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

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) [1]. 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) [2]. 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 [3]. 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 [4]. 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'.)

Use of anti-inflammatory reliever therapies to reduce asthma exacerbations (November 2024)

Use of inhalers containing both a fast-acting bronchodilator and anti-inflammatory inhaled corticosteroids (ICS) for relief of symptoms has reduced the rate of asthma exacerbations compared with short-acting beta-agonists (SABA) alone in several randomized trials of adolescents and adults. In a new network meta-analysis, compared with SABA alone, severe asthma exacerbations were significantly reduced for both ICS-formoterol (13 trials, 19,184 patients; risk difference 10.3 percent, risk ratio [RR] 0.65) and ICS-SABA (4 trials, 4852 patients; risk difference 4.7 percent, RR 0.84) [5]. Our authors recommend these anti-inflammatory reliever therapies for those with variable asthma symptoms or frequent exacerbations and prefer them for all patients with asthma. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Anti-inflammatory reliever therapy (AIR) to reduce exacerbations'.)

DRUG HYPERSENSITIVITY

JAK inhibitors for Stevens-Johnson syndrome/toxic epidermal necrolysis (December 2024)

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe drug-induced mucocutaneous reaction for which there is no established pharmacologic treatment other than supportive care. Based on in vitro and preclinical data showing marked upregulation of the JAK/STAT pathway in both keratinocytes and immune cells in SJS/TEN, seven patients were treated with an oral JAK inhibitor (abrocitinib or tofacitinib) for two weeks [6]. All patients also received high-dose intravenous glucocorticoids. In all patients, JAK inhibition was associated with rapid clinical improvement and re-epithelialization without treatment-related adverse events. These findings suggest a beneficial effect of JAK inhibitors for SJS/TEN, but further studies are needed to confirm their efficacy and optimal use. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'JAK inhibitors'.)

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 [7]. 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) [8]. 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

IL-1 blockade for Wiskott-Aldrich syndrome (November 2024)

Dysregulated overproduction of interleukin 1 beta (IL-1-beta) plays a role in the autoinflammatory/autoimmune features of Wiskott-Aldrich syndrome (WAS). In a multicenter, retrospective analysis of nine patients with WAS and prominent inflammatory manifestations unresponsive to systemic glucocorticoids, IL-1 blockade sufficiently controlled inflammatory disease in all patients, allowing them to progress to definitive therapy (hematopoietic cell transplantation [HCT] or gene therapy [GT]) [9]. Resumption of IL-1 blockade for recurrent inflammatory disease was required after HCT in patients with mixed or falling myeloid donor chimerism, but not for those with full myeloid donor chimerism or who had undergone GT. Further studies are needed to determine how to best incorporate IL-1 blockade for the treatment of WAS. (See "Wiskott-Aldrich syndrome", section on 'IL-1 blockade'.)

Busulfan conditioning for severe combined immunodeficiency hematopoietic cell transplantation (November 2024)

Busulfan is commonly used in pre-hematopoietic cell transplantation (HCT) conditioning regimens, but it has a narrow window of therapeutic efficacy. In a series that included 154 infants with severe combined immunodeficiency who received busulfan prior to HCT, event-free survival was higher in the groups who received a cumulative busulfan dose of <70 or 70 to 90 mg x hr/L compared with those who received >90 mg x hr/L [10]. Lower doses were associated with greater graft failure and higher doses with greater toxicity. Targeting a cumulative busulfan dose of 80 mg x hr/L may help optimize event-free survival and donor chimerism. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies", section on 'Efficacy'.)

Reanalysis of genetic testing for inborn errors of immunity (November 2024)

The continued increase in newly identified inborn errors of immunity (IEI) and improvement in diagnostic tools means that reanalysis of previously obtained data can identify additional causative defects. In one such reanalysis of exome data from 1300 adult and pediatric patients with suspected IEI, the diagnostic yield increased from 11.8 to 15.2 percent [11]. Although the absolute increase is small, 83 percent of those with a definitive molecular variant identified on reanalysis had an actionable diagnosis that could result in improved patient outcomes, supporting the benefit of this approach. (See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome", section on 'Systematic reanalysis'.)

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 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 [13]. 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'.)

Antileukotriene drugs minimally helpful in chronic spontaneous urticaria (November 2024)

The benefit of adding a leukotriene receptor antagonist (LTRA) such as montelukast for patients with chronic spontaneous urticaria that is not controlled with antihistamines alone has not been clear. In a new meta-analysis of 34 randomized trials including over 3000 children and adults, the efficacy of a LTRA added to a nonsedating antihistamine at standard dose was compared with antihistamine alone [14]. The addition of LTRAs provided some benefit, but the degree of improvement on the Urticaria Activity Score was just 5 points, which was less than half of the minimally important difference of 11 points for the symptom scale used. Based upon these findings, we do not advocate for the use of LTRAs in the routine management of chronic spontaneous urticaria. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Leukotriene modifiers'.)

VACCINES AND VACCINE HYPERSENSITIVITY

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

Some vaccines contain trace amounts of egg protein (table 1), 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 [15]. 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

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 [16]. 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'.)

Spesolimab for Sweet syndrome (November 2024)

Systemic glucocorticoids are the mainstays of treatment for Sweet syndrome, an uncommon disorder characterized by neutrophilic infiltrates in the skin and systemic symptoms. The first report of treatment of Sweet syndrome with spesolimab, an interleukin-36 receptor monoclonal antibody, describes rapid clinical improvement in a patient with Sweet syndrome who was refractory to systemic glucocorticoids [17]. Although this report suggests spesolimab is a potentially useful treatment for refractory Sweet syndrome, efficacy and safety for this indication have not been confirmed. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Management and prognosis", section on 'Recalcitrant disease'.)