Pediatrics – Allergy and Immunology
Phase 2 RCT: CRISPR-Based Therapy Reduces Attacks in Hereditary Angioedema
2 Jan, 2025 | 10:00h | UTCBackground: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by unpredictable attacks of angioedema involving cutaneous tissues, the gastrointestinal tract, and, potentially, the larynx, posing a risk of asphyxiation. Current prophylactic treatments require frequent administration, often leading to suboptimal adherence and ongoing disease burden. NTLA-2002 is an in vivo CRISPR-Cas9–based therapy designed to permanently inactivate the KLKB1 gene in hepatocytes, thereby reducing plasma kallikrein levels and, hypothetically, lowering attack frequency in patients with HAE.
Objective: To evaluate whether a single intravenous infusion of NTLA-2002 (25 mg or 50 mg) would safely and effectively decrease HAE attack rates and reduce plasma kallikrein protein levels over a 16-week primary observation period, as compared with placebo.
Methods: This phase 2, randomized, double-blind, placebo-controlled trial included 27 adults with confirmed type 1 or type 2 HAE. Participants were assigned in a 2:2:1 ratio to receive a one-time dose of 25 mg or 50 mg of NTLA-2002 or placebo. The primary endpoint was the investigator-confirmed number of angioedema attacks per month from Week 1 through Week 16. Secondary endpoints included the number of moderate-to-severe attacks, use of on-demand therapy, adverse events, and changes in total plasma kallikrein protein levels (analyzed by immunoassays). Exploratory measures encompassed patient-reported outcomes using the Angioedema Quality of Life (AE-QoL) questionnaire.
Results: During the 16-week period, the mean monthly attack rate decreased by 75% in the 25 mg group and 77% in the 50 mg group relative to placebo (estimated rates of 0.70 vs. 0.65 vs. 2.82 attacks per month, respectively). Notably, 4 of 10 patients (40%) in the 25 mg group and 8 of 11 (73%) in the 50 mg group reported no attacks or further prophylaxis use after dosing. Placebo recipients showed only a 16% reduction from baseline. Adverse events were predominantly mild to moderate; headache, fatigue, and nasopharyngitis were most common. Infusion-related reactions occurred in a few patients but resolved without sequelae. A single transient grade 2 elevation in alanine aminotransferase was recorded in one participant given 25 mg of NTLA-2002. By Week 16, total plasma kallikrein levels decreased by 55% in the 25 mg group and 86% in the 50 mg group, with no meaningful changes in placebo.
Conclusions: A single intravenous infusion of NTLA-2002 significantly lowered attack frequency and reduced total plasma kallikrein levels in HAE. Most patients treated at 50 mg experienced no attacks, suggesting that long-term prophylaxis might be unnecessary for many. Longer observation supports durability, yet cost and potential long-term effects of gene editing warrant cautious interpretation.
Implications for Practice: If confirmed by larger phase 3 trials, this gene-editing approach could alter the management of HAE, reducing or eliminating the need for continuous prophylaxis. However, clinicians must weigh the high upfront cost, possible unpredictable immune responses, and the novelty of CRISPR-based therapies before integrating them into standard care.
Study Strengths and Limitations: Strengths include a placebo-controlled design, meaningful improvement in patient-reported outcomes, and robust plasma kallikrein protein reduction. Limitations are the small sample size, short primary observation period, and uncertain long-term safety in diverse populations.
Future Research: Ongoing phase 3 studies with larger cohorts and extended follow-up are essential to confirm safety, long-term efficacy, and cost-effectiveness.
Reference: Cohn DM, Gurugama P, Magerl M, et al. CRISPR-Based Therapy for Hereditary Angioedema. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2405734
- Editorial: Musunuru K. A Milestone for Gene-Editing Therapies. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMe2412176
Review: Chronic Hand Eczema
29 Nov, 2024 | 12:28h | UTCIntroduction: Hand eczema is a highly prevalent inflammatory skin condition and one of the most common work-related disorders, with a lifetime prevalence of approximately 15%. In up to two-thirds of affected individuals, the disease becomes chronic—persisting for more than three months or recurring multiple times within a year—leading to substantial personal and occupational disability. This review by Weidinger and Novak synthesizes current knowledge on the epidemiology, risk factors, clinical features, diagnosis, mechanisms, and management of chronic hand eczema, highlighting the need for further research to enhance prevention and treatment strategies.
Key Recommendations:
- Risk Factor Identification: Recognize major risk factors, including current or past atopic dermatitis, dry skin, and occupational exposure to irritants and allergens. Occupational history is crucial, as hand eczema is prevalent in high-risk professions such as health care, hairdressing, and cleaning.
- Diagnosis and Assessment: Diagnose chronic hand eczema based on history and clinical features, considering differential diagnoses like psoriasis and tinea manus. Patch testing is recommended to identify contact allergens, especially in cases unresponsive to initial therapy.
- Patient Education and Prevention: Implement structured education on skin care, avoidance of trigger factors, and use of protective measures. Emphasize primary to tertiary prevention strategies, including workplace interventions and rehabilitation programs.
- Topical Therapies: Initiate treatment with topical glucocorticosteroids for anti-inflammatory effect. Use calcineurin inhibitors as second-line therapy, particularly for patients refractory to steroids or requiring long-term treatment. The topical pan-Janus kinase inhibitor delgocitinib is approved for moderate to severe chronic hand eczema unresponsive to corticosteroids.
- Phototherapy: Consider short-term phototherapy (4–8 weeks) with options like PUVA or narrow-band UVB for patients inadequately controlled with topical treatments.
- Systemic Therapies: For severe cases unresponsive to topical treatments, systemic retinoids such as alitretinoin are first-line therapy. Off-label use of immunosuppressants like ciclosporine, methotrexate, and azathioprine may be considered. Systemic immunomodulatory therapies approved for atopic dermatitis, including dupilumab and Janus kinase inhibitors, show promise, especially in atopic hand eczema.
- Adjunctive Measures: Encourage the use of emollients for skin barrier repair and recommend avoidance of harmful exposures. Patient self-management is crucial, including appropriate hand hygiene and use of protective gloves.
Conclusion: By adopting these evidence-based management strategies, clinicians can improve patient care by reducing symptoms, preventing disease progression, and enhancing quality of life for individuals with chronic hand eczema. Early identification of risk factors, comprehensive patient education, and individualized treatment plans are essential to mitigate the substantial personal and socioeconomic burden of this condition.
EULAR/PReS Guidelines for the Diagnosis and Management of Still’s Disease
20 Oct, 2024 | 17:41h | UTCIntroduction:
Still’s disease, encompassing systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), is a systemic inflammatory disorder characterized by spiking fevers, rash, arthralgia or arthritis, and elevated inflammatory markers. Historically treated as separate entities, sJIA and AOSD are now recognized as the same disease continuum. To unify and optimize diagnosis and management across all ages, the European Alliance of Associations for Rheumatology (EULAR) and the Paediatric Rheumatology European Society (PReS) have developed comprehensive, evidence-based recommendations.
Key Recommendations:
- Unified Terminology: sJIA and AOSD are the same disease and should be collectively termed “Still’s disease” to standardize diagnosis and treatment. (Recommendation: strong)
- Rapid Diagnosis Using Operational Definitions: Key clinical features include spiking fever ≥39°C lasting ≥7 days, transient rash coinciding with fever spikes, arthralgia or arthritis, and elevated inflammatory markers (CRP, ESR, neutrophils, ferritin). Arthritis is supportive but not essential for diagnosis. (Strong)
- Diagnostic Biomarkers: Elevated serum interleukin-18 (IL-18) and S100 proteins strongly support the diagnosis and should be measured when available. (Moderate)
- Exclude Alternative Diagnoses: Carefully consider infections, malignancies, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders to avoid misdiagnosis. (Strong)
- Treatment Goals: The ultimate goal is drug-free remission, defined as clinically inactive disease (CID) maintained for at least 6 months. CID entails absence of disease-related symptoms and normalization of ESR and CRP. Intermediate targets at specific time points guide treatment adjustments. (Strong)
- Early Use of IL-1 and IL-6 Inhibitors: To avoid prolonged glucocorticoid use, prioritize early initiation of interleukin-1 (IL-1) or interleukin-6 (IL-6) inhibitors upon diagnosis. (Strong)
- Glucocorticoid Tapering: Aim to achieve CID without glucocorticoids within 6 months. Maintain CID for 3–6 months before initiating tapering of biologic DMARDs. (Strong)
- Monitor for Complications: Be vigilant for life-threatening complications, including macrophage activation syndrome (MAS) and lung disease (LD), which require prompt recognition and management. (Strong)
- MAS Management: Consider MAS in patients with persistent fever, splenomegaly, elevated ferritin, cytopenias, abnormal liver function tests, coagulopathy, and hypertriglyceridemia. High-dose glucocorticoids are essential; anakinra, ciclosporin, and interferon-γ inhibitors may be added. (Strong)
- LD Screening and Management: Screen patients for LD via clinical assessment and pulmonary function tests; high-resolution CT scans are indicated for symptomatic patients. The presence of LD is not a contraindication for IL-1 or IL-6 inhibitors. (Strong)
Conclusion: Implementing these unified, evidence-based recommendations is expected to improve the diagnosis and management of Still’s disease across all ages, leading to earlier intervention, optimized treatment strategies, reduced complications, and enhanced patient outcomes, including achieving drug-free remission.
RCT: Milk Elimination Diet Comparable to Four-Food Elimination in Pediatric EoE
20 Oct, 2024 | 15:04h | UTCBackground: Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition characterized by eosinophil infiltration of the esophageal mucosa, leading to symptoms such as nausea, vomiting, abdominal pain, and dysphagia in children. While elimination of six common food allergens is effective, this approach is highly restrictive and may adversely affect quality of life (QoL). Less restrictive diets could potentially balance efficacy with improved QoL.
Objective: To compare the efficacy of a one-food elimination diet excluding milk (1FED) versus a four-food elimination diet excluding milk, egg, wheat, and soy (4FED) in treating pediatric EoE.
Methods: In this multicenter, randomized, nonblinded trial conducted at ten sites in the United States, 63 children aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to either 1FED (n = 38) or 4FED (n = 25) for 12 weeks. The primary endpoint was symptom improvement measured by the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS). Secondary endpoints included the proportion achieving histologic remission (<15 eosinophils per high-power field), changes in histologic features (histology scoring system), endoscopic severity (endoscopic reference score), transcriptome profiling (EoE diagnostic panel), QoL scores, and predictors of remission.
Results: Out of 63 participants, 51 completed the study (1FED, n = 34; 4FED, n = 17). The 4FED group showed a greater improvement in mean PEESS scores compared to the 1FED group (−25.0 vs. −14.5; P = .04). However, histologic remission rates were similar between 4FED and 1FED (41% vs. 44%; P = 1.00). Changes in the histology scoring system (−0.25 vs. −0.29; P = .77), endoscopic reference score (−1.10 vs. −0.58; P = .47), and QoL scores were comparable between groups. The withdrawal rate was higher in the 4FED group compared to the 1FED group (32% vs. 11%; P = .0496).
Conclusions: While the 4FED moderately improved symptoms more than the 1FED, both diets resulted in similar histologic, endoscopic, QoL, and transcriptomic outcomes. Given its comparable effectiveness, better tolerability, and simplicity, the 1FED is a reasonable first-choice therapy for pediatric EoE.
Implications for Practice: Eliminating cow’s milk alone may be preferable as initial dietary therapy for children with EoE due to its simplicity and similar efficacy compared to more restrictive diets. Clinicians should consider starting with a milk elimination diet before progressing to more restrictive elimination diets if necessary.
Study Strengths and Limitations: Strengths of the study include its randomized, multicenter design; standardized treatment instructions; and use of validated symptom and QoL instruments. Limitations include early termination due to low enrollment, a higher withdrawal rate in the 4FED group, nonblinded interventions, and potential bias from participant expectations.
Future Research: Further large-scale, randomized studies are needed to confirm these findings and to identify biomarkers that predict response to dietary therapy in pediatric EoE.
News Release – FDA Approves First Nasal Spray for Anaphylaxis Treatment: Neffy (Epinephrine Nasal Spray) – U.S. Food and Drug Administration
17 Aug, 2024 | 15:43h | UTCThe U.S. Food and Drug Administration (FDA) has approved Neffy, the first epinephrine nasal spray for the emergency treatment of anaphylaxis and other severe allergic reactions (Type I) in both adults and pediatric patients weighing at least 30 kilograms (approximately 66 pounds). This approval introduces a non-injectable option for the rapid administration of epinephrine, which is critical in managing life-threatening allergic reactions.
Key Points for Healthcare Providers:
– Alternative to Injection: Neffy provides a new option for patients who may delay or avoid epinephrine injections due to needle phobia. This could be particularly beneficial for children and others reluctant to use injectable epinephrine.
– Efficacy and Safety: Neffy’s approval is supported by studies comparing its pharmacokinetics and pharmacodynamics to traditional epinephrine injections. These studies showed comparable blood epinephrine levels and similar physiological effects, such as increased blood pressure and heart rate.
– Administration: Neffy is a single-dose nasal spray, administered into one nostril. If symptoms do not improve or worsen, a second dose may be administered in the same nostril. Patients should still seek emergency medical care to monitor the anaphylactic reaction.
– Warnings: Certain nasal conditions, such as nasal polyps or a history of nasal surgery, may impair Neffy’s absorption. In these cases, injectable epinephrine might be a more reliable option. The product also carries typical warnings for epinephrine use, particularly in patients with coexisting conditions.
– Side Effects: Common side effects include throat irritation, nasal discomfort, headaches, and jitteriness. Healthcare professionals should discuss these with patients to ensure informed use.
Clinical Implications:
Neffy may reduce barriers to the timely treatment of anaphylaxis, potentially improving outcomes by increasing the likelihood of rapid epinephrine administration. Healthcare providers should consider Neffy as an alternative for patients who are needle-averse or have difficulty using injectable epinephrine, while also ensuring patients understand the importance of prompt medical attention following its use.
Approval Background:
Neffy was granted Fast Track designation by the FDA, emphasizing the need for an alternative to injectable epinephrine. The approval was awarded to ARS Pharmaceuticals.
Source: FDA News Release: FDA Approves First Nasal Spray for Treatment of Anaphylaxis
RCT | Maternal egg intake in early neonatal period does not impact infant egg allergy risk
2 Aug, 2023 | 13:47h | UTCSee also: Visual Abstract
An ESPGHAN position paper on the diagnosis, management and prevention of cow’s milk allergy
31 Jul, 2023 | 14:28h | UTC
Adrenaline auto-injector prescription for patients at risk of anaphylaxis: BSACI guidance for primary care
6 Jun, 2023 | 14:28h | UTC
RCT | Peanut patch therapy is effective in desensitizing young children with allergies, but raises risk of serious adverse events
15 May, 2023 | 13:10h | UTCPhase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy – New England Journal of Medicine (link to abstract – $ for full-text)
Commentary on Twitter
In the phase 3 EPITOPE trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy by means of a peanut patch was superior to placebo in desensitizing children to peanut. https://t.co/USk6HBI9Qh#pediatrics
— NEJM (@NEJM) May 10, 2023
M-A | Timing of allergenic food introduction and risk of immunoglobulin E–mediated food allergy
11 Apr, 2023 | 14:32h | UTCNews Release: Earlier introduction of allergenic foods in children may prevent food allergies – Imperial College London
Commentary: Allergenic Food Introduction Led to Fewer Allergies, Higher Withdrawal Rate from Intervention – HCP Live
Related:
AAP Updated Recommendations for Dietary Interventions to Prevent Atopic Disease
Timing of introduction of allergenic solids for infants at high risk – Canadian Paediatric Society
Commentary on Twitter
In this study, earlier introduction of multiple allergenic foods was associated with a reduced risk of food allergy but with significant rates of withdrawal from the intervention. https://t.co/lZFkQIH9q7
— JAMA Pediatrics (@JAMAPediatrics) March 27, 2023
Cohort Study | Associations between fetal or infancy pet exposure and food allergies
3 Apr, 2023 | 13:26h | UTC
Two phase 3 trials of lebrikizumab for moderate-to-severe atopic dermatitis
21 Mar, 2023 | 13:23h | UTCTwo Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis – New England Journal of Medicine (link to abstract – $ for full-text)
News Release: Largest study to date of lebrikizumab supports its use for treatment of atopic dermatitis – George Washington University
Commentary: Lebrikizumab Effective for Adults, Teens With Atopic Dermatitis – HealthDay
Study | Public health policies should recommend introducing peanut products to infants at 4-6 months of age to prevent peanut allergy
20 Mar, 2023 | 13:33h | UTCCommentary: Expert reaction to research on giving peanut products to babies – Science Media Centre
Related study: Early Introduction of Allergenic Foods Can Prevent Food Allergies in High Risk Infants
Related Guidelines:
AAP Updated Recommendations for Dietary Interventions to Prevent Atopic Disease
Timing of introduction of allergenic solids for infants at high risk – Canadian Paediatric Society
Commentary from the author on Twitter
Latest paper from #LEAPStudy is now published in @JACIonline. We have looked at what happens if peanut products are introduced into the infant diet at different ages across the whole population. https://t.co/zpOlrNHOSihttps://t.co/xDIgYjezyS
More details below. @GoAllergy 1/12 pic.twitter.com/jY5MvdJ2AZ— Graham Roberts (@ProfGRoberts) January 12, 2023
RCT | Methylprednisolone vs. immunoglobulins equally effective in PIMS temporally associated with SARS-CoV-2
8 Feb, 2023 | 12:42h | UTC
SR | Skin care interventions in infants for preventing eczema and food allergy.
12 Dec, 2022 | 12:23h | UTCSkin care interventions in infants for preventing eczema and food allergy – Cochrane Library
Summary: Skin care interventions for preventing eczema and food allergy – Cochrane Library
Commentary on Twitter
Read our newest review on skin care interventions in infants for preventing eczema and food allergy! https://t.co/o8HtBXRVM5 pic.twitter.com/BPzsjJZvTf
— Cochrane Skin (@CochraneSkin) November 15, 2022
RCT | Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis.
20 Sep, 2022 | 13:20h | UTCCommentary: Dupilumab Eases Atopic Dermatitis in Children Younger Than 6 Years – HealthDay
Systematic Review | Anti‐IL‐5 therapies for asthma.
14 Jul, 2022 | 12:40h | UTCAnti‐IL‐5 therapies for asthma – Cochrane Library
Review: Management of moderate-severe atopic dermatitis in pediatric age.
27 Jun, 2022 | 11:32h | UTC
EULAR/ACR points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases.
24 Jun, 2022 | 11:23h | UTC
RCT: Effectiveness and safety of lotion, cream, gel, and ointment emollients for childhood eczema.
15 Jun, 2022 | 11:20h | UTCNews Release: The right moisturiser for children with eczema is the one that they like to use, study finds – University of Nottingham
Commentary: Lotion, Cream, Gel, and Ointment Similarly Effective for Childhood Eczema – HealthDay
Commentary on Twitter
New: @bee_study led by @riddmj found no difference in effectiveness between the four main types of emollients —lotions, creams, gels, and ointments—for childhood #eczema
The right #moisturizer is the one that children will use. https://t.co/45N5A136Kx
— The Lancet Child & Adolescent Health (@LancetChildAdol) May 24, 2022
M-A: Reproducibility of food challenge to cow’s milk.
15 Jun, 2022 | 10:42h | UTC
Position Paper: Diagnostic therapeutic care pathway for pediatric food allergies and intolerances.
14 Jun, 2022 | 11:05h | UTC
Another study suggests the Omicron variant is associated with a reduced risk of Multisystem Inflammatory Syndrome in Children compared to previous SARS-CoV-2 variants.
10 Jun, 2022 | 12:38h | UTCRelated study: Severity and Incidence of Multisystem Inflammatory Syndrome in Children During 3 SARS-CoV-2 Pandemic Waves in Israel – JAMA AND Commentary: Kids’ COVID syndrome—MIS-C—less severe in Omicron – CIDRAP
Commentary on Twitter
Study found that the risk of multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection during the #Omicron wave substantially lower compared to previous #SARSCoV2 variants. https://t.co/GYrz9XA72Z
— JAMA Pediatrics (@JAMAPediatrics) June 8, 2022
Consensus on the diagnosis and treatment of cow’s milk protein allergy.
2 Jun, 2022 | 10:56h | UTC
Cohort Study: Most egg allergy and nearly one-third of peanut allergy resolves naturally by age 6 years.
27 May, 2022 | 11:46h | UTCThe natural history of peanut and egg allergy in children up to age 6 years in the HealthNuts population-based longitudinal study – The Journal of Allergy & Clinical Immunology (link to abstract – $ for full-text)