Research

Infect Dis (Lond). 2025 Apr 3:1-35. doi: 10.1080/23744235.2025.2483339. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) are congenital disorders of the immune system. Due to impaired immune system, they are at a higher risk to develop a more severe COVID-19 course compared to general population.

OBJECTIVES: Herein, we aimed to systematically review various aspects of IEI patients infected with SARS-CoV-2. Moreover, we performed a meta-analysis to determine the frequency of COVID-19 in patients with different IEI.

METHODS: Embase, Web of Science, PubMed, and Scopus were searched introducing terms related to IEI and COVID-19.

RESULTS: 3646 IEI cases with a history of COVID-19 infection were enrolled. The majority of patients had critical infections (1013 cases, 27.8%). The highest frequency of critical and severe cases was observed in phenocopies of IEI (95.2%), defects in intrinsic and innate immunity (69.4%) and immune dysregulation (23.9%). 446 cases (12.2%) succumbed to the disease and the highest mortality was observed in IEI phenocopies (34.6%). COVID-19 frequency in immunodeficient patients was 11.9% (95% CI: 8.3 to 15.5%) with innate immunodeficiency having the highest COVID-19 frequency [34.1% (12.1 to 56.0%)]. COVID-19 case fatality rate among IEI patients was estimated as 5.4% (95% CI: 3.5-8.3%, n = 8 studies, I2 = 17.5%).

CONCLUSION: IEI with underlying defects in specific branches of the immune system responding to RNA virus infection experience a higher frequency and mortality of COVID-19 infection. Increasing awareness about these entities and underlying genetic defects, adherence to prophylactic strategies and allocating more clinical attention to these patients could lead to a decrease in COVID-19 frequency and mortality in these patients.

PMID:40178994 | DOI:10.1080/23744235.2025.2483339

Cureus. 2025 Mar 3;17(3):e79976. doi: 10.7759/cureus.79976. eCollection 2025 Mar.

ABSTRACT

Hyper IgE syndrome (HIES) is a rare primary immunodeficiency characterized by chronic eczema, recurrent staphylococcal infections on the skin and pulmonary system, and high serum IgE concentrations. The first clinical sign of HIES is eczema, usually in early infancy. Severe atopic dermatitis (AD) may also mimic HIES with findings of eczema, high serum immunoglobulin E levels, and eosinophilia. Therefore, differential diagnosis may be difficult. Here, we present a case with eczematoid skin rashes, asthma, elevated serum IgE levels, and skin infections that started in infancy and were followed for nine years by the pediatric allergy and immunology clinic with the diagnosis of HIES, but in fact, had severe AD. Because the patient had no recurrent infections that would suggest immune deficiency during his clinical follow-up, other than the skin infections at the time of diagnosis. In addition, the patient had no non-immunological symptoms of hyper IgE syndrome.

PMID:40177449 | PMC:PMC11964334 | DOI:10.7759/cureus.79976

J Pathol. 2025 Apr 3. doi: 10.1002/path.6413. Online ahead of print.

ABSTRACT

Chronic histiocytic intervillositis (CHI) is an inflammatory condition of the placenta, characterised by an abnormal, mainly macrophagic infiltrate within the intervillous space. Recent research suggests that CHI results from a ‘maternal-foetal rejection’ mechanism, because at least some CHI cases fulfil the criteria for antibody-mediated rejection (AMR) of kidney allografts according to the Banff classification [i.e. presence of anti-human leukocyte antigen (HLA) paternal antibodies activating the complement or foetal-specific antibodies (FSA), a macrophage-rich infiltrate, and positive C4d immunostaining]. To gain further insights into CHI pathogenesis, we aimed to refine the phenotype of the inflammatory infiltrate using a multiplex immunofluorescence technique and to compare the mRNA signatures between CHI and AMR of kidney allografts. Twelve patients with C4d + FSA+ CHI were included in the study and compared to a control group of 5 patients without inflammatory lesions on placental examination. We developed a multiplex immunofluorescence panel to identify CD4+ and CD8+ T lymphocytes, CD68+/CD206- and CD68+/CD206+ macrophages, and NK cells in the villi and intervillous space. Molecular signatures were studied using NanoString® technology and the B-HOT panel recommended by the Banff classification for kidney allografts. Multiplex immunofluorescence revealed that the infiltrate in the intervillous space was mainly composed of CD68+/CD206- macrophages as well as a higher proportion of CD8+ lymphocytes in patients with CHI compared to controls. Densities of NK cells and CD4 T cells were very low. Molecular signatures showed an overexpression of HLA class II genes, an IFN-γ signature, and cytokine gene sets in C4d + FSA+ CHI patients, also involved in kidney AMR. These results reinforce the paradigm of maternal-foetal rejection. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:40178007 | DOI:10.1002/path.6413

Hum Vaccin Immunother. 2025 Dec;21(1):2484882. doi: 10.1080/21645515.2025.2484882. Epub 2025 Apr 2.

ABSTRACT

Children with primary immunodeficiency disorder (PID) are at higher risk of developing vaccine-associated paralytic poliomyelitis (VAPP) or vaccine-derived polioviruses (VDPV) infection when inadvertently expose to poliovirus vaccine, oral (OPV). A pilot study was initiated to describe the epidemiology of immunodeficiency-associated VDPV (iVDPV) and to estimate the risk of iVDPV shedding among individuals with PID. Children under 18 years of age newly diagnosed with PID were recruited for investigation and tested for poliovirus excretion. Children with poliovirus-positive stool samples had regular follow-up testing for poliovirus excretion and determination of clinical prognosis. A patient with severe combined immunodeficiency (SCID) with compound heterozygous mutations in the RAG1 gene was found to be excreting Sabin-like type 3 (SL3) poliovirus. Excretion stopped six weeks after hematopoietic stem-cell transplantation (HSCT). Graft versus host disease (GVHD) and poor graft function (PGF) occurred after HSCT, resulting in failure of hematopoiesis and immune system reconstitution. Given deficient innate and adaptive immunity, immune-mediated destruction of gastrointestinal (GI) tract caused by GVHD and inflammatory diarrheal illness of the girl may have contributed to her clearance of SL3 poliovirus. Intermittent surveillance of immune system parameters for iVDPV excreters receiving HSCT should be included in the PID surveillance program for further understanding poliovirus clearance mechanisms.

PMID:40170570 | DOI:10.1080/21645515.2025.2484882

Clin Exp Dermatol. 2025 Apr 2:llaf155. doi: 10.1093/ced/llaf155. Online ahead of print.

NO ABSTRACT

PMID:40171604 | DOI:10.1093/ced/llaf155

Pediatr Allergy Immunol. 2025 Apr;36(4):e70072. doi: 10.1111/pai.70072.

ABSTRACT

BACKGROUND: Symptoms of hereditary angioedema (HAE) typically first present during childhood, but the frequency/severity of attacks often increases at puberty. Real-world data on long-term HAE prophylaxis in adolescents are limited. We report pooled data from adolescent patients enrolled in two Phase 4 studies (EMPOWER, ENABLE) evaluating the effectiveness/safety of lanadelumab (monoclonal antibody directed against plasma kallikrein) for the prevention of HAE attacks.

METHODS: Adolescent patients (aged 12 to <18 years) with HAE-C1INH enrolled in EMPOWER and ENABLE received open-label lanadelumab 300 mg once every 2 weeks. Effectiveness outcomes were based on patient-reported assessments of on-treatment HAE attacks. Safety was assessed through the recording of treatment-emergent adverse events (TEAEs) and serious adverse events. This analysis categorized patients as “new” or “established” lanadelumab patients.

RESULTS: Thirteen new and seven established patients on lanadelumab were included. The observed monthly attack rate in new patients fell from 3.8 (mean) and 2.8 (median) during the pre-enrollment period to 0.65 (mean) and 0.21 (median) during the cumulative study period after lanadelumab initiation (84.2% and 92.9% reductions, respectively). In established patients, mean (SD) HAE attack rate (as treated) during the overall study period was 0.04 (0.03) attacks/month. Most HAE attacks were of mild/moderate severity. Nine new patients reported 42 TEAEs, mostly mild/moderate in severity, with 3 TEAEs reported as serious. Seven established patients reported 12 TEAEs (all mild/moderate and non-serious). No TEAEs were related to lanadelumab.

CONCLUSION: These data support lanadelumab’s effectiveness/safety in adolescents with HAE, consistent with results from Phase 3 lanadelumab studies in mixed adult/adolescent populations.

CLINICAL TRIAL IDENTIFIERS: NCT03845400 (EMPOWER) and NCT04130191 (ENABLE).

PMID:40171989 | DOI:10.1111/pai.70072

J Hematop. 2025 Apr 2;18(1):13. doi: 10.1007/s12308-025-00628-8.

ABSTRACT

A 20-year-old man with a history of Wiskott-Aldrich syndrome (WAS) underwent excisional biopsy of a femoral lymph node for evaluation of lymphadenopathy. Histologic examination showed paracortical expansion by a lymphohistiocytic infiltrate, and reactive follicles with regressive changes. The interfollicular histiocytes had clumped nuclei and showed occasional emperipolesis. Special stains were negative for infectious organisms. The microscopic findings in this lymph node are related to the underlying WAS. Emperipolesis has previously been reported in lymph nodes of patients with WAS. Recognition of reactive microscopic features in lymph nodes of these patients is important, as they are at increased risk for lymphoproliferative disorders.

PMID:40169435 | DOI:10.1007/s12308-025-00628-8

Pediatr Rheumatol Online J. 2025 Mar 31;23(1):35. doi: 10.1186/s12969-025-01086-3.

ABSTRACT

BACKGROUND: Childhood-onset eosinophilic granulomatosis with polyangiitis (cEGPA) is a rare type of systemic autoimmune disorder. Variants in the NFKB2 gene can manifest as common variable immunodeficiency or combined immunodeficiency, often accompanied by autoimmunity and ectodermal dysplasia. Here, we report a case of a Chinese patient who carries NFKB2 variants that coexist with cEGPA, a novel combination which, to our knowledge, has not been previously published.

CASE PRESENTATION: We reported a 9-year and 10-month-old girl who presented with cough, wheezing, dyspnea, hypereosinophilia, and vasculitis. Notably, she had significant bilateral pulmonary interstitial lesions. We performed metagenomic next-generation sequencing (mNGS), bronchoscopy and immunological analysis. She was considered to have refractory cEGPA after six months of corticosteroid and immunosuppressive treatment. Tapering off corticosteroids posed a challenge, and multiple immunosuppressive agents were ineffective. Our patient suffered from recurrent fever, wheezing, dyspnea and perianal abscess, along with life-threatening infections, including pneumocystis jirovecii pneumonia (PJP) and severe coronavirus disease 2019 (COVID-19) pneumonia during the pandemic. Her cytokines and inflammatory markers showed a profound collapse. She developed significant hypoxemia, which necessitated mechanical ventilation. Primary immunodeficiency gene panel testing revealed a novel de novo variant in NFKB2 (c.2578 + 2 dup) that was classified as pathogenic. Despite treatment with antibacterial, antiviral, and antifungal agents, biologics, and plasma exchange, she ultimately succumbed to respiratory failure.

CONCLUSIONS: This case report establishes a novel link between NFKB2 variants and EGPA, particularly in the context of the COVID-19 pandemic. This study expands the spectrum of NFKB2 variants and vividly illustrates the complex interrelationships among autoimmunity, infection, and immunodeficiency.

PMID:40165201 | DOI:10.1186/s12969-025-01086-3

Blood Adv. 2025 Mar 31:bloodadvances.2024015000. doi: 10.1182/bloodadvances.2024015000. Online ahead of print.

ABSTRACT

Acute Graft-versus-Host Disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). The majority of allo-HCT patients receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metabolites. We investigated the impact of microbiome modifications on CNS-GVHD and therapeutic strategies to overcome the microbiome-derived metabolite depletion. Antibiotic treatment of mice undergoing allo-HCT increased microglia numbers in the brain, indicating increased inflammation. In addition, microglia morphology shifted towards a highly branched phenotype. Consistent with a pro-inflammatory phenotype microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived arylhydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of primary microglia with the AhR-ligand- 6-formylindolo (3, 2-b) carbazole (FICZ) reduced NF-κB activity and phagocytic potential. Microglia expansion and morphological changes were reversed by AhR-ligand-FICZ-treatment. Moreover, the AhR-ligand indole-3-acetate was also reduced in the CNS of patients that developed acute GVHD concomitant with increased microglial NF-κB expression. In summary, we demonstrated that antibiotic treatment and a subsequent decrease of AhR-ligands resulted in increased microglia activation during CNS-GVHD. FICZ-treatment hampered CNS inflammation by inhibiting NF-κB activity, thereby providing a metabolic modifier to interfere with pathogenic microglia signaling and CNS-GVHD in vivo.

PMID:40163754 | DOI:10.1182/bloodadvances.2024015000

Mol Ther. 2025 Mar 28:S1525-0016(25)00220-5. doi: 10.1016/j.ymthe.2025.03.045. Online ahead of print.

ABSTRACT

Primary Immunodeficiency Diseases (PIDs) are associated with multiple genetic alterations including mutations of the LPS responsive Beige anchor (LRBA) gene. Nonsense mutations in the LRBA gene resulting in premature termination codons cause the loss of LRBA protein expression in PID. We evaluated the impact of a translational readthrough-inducing drug (TRID) ataluren as a nonsense suppression therapy in a PID patient with a homozygous stop codon mutation in exon 30 of LRBA. A precision medicine approach allowed us to pass from “in silico” to “in vitro” to the “bedside”: following the in vitro treatment of patient-derived primary fibroblasts with ataluren, we observed a restoration of the LRBA protein expression and localization. In silico predictions suggested LRBA retained function after readthrough. Based on the successful experimental and computational results we treated the patient with ataluren resulting in an improvement of his clinical symptoms and quality of life. Importantly, the clinical symptoms were associated with a recovery of LRBA expression in liver biopsies post-treatment compared to pre-treatment. Our results provide a proof-of-concept demonstrating that ataluren, can rescue LRBA expression in PID. This work highlights the potential for personalized precision medicine approaches to be exploited for different genetic diseases due to premature termination codons.

PMID:40158206 | DOI:10.1016/j.ymthe.2025.03.045