What's new in allergy and immunology

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ASTHMA AND COPD

Anti-inflammatory reliever therapy in patients with mild asthma (May 2025)

As-needed inhaled glucocorticoids reduce asthma exacerbations in those with poor control despite multiple maintenance therapies, but whether this practice benefits patients with more mild disease has been unclear. In a trial that enrolled over 2400 patients with poor asthma control on albuterol alone (71 percent) or low-dose inhaled glucocorticoids, use of albuterol-budesonide as needed reduced the risk of exacerbations requiring systemic glucocorticoids compared with albuterol as-needed alone (5.3 versus 9.4 percent; hazard ratio 0.54) [1]. However, given their poor asthma control at baseline, all patients enrolled in this study would qualify for a step-up in asthma therapy, which was not initiated in the control group. These results support our recommendation for anti-inflammatory reliever therapy as a preferred initial controller option for patients with asthma who have moderately frequent symptoms. (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'As-needed low-dose ICS and SABA (step 1)'.)

Factors increasing risk of poor respiratory outcomes in those without airway obstruction (May 2025)

A new "multidimensional diagnostic framework" proposes to define chronic obstructive pulmonary disease (COPD) based on the presence of respiratory symptoms and imaging findings (table 1) rather than relying on spirometry [2]. This study identified over 800 patients enrolled in the COPDGene cohort who lacked obstruction on spirometry, but were classified as having COPD using these new criteria. These reclassified patients had an approximately twofold increased risk of all-cause mortality and respiratory exacerbations over a median 10-year follow-up compared with participants who lacked clinical or imaging evidence of COPD. While this proposed framework helped identify patients at risk for poor respiratory outcomes, patients without obstruction remained at lower risk than those meeting current COPD diagnostic criteria (ie, spirometric obstruction and compatible pulmonary symptoms); they may also represent a heterogenous group with different respiratory pathologies. We continue to use traditional criteria to diagnose COPD until there is more research to better understand and treat these non-obstructed patients. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Interrelationships among these conditions'.)

Neuropsychiatric events with initiation of montelukast versus long-acting beta-agonist for asthma (April 2025)

Whether leukotriene antagonist administration results in increased neuropsychiatric events (NPEs) in children and adolescents is controversial. Large observational studies often demonstrate an association with increased risk; however, this may be related to worsening asthma control in those who required leukotriene antagonist initiation. In a new national database study from Sweden, investigators compared new montelukast users with new long-acting beta-agonist (LABA) users to help avoid this confounding. Incident neuropsychiatric adverse events were uncommon and nearly identical in those with new montelukast use compared with those with LABA use (2.39 versus 2.41 per 100 patient-years; hazard ratio 0.99) [3]. These data should offer reassurance to clinicians and caregivers of those who require these medications. (See "Antileukotriene agents in the management of asthma", section on 'Leukotriene receptor antagonists'.)

Prevalence of eosinophilic granulomatosis with polyangiitis in patients presenting with severe asthma (March 2025)

Patients presenting with difficult-to-control asthma require careful clinical assessment to determine optimal therapy and rule out other disease processes. This is well illustrated by a recent study of 596 patients presenting with severe asthma, of whom nearly 4 percent were found to have eosinophilic granulomatosis with polyangiitis (EGPA) [4]. Nearly all patients identified with EGPA had a peak blood eosinophil count greater than 1000 cells/microL, and the most frequent additional disease manifestations were upper airway disease, neuropathy, and kidney involvement. Our authors support carefully assessing all severe asthma patients for hypereosinophilia and extrapulmonary disease. (See "Evaluation of severe asthma in adolescents and adults", section on 'Assessing conditions that mimic asthma'.)

Transcriptional profiling of asthma in children and adolescents (January 2025)

Childhood-onset asthma traditionally is thought to be primarily mediated by allergic processes (typically characterized by hypereosinophilia and elevated levels of interleukins 4, 5, and 13). However, a new cross-sectional analysis of nasal epithelial transcription profiles from three studies of predominantly African American and Puerto Rican youths with asthma (aged 6 to 20 years) found that nearly 75 percent of participants did not have an allergic (type 2) gene signature [5]. Instead, these patients had transcriptomic profiles consistent with either Th17-mediated inflammation or a third endotype that included neither type 2 nor Th17-responsive genes. This finding may explain why pediatric asthma may not respond to therapies that target type 2 immune responses and implies that many patients would benefit from treatments that focus on other inflammatory pathways. (See "Characterizing severe asthma phenotypes", section on 'Neutrophilic asthma'.)

Ultra-long-acting asthma biologic therapy (January 2025)

Biologic therapies are highly effective for severe asthma, but routine re-administration can be burdensome. In two simultaneous placebo-controlled trials of an ultra-high affinity antibody targeting interleukin-5 (depemokimab), 792 adolescents or adults with at least two asthma exacerbations in the past year despite medium- or high-dose inhaled glucocorticoids and an elevated blood eosinophil count were randomly assigned to depemokimab (100 mg subcutaneously every six months) or placebo and followed for one year [6]. Patients receiving depemokimab demonstrated a substantial reduction in annualized asthma exacerbations compared with patients receiving placebo (rate ratio 0.46) but no meaningful improvements in daily asthma symptoms or respiratory quality of life. Rates of adverse events were largely similar among the two groups. These favorable results may portend regulatory approval of ultra-long-acting asthma biologics. (See "Treatment of severe asthma in adolescents and adults", section on 'Experimental approaches'.)

DRUG HYPERSENSITIVITY

Premedication of patients with a history of iodinated contrast hypersensitivity reaction (May 2025)

Modern low-osmolality iodinated contrast media carry a small risk of immediate ("allergic-like") hypersensitivity reactions, but the benefit of premedicating patients with any severity of past reaction is unclear. A new multidisciplinary consensus guideline no longer recommends premedicating patients with a history of mild allergic-like reactions since any benefit is small, whereas adverse reactions from glucocorticoids and antihistamines can occur [7]. The guideline recommends changing contrast agents in all patients with a history of past reaction, when feasible, since data support the favorable impact of this practice. We generally agree with these recommendations, and continue to administer premedication in those with a history of moderate or severe allergic-like reactions. (See "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography", section on 'Preventing recurrent allergic-like reactions'.)

FOOD ALLERGY AND INTOLERANCE

Peanut oral immunotherapy for patients with higher reaction thresholds (May 2025)

Most oral immunotherapy (OIT) studies have only included patients with low reaction thresholds (≤100 mg peanut protein), but the majority of patients with peanut allergy have higher thresholds and may also benefit from OIT. In an open-label trial, 73 children aged 4 to 14 years with peanut allergy who reacted to a higher double-blind placebo-controlled food challenge (DBPCFC) dose of 443 to 5043 mg were randomly assigned 1:1 to peanut OIT using home-measured, retail-purchased peanut with medically supervised updosing every eight weeks to a maximum dose of 3396 mg (or 72 weeks if that dose was not reached) or to avoidance [8]. All children in the OIT group tolerated the full post-treatment DBPCFC dose (9043 mg) compared with 10 percent of children in the avoidance group, and most of these children had sustained unresponsiveness (passed another DBPCFC after avoiding peanut for eight weeks). (See "Food allergy management: Allergen-specific immunotherapy", section on 'Peanut OIT for higher-threshold patients'.)

Updated guidelines on eosinophilic esophagitis (January 2025)

The American College of Gastroenterology has published updated guidelines on diagnosis and management of eosinophilic esophagitis (EoE) [9]. The guidelines establish the diagnosis of EoE based esophageal symptoms, ≥15 eosinophils per high-power field on biopsy, and excluding other causes of eosinophilia. Endoscopic evaluation includes obtaining multiple biopsies from two esophageal levels (ie, proximal/mid and distal esophagus). For initial treatment, the guidelines endorse a limited empiric food elimination diet or pharmacologic (proton pump inhibitor or topical glucocorticoid) therapy. Our approach is generally consistent with these guidelines. (See "Treatment of eosinophilic esophagitis (EoE)", section on 'Introduction'.)

IMMUNODEFICIENCY

Gene therapy for leukocyte adhesion deficiency type I (May 2025)

Leukocyte adhesion deficiency type I (LAD I) is a rare disorder of impaired leukocyte migration into tissues due to deficiency/defects in the integrin CD18. Absent pus formation is a hallmark finding, and affected infants can present with omphalitis, delayed separation of the umbilical cord, and recurrent bacterial infections. Without allogeneic hematopoietic cell transplant (HCT), only 40 percent of children survive to adulthood. In a phase 1 to 2 trial, nine children with severe LAD I were treated with autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing a normal CD18 gene [10]. The primary endpoint of survival without the need for HCT for one to two years was met by all nine children. Annual rates of serious infections were 85 percent lower than historical controls (patients with LAD I who did not receive HCT). Pending longer-term follow up, gene therapy may become a lifesaving intervention for severe LAD I, especially in cases where no matched donor for HCT is available. (See "Leukocyte-adhesion deficiency disorders", section on 'Gene therapy'.)

Updated IUIS inborn errors of immunity classification (May 2025)

The International Union of Immunological Societies (IUIS) has updated its inborn error of immunity (IEI) classification (table 2) [11].The number of genes associated with IEI continues to increase, with defects in 508 different genes and 17 phenocopies now identified, including 67 newly discovered or confirmed and/or expanded novel monogenic defects and 2 phenocopies due to neutralizing anticytokine autoantibodies or somatic mutations in 2022 to 2024. Different variants in the same gene can result in clinically and phenotypically distinct IEI. In addition, the gene dose can influence disease phenotype and severity. Recognition of pathogenic mechanisms through the identification of IEI has resulted in numerous gene- and pathway-specific therapies.(See "Inborn errors of immunity (primary immunodeficiencies): Classification", section on 'Classification'.)

RHINITIS AND RHINOSINUSITIS

Tezepelumab for chronic rhinosinusitis with nasal polyposis (April 2025)

Chronic rhinosinusitis with nasal polyposis (CRSwNP) can be a debilitating disorder that remains difficult to control. Tezepelumab is a monoclonal antibody to thymic stromal lymphopoietin (TSLP), a cytokine important in initiating type 2 inflammation, which is abundant in nasal polyp tissue. Efficacy in severe CRSwNP was demonstrated in a trial of over 400 adults randomized to standard care plus either tezepelumab or placebo injected subcutaneously monthly for 52 weeks [12]. Patients who received tezepelumab had clinically meaningful improvements in the primary endpoints of nasal polyp and nasal congestion scores, as well as in smell scores and quality of life. Tezepelumab also reduced the need for systemic glucocorticoids and sinus polyp surgery. Tezepelumab is not yet approved for CRSwNP, although it is available for the treatment of moderate-to-severe asthma. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Investigational biologic agents'.)

URTICARIA AND ANGIOEDEMA

Investigational remibrutinib for refractory chronic spontaneous urticaria (May 2025)

Chronic spontaneous urticaria (CSU) can be a debilitating condition that is treated with oral antihistamines and, if refractory, with injectable biologics. Remibrutinib is an oral Bruton tyrosine kinase inhibitor (TKI) that blocks signaling through the high-affinity immunoglobulin E (IgE) receptor on mast cells and basophils. It was studied in two identical phase 3 randomized trials of over 400 adults each with CSU refractory to one to four doses of a nonsedating antihistamine [13]. For the primary endpoint of lowered Urticaria Activity Scores (UAS7) from baseline to week 12, remibrutinib reduced scores by approximately 20 points, with a minimal important difference of 10 points, and responses were seen as early as one week. Therapy was well tolerated, although transient petechiae were noted in some participants receiving remibrutinib. This promising agent would offer an oral treatment for refractory CSU. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Investigational agents'.)

Dupilumab for refractory chronic spontaneous urticaria (May 2025)

Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin (IL)-4 receptor and inhibits the activity of IL-4 and IL-13, type 2 cytokines involved in allergic inflammation. In April 2025, it was approved for use in chronic spontaneous urticaria (CSU) in patients ≥12 years who remain symptomatic despite H1 antihistamines [14]. Prior to this approval, omalizumab was the only biologic agent available for the management of this disorder. Although head-to-head studies comparing the two agents are lacking, dupilumab appears to have a somewhat slower onset of action and didn't perform well in most patients who did not benefit from or tolerate omalizumab [15]. Thus, its role in therapy will likely be as a primary alternative to omalizumab in select patients who have concomitant conditions that could also be treated with dupilumab, or those who prefer it to omalizumab for other reasons. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Dupilumab'.)

Investigational gene editing therapy for hereditary angioedema (February 2025)

Hereditary angioedema (HAE) is a disorder in which deficient or dysfunctional C1 inhibitor causes episodes of angioedema with laryngeal swelling that can be fatal. NTLA-2002 is an investigational gene editing therapy that targets the gene that encodes kallikrein B1; this gene is normal in HAE, but kallikrein is critical for the excessive bradykinin production that precipitates symptoms (figure 1). In a phase II randomized trial of 27 patients with HAE, a single infusion of 25 or 50 mg of NTLA-2002 reduced attacks per month at 16 weeks (0.7 and 0.6 attacks with 25 and 50 mg NTLA-2002,respectively) compared with placebo (2.8 attacks per month); 80 percent of patients became attack free on the higher dose [16]. Although promising, the strategy of knocking down a normal gene rather than correcting a pathogenic variant requires further studies of long-term safety. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Therapies altering gene or protein expression'.)

VACCINES AND VACCINE HYPERSENSITIVITY

Egg allergy no longer a concern for any vaccines (February 2025)

Some vaccines contain trace amounts of egg protein (table 3), but none contain enough to cause reactions in egg-allergic patients. For the last several years, it has been recommended that patients not be asked about egg allergy prior to receiving influenza vaccine. More recently, data have accumulated to show that egg allergy is similarly not a concern for administration of the yellow fever vaccine. In the largest study to date, 171 children with egg allergy, including 24 percent with a history of anaphylaxis, underwent skin testing with the yellow fever vaccine and then received it regardless of skin test results, with no allergic reactions [17]. Thus, we no longer inquire about egg allergy prior to the administration of any vaccine. Vaccine providers should remain prepared to treat rare allergic reactions that may occur after any vaccine, but no special precautions are necessary for recipients with egg allergy. (See "Allergic reactions to vaccines", section on 'Hen's egg'.)

OTHER GENERAL ALLERGY AND IMMUNOLOGY

Duration of observation for children treated with epinephrine for anaphylaxis (June 2025)

Consensus does not exist regarding the optimal observation period for a child successfully treated for anaphylaxis; concern for biphasic reactions results in significant practice variation and potentially unnecessary hospital observation. In a retrospective study of over 5600 children with acute allergic reactions that were treated with epinephrine before or shortly after presentation to the emergency department (ED), there was a minimal (<2 percent) hourly increase in receiving additional epinephrine after four hours, even in patients who presented with cardiovascular involvement [18]. These findings support our recommendation for discharging patients, including children, from the ED after an appropriate observation period following resolution of anaphylaxis signs and symptoms. (See "Anaphylaxis: Emergency treatment", section on 'Duration of observation'.)

Nemolizumab for children with atopic dermatitis (May 2025)

Nemolizumab, a humanized monoclonal antibody against the interleukin (IL)-31 receptor, is approved in the United States for the treatment of moderate to severe atopic dermatitis (AD) in patients ≥12 years, but data on long-term efficacy and safety in younger children are lacking. In a small Japanese trial, 88 children aged 6 to 12 years, previously randomly assigned to nemolizumab or placebo for 16 weeks, were enrolled in an extension study in which all received nemolizumab [19]. At 68 weeks, all patients, irrespective of the group to which they were assigned during the randomized trial, experienced a sustained reduction in pruritus and improvement of cutaneous symptoms from baseline. Adverse effects (most frequently exacerbation of AD and upper respiratory infections) were generally mild. These results suggest that nemolizumab is a potentially useful addition to the treatment for AD in children, but larger studies involving more diverse populations are needed for confirmation. (See "Management of severe, refractory atopic dermatitis (eczema) in children", section on 'Nemolizumab'.)

Withdrawal pruritus with cetirizine and levocetirizine (May 2025)

Cetirizine and levocetirizine are effective nonsedating antihistamines that are commonly recommended for urticaria, seasonal allergies, and various pruritic conditions. However, the US Food and Drug Administration (FDA) issued a safety communication that rare patients may experience increased itching that is sometimes disabling when reducing or discontinuing these medications, particularly after three or more months of regular administration [20]. Restarting the medication and slowly tapering down the dose may help in some cases, and the problem is generally self-limited. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Withdrawal pruritus with cetirizine and levocetirizine'.)

Topical roflumilast for atopic dermatitis (February 2025)

Roflumilast is a selective, highly potent phosphodiesterase-4 inhibitor with anti-inflammatory properties. In two identical randomized trials including over 1300 patients with mild or moderate atopic dermatitis (AD), more patients assigned to roflumilast cream 0.15% once daily achieved the primary endpoint of Investigator Global Assessment (IGA) clear/almost clear at four weeks compared with those assigned to a vehicle control [21]. Treatment-emergent adverse effects were mild or moderate and included headache, nausea, application site pain, and nasopharyngitis. Based on these data, topical roflumilast cream 0.15% was approved by the United States Food and Drug Administration for the treatment of mild to moderate AD in adults and children ≥6 years. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical roflumilast'.)