elevated in asthma due to allergic immune processes, but endogenous nitric oxide is also known to modulate CNS activity. We measured fMRI blood oxygen-dependent (BOLD) brain activation to negative (blood-injection-injury themes) and neutral films in 31 participants (15 with asthma). Regions-of-interest analysis was performed on key areas relevant to central adaptive control, threat processing, or salience networks, with dorsolateral prefrontal cortex (PFC), anterior insula, dorsal anterior cingulate cortex (dACC), amygdala, ventral striatum, ventral tegmentum, and periaqueductal gray, as well as top-down modulation of emotion, with ventrolateral and ventromedial PFC. Both groups showed less BOLD deactivation from fixation cross-baseline in the left anterior insula and bilateral ventromedial PFC for negative than neutral films, and for an additional number of areas, including the fusiform gyrus, for film versus recovery phases. Less deactivation during films followed by less recovery from deactivation was found in asthma compared to healthy controls. Changes in PCO2 did not explain these findings. FENO was positively related to BOLD activation in general, but more pronounced in healthy controls and more likely in neutral film processing. Thus, asthma is associated with altered processing of film stimuli across brain regions not limited to central adaptive control, threat processing, or salience networks. Higher levels of NO appear to facilitate CNS activity, but only in healthy controls, possibly due to allergy's masking effects on FENO.

Drug Allergy Mimics.

When approaching a case of apparent drug allergy, the consulting clinician should consider a broad differential diagnosis. This article presents a series of cases that could be commonly referred to an allergist for assessment as "drug allergy," however, a real diagnosis exists that mandates a different diagnostic and treatment strategy, including a case of inducible laryngeal obstruction, multiple drug intolerance syndrome, viral rash, seizure due to metastatic malignancy, and hemophagocytic lymphohistiocytosis initially diagnosed as drug reaction and eosinophilia with systemic symptoms. The initial misdiagnoses of these patients delayed or interfered with their medical care, emphasizing the importance of accurate diagnoses for the benefit of our patients.

Severe Multiple Drug Intolerance Syndrome in Fibromyalgia and Irritable Bowel Syndrome.

BACKGROUND: Multiple drug intolerance syndrome (MDIS) describes patients with multiple nonimmunologically mediated adverse reactions to medications. Patients with more than 10 medication intolerance labels are considered to have severe MDIS. There is overlap in the characteristics of patients with MDIS and fibromyalgia and irritable bowel syndrome (IBS). Severe MDIS can limit treatment options in this already complex patient group. OBJECTIVE: This study assessed the prevalence of severe MDIS in patients with fibromyalgia and IBS and its associated risk factors. METHODS: A retrospective chart review identified patients diagnosed with fibromyalgia or IBS who had been seen at a large academic center from August 2019 to July 2020. Exact birthdate- and sex-matched controls who had been seen within the same time frame were selected at random. Listed drug intolerance data and patient characteristics were then analyzed with logistic regression and χ2 testing. RESULTS: Patients with fibromyalgia and IBS were 12 and 3 times more likely to have severe MDIS compared with controls, respectively. Severe MDIS was associated with polypharmacy in both groups. Opiates were the most frequently reported drug intolerance across all participants. Although patients with IBS more often reported gastrointestinal symptoms as adverse reactions, individuals with fibromyalgia did not more frequently report pain or behavioral changes as adverse reactions. CONCLUSIONS: There was an increased rate of severe MDIS in patients diagnosed with fibromyalgia and IBS. Additional studies are needed to better understand the morbidity of MDIS and how it can best be managed in patients with fibromyalgia and IBS.

The efficacy of citalopram or escitalopram in patients with asthma and major depressive disorder.

BACKGROUND: Major depressive disorder is common in people with asthma. Yet, few studies have evaluated depression treatment in those with asthma. OBJECTIVE: To explore the relationship between antidepressant use, depressive symptoms, and asthma control, pooled data from 3 randomized trials of either citalopram or escitalopram were assessed. METHODS: Linear fixed effects and binary logistic regression analyses were conducted with between-subject covariates including treatment group, (original) study, and demographics. The within-subject effect of visit, and a treatment group-visit (between-within) interaction effect, were also evaluated. Analyses were repeated in a high asthma exacerbation subgroup having at least 3 oral corticosteroid bursts in the previous 12 months. Outcomes included the Hamilton rating scale for depression (HAM-D17), the 7-item asthma control questionnaire (ACQ), and oral corticosteroid use (yes or no). RESULTS: In the pooled sample (n = 255), the antidepressant treatment group exhibited lower HAM-D17 overall (P ≤ .001) and a lower likelihood for oral corticosteroid use (P ≤ .001) relative to the placebo group. In the high-exacerbation subgroup (n = 96), treatment group participants had lower overall asthma control questionnaire (P = .004) and HAM-D17 scores (P ≤ .001), and a lower likelihood of oral corticosteroid use (P = .003), relative to placebo participants. All treatment group interaction effects were not significant. CONCLUSION: Citalopram or escitalopram exhibited efficacy in reducing depressive symptoms and the need for rescue oral corticosteroids in patients with asthma and major depressive disorder. Future work should determine whether selective serotonin reuptake inhibitors are effective at improving asthma outcomes in those with asthma who are not depressed. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00621946 and NCT01324700 (one study was conducted before ClinicalTrials.gov requirements).

Association of serotonin reuptake inhibitors with asthma control.

Background: Clinical trials demonstrated that selective serotonin reuptake inhibitors (SSRI) can improve asthma control in patients with comorbid major depressive disorder (MDD) and that this effect may be greater than the effect of SSRIs on depression. These findings suggest that SSRIs may improve asthma control in patients without MDD. Objective: The current retrospective study examined the effect of SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRI) on asthma control in adult patients. We hypothesized that patients would have fewer asthma exacerbations after treatment with an SSRI or SNRI. Methods: Electronic health record data of adult patients (N = 592) who were seen at a University of Texas Southwestern (UTSW) hospital or clinic and had (1) an SSRI or SNRI prescription, (2) a previous asthma diagnosis, and (3) no mood disorder diagnosis were extracted by using the UTSW Clinical Data Exchange Network. Wilcoxon signed rank tests were used to compare oral corticosteroid prescriptions and asthma-related emergency department (ED) visits and hospitalizations in the 12 months before and after the start of an SSRI/SNRI. Results: Therapy with SSRIs/SNRIs was associated with a significant decrease in oral corticosteroid use (p = 0.003), ED visits (p = 0.002), and hospitalizations (p < 0.001). Conclusion: Results from the current study add to the existing literature by demonstrating a reduced rate of severe exacerbations in patients with asthma by using an SSRI/SNRI without limiting the analytic sample to a high-illness-severity subgroup defined by symptoms of asthma or depression. Future work should include a prospective, placebo controlled study with individuals who have asthma and no comorbid mental health condition, verified by a mental health professional.

United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.

BACKGROUND: There is no accepted grading system classifying the severity of immediate reactions to drugs. OBJECTIVE: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium. METHODS: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research. RESULTS: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis. CONCLUSION: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice.

Drug allergy in older adults: A study from the United States Drug Allergy Registry.

BACKGROUND: Older adults have an increased risk of adverse drug reactions and negative effects associated with alternative antibiotic use. Although the number of antibiotic allergies reported increases with age, the characteristics and outcomes of older adults receiving drug allergy assessment are unknown. OBJECTIVE: To assess the characteristics and outcomes of drug allergy evaluations in older adults. METHODS: We considered patients aged above or equal to 65 years enrolled in the United States Drug Allergy Registry (USDAR), a US multisite prospective cohort (January 16, 2019 to February 28, 2022). Data were summarized using descriptive statistics. RESULTS: Of 1678 USDAR participants from 5 sites, 406 older adults aged above or equal to 65 years (37% 65-69 years, 37% 70-74 years, 16% 75-79 years, and 10% ≥80 years) received 501 drug allergy assessments. USDAR older adults were primarily of female sex (69%), White (94%), and non-Hispanic (98%). Most USDAR older adults reported less than or equal to 1 infections per year (64%) and rated their general health as good, very good, or excellent (80%). Of 296 (59%) penicillin allergy assessments in USDAR older adults, 286 (97%) were disproved. Other drug allergy assessments included sulfonamide (n = 41, 88% disproved) and cephalosporin (n = 20, 95% disproved) antibiotics. All 41 drug allergy labels in USDAR participants aged above or equal to 80 years and all 80 penicillin allergy labels in USDAR men aged above or equal to 65 years were disproved. CONCLUSION: Older adults represented a quarter of USDAR participants but were neither racially nor ethnically diverse and were generally healthy without considerable antibiotic need. Most older adults presented for antibiotic allergy assessments, the vast majority of which were disproved. Drug allergy assessments may be underutilized in the older adults who are most vulnerable to the harms of unconfirmed antibiotic allergy labels.

The Value of Current Laboratory Tests in Diagnosing Food, Venom, and Drug Allergies.

An accurate diagnosis of IgE-mediated allergies is necessary to inform risk management for severe allergic reactions including anaphylaxis for food, venom, and drug allergies. The most widely available laboratory test for allergy is serum-specific IgE testing, which is routinely used for food allergy and insect sting allergy. Testing for specific IgE is limited by high sensitivity and low specificity, resulting in concern regarding overdiagnosis. Testing of allergen components has led to improved diagnosis for some food and venom allergens. Additional options for laboratory tests, such as epitope analysis, basophil activation, and mast cell activation, are being investigated for their potential to optimize diagnosis and provide predictors for reaction severity and treatment response. In contrast, laboratory testing for drug allergy is more limited because to date, there are no well-validated commercial assays in the United States. Furthermore, it is important to diagnose delayed reactions to medications, because these also significantly affect decision-making regarding therapeutic options for infectious disorders. Reliable tests for both immediate and delayed drug hypersensitivity are much needed, because drug allergy labels can significantly limit treatment options for patients. Research in this area is emerging.

Updated guidance regarding the risk of allergic reactions to COVID-19 vaccines and recommended evaluation and management: A GRADE assessment and international consensus approach.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.