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Allergy Asthma Proc. 2025 May 1;46(3):e71-e81. doi: 10.2500/aap.2025.46.250017.

ABSTRACT

Background: Hereditary angioedema (HAE) is a rare genetic disorder marked by unpredictable episodes of recurrent swelling. This unpredictability, combined with the risk of death and its impact on daily life, leads to significant psychological distress, which profoundly affects patients’ quality of life. Objective: This study assessed the levels of depression, general anxiety, and death anxiety in patients with HAE, along with the factors that influence them. Methods: This single-center cohort study included patients ages ≥18 years and with HAE type 1 or 2, who were followed up at the Allergy and Clinical Immunology Department, Medical Faculty, Ege University, between December 2023 and September 2024. Participants completed questionnaires with regard to their demographics, general health, and disease characteristics. In addition, their psychological conditions were assessed by using the Hospital Anxiety and Depression Scale (HADS) and Templer Death Anxiety Scale, a tool that has not been previously applied to this group. Results: One hundred patients participated in the study, with a mean ± standard deviation age of 40.5 ± 14.5 years; 66% (n = 66) were women. Among the participants, 30% (n = 30) had a family history of death related to HAE, and 74% (n = 74) reported experiencing oropharyngeal/laryngeal edema. Anxiety was observed in 54% of the patients (n = 54), whereas 36% (n = 36) experienced depression. Women had higher levels of anxiety than men (p = 0.048), and younger patients (ages <65 years) exhibited greater anxiety levels (p = 0.022). Mild-to-moderate depression was more prevalent among patients who had experienced a recent laryngeal attack (p = 0.031). Seventy-seven percent of the patients (n = 77) reported experiencing death anxiety, which was notably higher in those who had recent laryngeal attacks (p = 0.004) and moderate-to-severe attacks (p = 0.003). Conclusion: Patients with HAE, especially those who experienced frequent severe attacks or recent laryngeal episodes, face a higher risk of psychological distress.

PMID:40380370 | DOI:10.2500/aap.2025.46.250017

Allergy Asthma Proc. 2025 May 1;46(3):185-191. doi: 10.2500/aap.2025.46.250013.

ABSTRACT

Angioedema is nonpitting swelling that involves the deeper subcutaneous and submucosal layers of tissue. Angioedema can be classified as histaminergic, bradykinin mediated, or idiopathic in etiology. Bradykinin-mediated angioedema presents without urticaria, whereas histaminergic angioedema is usually associated with urticaria (i.e., chronic spontaneous urticaria and angioedema) but manifests with isolated angioedema in ∼20% of patients and clinically overlaps with idiopathic angioedema. Bradykinin-mediated angioedema most commonly occurs in hereditary angioedema (HAE) with or without C1-esterase inhibitor (C1-INH) (HAE-C1INH) deficiency, acquired C1-INH deficiency, and angiotensin-converting enzyme (ACE) inhibitor angioedema. HAE is a life-threatening genetic autosomal dominant disorder most commonly due to a mutation in the serpin family G member 1 (SERPING1) gene, which leads to a deficiency in C1-INH, although multiple new genetic mutations have also been described in HAE with normal C1-INH (HAE-nl-C1INH) level. Clinically, patients have edema that can lead to life-threatening laryngeal edema and asphyxiation. HAE-nl-C1INH describes patients with similar symptoms to those with HAE-C1INH deficiency but have normal C1-INH function and are distinguished by various genetic mutations and a family history of angioedema. Acquired C1-INH deficiency also mimics HAE with symptoms but is due to circulating anti-idiotypic antibodies, leading to either C1-INH consumption or inactivation. Patients are often diagnosed with underlying malignant, lymphoproliferative, or autoimmune disorders. ACE-inhibitor angioedema classically presents with facial, tongue, and oral cavity swelling not associated with pruritus accompanied by normal laboratory studies. Treatment involves stopping the ACE inhibitor though recurrence can occur for a few weeks to months after discontinuation. Idiopathic angioedema is the largest category and is diagnosed when patients experience angioedema without an identifiable etiology with nl-C1INH function and no family history of angioedema. Idiopathic angioedema is further characterized into histaminergic or nonhistaminergic angioedema, depending on the response to high-dose antihistamines. Given the considerable impact of angioedema, physicians and patients must collaborate to craft personalized management strategies. For those with HAE, short- and long-term prophylaxis and on-demand therapy must be considered.

PMID:40380367 | DOI:10.2500/aap.2025.46.250013

Allergy Asthma Proc. 2025 May 1;46(3):192-199. doi: 10.2500/aap.2025.46.250027.

ABSTRACT

Background: Hereditary angioedema (HAE) attacks substantially impair health-related quality of life (HRQoL). Current World Allergy Organization and the European Academy of Allergy and Clinical Immunology guidelines goals include complete control and normalization of patients’ lives. Garadacimab (anti-activated factor XII monoclonal antibody) reduced the mean attack rate after first administration in the pivotal phase III (VANGUARD; NCT04656418) and ongoing long-term phase III open-label extension (OLE) (NCT04739059) studies. Objective: To report exploratory HRQoL data from the interim analysis of the phase III OLE study (data cutoff February 13, 2023). Methods: Patients ages ≥12 years and with HAE received garadacimab 200 mg subcutaneously once monthly in the OLE study. The patient population comprised patients who were garadacimab naive (received placebo in the previous phase III study and newly enrolled patients) and patients who received garadacimab in previous phase II/III studies. The Angioedema Quality of Life (AE-QoL) questionnaire, Treatment Satisfaction Questionnaire for Medication version II (TSQM II), and Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire were administered at baseline and every 3 months during the OLE study. AE-QoL and TSQM II scores were evaluated in comparison with minimal clinically important differences (MCID). Results: Overall, 90 patients who were garadacimab naive and 71 patients with previous garadacimab exposure received garadacimab in the phase III OLE study. The mean ± standard deviation AE-QoL total score improved by 34.2 ± 18.8 points in patients who were garadacimab naive and by 2.3 ± 13.1 points further to the reduction experienced in patients with previous garadacimab exposure. The AE-QoL MCID was met by 92.1% of patients who were garadacimab naive; 81.6% of patients with previous garadacimab exposure experienced stable AE-QoL scores or further improvements per MCID. TSQM II scores were improved from day 1 with garadacimab and sustained to month 12. Improvements in WPAI:GH scores were consistent with AE-QoL and TSQM II. Conclusion: Garadacimab elicited clinically meaningful long-term improvements in HRQoL, work productivity, and treatment satisfaction in patients with HAE, which brought them closer to complete disease control and normalization of life.Clinical trial NCT04739059, <ext-link xmlns:xlink=”http://www.w3.org/1999/xlink” ext-link-type=”uri” xlink:href=”http://clinicaltrials.gov”>clinicaltrials.gov</ext-link>.

PMID:40380363 | DOI:10.2500/aap.2025.46.250027

Allergy Asthma Proc. 2025 May 1;46(3):200-208. doi: 10.2500/aap.2025.46.250026.

ABSTRACT

Background: Hereditary angioedema (HAE) is associated with substantial health-related quality of life (HRQoL) impairments. Complete disease control and life normalization are key treatment goals. In previous studies, garadacimab prevented HAE attacks with a favorable safety profile and HRQoL improvements. Objective: HRQoL was evaluated in patients with HAE receiving garadacimab stratified by attack-free status. Methods: In the pivotal phase III study (NCT04656418), 39 patients received garadacimab 200 mg subcutaneously once monthly and 25 volume-matched placebo. In the phase III open-label extension (OLE), 90 patients in the garadacimab-naive group (received placebo in previous studies or newly enrolled) and 71 patients in the previous garadacimab exposure group (received garadacimab in previous studies) received garadacimab (NCT04739059). Patients ages ≥ 18 years completed the Angioedema Quality of Life (AE-QoL) questionnaire in both studies; scores were evaluated post hoc by attack-free status. Results: In the pivotal phase III and phase III OLE studies, 62% and 60% of patients, respectively, were attack-free. In the pivotal phase III study, the mean AE-QoL total score improved with garadacimab, from 38.8 (day 1) to 6.6 (month 6) for attack-free patients (n = 19) and to 18.4 for patients with one or more attacks (n = 14) versus a change in mean AE-QoL total score from 43.7 to 40.5 with placebo (n = 20). In the phase III OLE study, the mean AE-QoL total score for patients who were garadacimab naive decreased from 46.2 (day 1) to 8.6 (month 12) for attack-free patients (n = 34) and from 54.5 to 23.5 for patients with one or more attacks (n = 30). For the previous garadacimab exposure group, AE-QoL improvements were maintained from previous studies, regardless of attack-free status. Conclusion: Garadacimab was associated with HRQoL improvement versus run-in in all groups. After garadacimab exposure in previous studies, improvements were maintained in the phase III OLE study. Attack-free patients had the greatest HRQoL improvements, bringing them closer to complete disease control and life normalization.Clinical trials NCT04656418, NCT04739059, <ext-link xmlns:xlink=”http://www.w3.org/1999/xlink” ext-link-type=”uri” xlink:href=”http://www.clinicaltrials.gov”>www.clinicaltrials.gov</ext-link>.

PMID:40380356 | DOI:10.2500/aap.2025.46.250026

Immunol Res. 2025 May 16;73(1):82. doi: 10.1007/s12026-025-09638-1.

ABSTRACT

Severe combined immunodeficiency (SCID) represents a life-threatening inborn error of immunity, necessitating rapid diagnosis and intervention to prevent fatal outcomes. While SCID is characterized by profound T-cell lymphopenia, it may overlap with other conditions like ataxia-telangiectasia (AT), which also presents with T-cell deficiencies. This study examines two cases of suspected SCID in infants, later identified as AT due to pathogenic variants in the ATM gene. Despite initial negative results from SCID-targeted gene panels, further genetic testing revealed nonsense mutations (p.Y2036X and p.E1996X) in the FAT domain of the ATM gene, confirmed by Sanger sequencing. The patients exhibited significant T-cell lymphopenia and reduced ATM protein activity, indicative of AT. These findings highlight the importance of comprehensive genetic screening beyond common SCID-associated genes, especially in patients with atypical presentations. Early and accurate diagnosis can prevent mismanagement and guide appropriate therapies, improving patient outcomes.

PMID:40379838 | DOI:10.1007/s12026-025-09638-1

Lancet Child Adolesc Health. 2025 Jun;9(6):383-392. doi: 10.1016/S2352-4642(25)00094-X.

ABSTRACT

BACKGROUND: Risk stratification tools for paediatric community-acquired pneumonia (CAP) in well-resourced settings are scarce. We prospectively developed models to predict CAP severity within a multinational cohort of paediatric emergency departments (EDs). Our primary objective was to develop a risk prediction model to discriminate between mild CAP and moderate or severe CAP to assist clinicians in determining the need for hospitalisation.

METHODS: This prospective cohort study was conducted from Feb 6, 2019, to June 30, 2021, at 73 EDs in 14 countries. Children aged 3 months to <14 years with clinical diagnoses of CAP were included. Children were excluded if they were recently hospitalised or had a chronic complex condition (eg, immunodeficiency). The primary outcome was severity, defined as mild (CAP treated in the outpatient setting or hospitalisation <24 h with no use of oxygen or intravenous fluids during that time), moderate (hospitalisation <24 h with oxygen or fluids, or hospitalisation ≥24 h regardless of interventions but without an outcome qualifying as severe CAP), or severe (chest drainage, intensive care unit admission >24 h, positive-pressure ventilation, septic shock, vasoactive infusions, extracorporeal membrane oxygenation, or death) occurring within 7 days of the ED visit. Models were developed using logistic regression with bootstrap validation.

FINDINGS: Of 2222 children in the overall study population (1103 [49·7%] female, 1119 [50·3%] male; median age 3 years [IQR 1-5]), 1290 (58·1%) had mild CAP, 812 (36·5%) moderate, and 120 (5·4%) severe. Primary analyses were performed in 1901 patients with complete data: 1011 (53·2%) mild, 772 (40·6%) moderate, and 118 (6·2%) severe CAP. Congestion or rhinorrhoea was negatively associated with moderate or severe CAP (adjusted odds ratio 0·59 [95% CI 0·46-0·76]), while abdominal pain (1·52 [1·17-1·97]), refusal to drink (1·57 [1·24-2·00]), antibiotics before ED visit (1·64 [1·29-2·10]), chest retractions (2·86 [2·24-3·65]), respiratory rate above the 95th percentile for age (1·63 [1·29-2·06]), heart rate above the 95th percentile for age (1·64 [1·27-2·12]), and hypoxaemia (oxygen saturation 90-92%, 3·24 [2·46-4·27]; <90%, 13·39 [8·64-20·73]) were positively associated. The model accurately discriminated between mild CAP and moderate or severe CAP (c-statistic 0·82 [95% CI 0·80-0·84]). Similar results were found in those with radiographic CAP, with decreased breath sounds and multifocal opacities on radiography as additional predictors (c-statistic 0·82 [0·80-0·85]).

INTERPRETATION: We developed accurate, pragmatic severity risk prediction models among children with CAP. After future external validation, these models have the potential to provide individualised risk assessments that can be incorporated into clinical judgement in well-resourced health systems to improve management.

FUNDING: Division of Emergency Medicine at Cincinnati Children’s Hospital Medical Center, Division of Emergency Medicine at Ann & Robert H. Lurie Children’s Hospital of Chicago, and Department of Emergency Medicine at University of California, Davis.

PMID:40379430 | DOI:10.1016/S2352-4642(25)00094-X

J Allergy Clin Immunol. 2025 May 14:S0091-6749(25)00515-9. doi: 10.1016/j.jaci.2025.04.031. Online ahead of print.

ABSTRACT

BACKGROUND: A large proportion of patients with common variable immunodeficiency (CVID) have autoimmune and inflammatory manifestations characterized by chronic T-cell- and monocyte/macrophage activation of unknown etiology. The tryptophan-kynurenine pathway has previously been linked to immune activation involving T cells and monocytes/macrophages, as well as with gut microbial dysbiosis in some inflammatory diseases.

OBJECTIVE: We aimed to characterize the tryptophan-kynurenine pathway in CVID and its potential association with clinical/immunologic phenotype and gut microbial dysbiosis.

METHODS: Serum concentrations of a set of tryptophan-kynurenine pathway metabolites and neopterin were measured using liquid chromatography-tandem mass spectrometry in a discovery cohort (n = 40), a validation cohort (n = 53), and healthy controls (n = 60). B-cell phenotype was analyzed in both cohorts, whereas inflammatory markers (enzyme immunoassay), lipopolysaccharide, gut microbial composition, and food frequency questionnaire were measured in the discovery cohort.

RESULTS: Compared to healthy controls, CVID patients had increased metabolism of the tryptophan-kynurenine pathway as assessed by increased kynurenine/tryptophan ratio, quinolinic acid, and 3-hydroxykynurenine in both the discovery and validation cohorts. The findings were most pronounced in the subgroup with autoimmune/inflammatory complications but was to some degree also observed in CVID patients with infection only. In CVID, the metabolites in the tryptophan-kynurenine pathway associated with soluble (s) markers of monocyte (sCD14, sCD163, neopterin) and T-cell (sCD25) activation as well as B-cell phenotype (eg, naïve B cells). Individual gut microbial taxa may influence tryptophan-kynurenine pathway metabolites, but not lipopolysaccharide or diet.

CONCLUSION: We found altered levels of several metabolites in the tryptophan-kynurenine pathway in two different CVID cohorts associated with systemic inflammation and B-cell phenotype.

PMID:40378971 | DOI:10.1016/j.jaci.2025.04.031

J Allergy Clin Immunol. 2025 May 14:S0091-6749(25)00516-0. doi: 10.1016/j.jaci.2025.04.032. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary involvement (repeated lung infections, lung parenchymal inflammation, scarring, and malignancies) is frequent in patients with inborn errors of immunity (IEI) and accounts for a significant proportion of the disease burden. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can cure most severe IEI. The indications for allo-HSCT have recently been extended to adults.

OBJECTIVE: We sought to assess the impact of allo-HSCT specifically on respiratory status METHODS: We retrospectively analyzed data on 50 patients with IEI who underwent a first allo-HSCT after the age of 16 at three expert centers in France.

RESULTS: The median [interquartile range] length of follow-up was 4.8 years [IQR: 1.6;9.2] before allo-HSCT and 3 years [1.4;6.0] afterwards. Ten patients died from allo-HSCT-related complications. Four patients developed bronchiolitis obliterans syndrome. After the first-year post-transplantation, the mean annualized rate of severe respiratory infections (0.14 (95%CI: 0.04;0.24)) was lower than the value recorded before transplantation (0.54 (95%CI: 0.25;0.82); p=0.003 for paired comparisons of equivalent durations). Lung function was declining before allo-HSCT (mean (95%CI) FEV₁: -2.09 %predicted/year (-7.27;3.09)] but increased afterwards (+2.44 %predicted/year (-4.79;9.69), p=0.0034 for paired comparisons). On CT scans of the chest, bronchial disorders and lung parenchyma cavities were the most frequent abnormal findings. The bronchial thickening and bronchiolar micronodules regressed after allo-HSCT, while bronchiectasis and residual parenchymal cavities were stable.

CONCLUSION: Allo-HSCT appears likely to protect the long-term pulmonary prognosis of adults with IEI; it is associated with a significantly lower incidence of severe respiratory infections, better lung function, and the radiological stabilization of lung damage.

PMID:40378970 | DOI:10.1016/j.jaci.2025.04.032

J Clin Immunol. 2025 May 15;45(1):94. doi: 10.1007/s10875-025-01887-x.

ABSTRACT

Severe combined immunodeficiency (SCID) is a heterogeneous genetic disease characterized by severe T-cell lymphopenia with a profound impairment of T- and B-cells’ function and, in some types, also NK cells. Hematopoietic cell transplantation (HCT) is the only curative treatment currently available in Brazil. Late diagnosis and treatment are the main factors affecting the survival of these children. This study aims to describe the demographic, phenotypic, genotypic, and clinical characteristics of twenty SCID patients (including typical SCID, leaky-SCID, and Omenn Syndrome) followed at a Brazilian referral center and correlate these data with their clinical outcome. The children were analyzed into two groups: patients diagnosed early by newborn screening (NBS) or family history, n = 7, and patients with late diagnosis, by clinical presentation, n = 13. The 2-year overall survival (OS) of the late group was 29.2%, in contrast to the 2-year OS of the early diagnosis group of 71.4% (p = 0.053). However, despite early diagnosis in the first group, timely access to HCT was delayed, with a median of 11 months. This research reveals that survival depends not only on timely diagnosis but also on early definitive treatment. To improve SCID survival rates, developing countries need public policies that allow rapid access to curative treatment for these patients.

PMID:40374985 | DOI:10.1007/s10875-025-01887-x

Clin Lymphoma Myeloma Leuk. 2025 Apr 16:S2152-2650(25)00142-9. doi: 10.1016/j.clml.2025.04.011. Online ahead of print.

ABSTRACT

CD7 CAR-T cell therapy has emerged as a promising treatment for relapsed/refractory (R/R) CD7-positive hematological malignancies, offering new hope for patients with limited therapeutic options. This review examines the recent clinical advances, challenges, and future directions of CD7 CAR-T therapy. Clinical trials have demonstrated remarkable efficacy of CD7 chimeric antigen receptor T (CD7 CAR-T) cells in treating T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LBL), and other CD7-positive malignancies, with complete remission (CR) rates of 90-95% in bone marrow (BM) and 50% to 60% in extramedullary disease (EMD). Various engineering strategies, including naturally selected CD7-targeted CAR-T cells, gene editing, protein blockers and universal CAR-T cells, have been developed to overcome challenges such as fratricide. While CD7 CAR-T therapy has shown promising initial responses, durable remissions often depend on consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ongoing research is focused on optimizing CAR designs, improving CAR-T cell persistence, and developing novel combination strategies to enhance long-term outcomes. Safety profiles have been generally manageable, with cytokine release syndrome (CRS) and neurotoxicity being the primary concerns. However, prolonged cytopenias and potential long-term immunodeficiency due to depletion of healthy CD7-positive cells remain areas of active investigation. As CD7 CAR-T therapy continues to evolve, future directions include refining patient selection, exploring dual-targeting approaches, and investigating innovative strategies to integrate CAR-T therapy with allo-HSCT. These advancements aim to improve the efficacy, safety, and accessibility of CD7 CAR-T therapy for patients with CD7-positive hematological malignancies.

PMID:40374439 | DOI:10.1016/j.clml.2025.04.011