Manish Butte

EClinicalMedicine. 2025 Jul 22;86:103358. doi: 10.1016/j.eclinm.2025.103358. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Rovunaptabin neutralises functional autoantibodies targeting G-Protein coupled receptors (GPCR-fAAbs), observed in patients with Post-COVID syndrome. As we hypothesise an improvement of PCS by rovunaptabin, the aim of reCOVer was to investigate safety, tolerability, and clinical effects of rovunaptabin in PCS patients.

METHODS: reCOVer is a prospective, exploratory, placebo-controlled, double-blind, randomised phase IIa clinical investigator initiated trial with 1350 mg rovunaptabin with additional cross-over at the Universitätsklinikum Erlangen, Germany. The trial was registered in EudraCT, 2022-001781-35. Screening was done between 21·11·2023 and 25·06·2024. Eligible participants (18-80 years) showed GPCR-fAAbs, at least 3/8 defined PCS symptoms persisting ≥3 months after COVID-19 and fatigue as major symptom. Participants were randomly assigned (1:1) to either receive rovunaptabin or placebo at day 0 (d0) and d48 with a follow-up of 28 days, respectively. Primary endpoint was the number of treatment emergent adverse events (TEAE) at d28 (co-primary endpoint: TEAE at d70); secondary endpoint focused on fatigue and quality of life.

FINDINGS: Thirty PCS patients were randomised and analysed. RCT analysis showed nine (rovunaptabin) and five TEAEs (placebo), yet without statistically significance (p = 0·1299; CI -14·80%; 63·02%); one serious adverse event, not related to treatment, was recorded. Rovunaptabin showed a neutralisation of GPCR-fAAb and a significant improvement of FACIT Fatigue Scale (effect size = 2·10, p = 0·0378), Bell score (effect size = 3·64, p = 0·0004), Fatigue Severity Scale (effect size = -2·66, p = 0·0088), and quality of life (4/8 items).

INTERPRETATION: As this proof-of-concept study showed effects on the patient-centred endpoint PCS and a good safety profil, subsequent studies are needed to confirm these results in a larger cohort.

FUNDING: German Federal Ministry of Education and Research, German Research Foundation.

PMID:40735347 | PMC:PMC12304723 | DOI:10.1016/j.eclinm.2025.103358

Blood. 2025 Jul 29:blood.2024028216. doi: 10.1182/blood.2024028216. Online ahead of print.

ABSTRACT

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disorder caused by acquired somatic UBA1 mutations in hematopoietic stem cells, affecting peripheral myeloid and natural killer (NK) cells. Given the high rate of severe infections observed in VEXAS patients, we hypothesized that NK cell dysfunction contributes to this increased susceptibility. We conducted a comprehensive immune characterization of peripheral NK cells in patients with VEXAS (n=40), patients with autoinflammatory diseases without UBA1 mutations (n=22), and elderly gender-matched healthy controls (HCs) (n=16). Multiparameter phenotyping was performed using CyTOF, scRNAseq, whole blood stimulation assays and in vitro NK cell cytotoxic assay. Peripheral NK cells in VEXAS were quantitatively and qualitatively impaired. Mass cytometry revealed reduced frequencies of mature cytotoxic CD56dim NK cells and an expansion of the CD56high CD16dim subset. NK cells exhibited features of exhaustion, including increased PD-1 expression, and reduced levels of cytotoxic markers such as NKp46 and CD8α. scRNAseq analysis showed decreased signatures of cytotoxicity and IL-2 and IFN-γ production, alongside increased inflammatory signatures. Whole blood stimulation assays confirmed impaired IL-2, IFN-γ, and granzyme B production following TLR3, TLR4, and TLR7/TLR8 agonist stimulation. Extended NK phenotyping by flow cytometry confirmed reduced activating receptors’ expression and impaired IFN-γ production in VEXAS. Moreover, in vitro UBA1 inhibitors impaired NK cell cytotoxic capacity and promote cell death. Finally, reduced NK cell frequencies were independently associated with an increased risk of severe infections. These findings suggest that NK cell dysfunction in VEXAS syndrome contributes to increased susceptibility to severe infections.

PMID:40729686 | DOI:10.1182/blood.2024028216

Arch Argent Pediatr. 2025 Jul 31:e202410599. doi: 10.5546/aap.2024-10599.eng. Online ahead of print.

ABSTRACT

Invasive fungal infections, especially aspergillosis, severely affect immunocompromised patients. The use of azoles, particularly voriconazole, has been considered an effective antifungal therapy for the treatment of these infections and prevention. However, cases of peripheral neuropathy have been reported in patients treated with this drug. We present two clinical cases of patients with immunocompromise (acute myeloblastic leukemia and primary immunodeficiency) who, during treatment with voriconazole, developed peripheral sensory motor axonal polyneuropathy, which completely resolved after discontinuation of the medication. Given the rapid resolution of the clinical manifestations after discontinuation of the drug, we consider it essential to keep this neurotoxicity in mind as a differential diagnosis in children exposed to multiple medications.

PMID:40728252 | DOI:10.5546/aap.2024-10599.eng

Life (Basel). 2025 Jul 13;15(7):1098. doi: 10.3390/life15071098.

ABSTRACT

Non-celiac villous atrophy (NCVA) is a multifaceted and under-recognized clinical entity with an etiology beyond celiac disease. This review critically examines the diverse pathophysiological mechanisms underlying NCVA, including autoimmune enteropathies, immune deficiency-related disorders, infectious processes, drug-induced trauma, and metabolic or environmental influences. A comprehensive synthesis of peer-reviewed literature, clinical studies, and case reports was conducted, adopting a multidisciplinary perspective that integrates immunologic, infectious, metabolic, and pharmacologic insights. The literature search was performed in three phases: identification of relevant studies, critical assessment of selected publications, and synthesis of key findings. Searches were carried out in PubMed, Scopus, Web of Science, and Google Scholar databases. The final search, completed in June 2025, included international, English-language articles, electronic books, and online reports. Studies were included if they addressed NCVA in the context of pathophysiology, clinical manifestations, or management strategies, with priority given to publications from the last ten years (2015-2025). The search strategy used the primary term “non-celiac villous atrophy” combined with supplementary keywords such as autoimmune enteropathy, common variable immunodeficiency, tropical sprue, drug-related enteropathy, pathophysiology, immunological mechanisms, chronic inflammation, genetic factors, environmental influences, and clinical management. Histopathological evaluations reveal that NCVA often manifests with varying degrees of villous blunting, crypt hypertrophy, and intraepithelial lymphocytosis, albeit without the gliadin-specific immune response seen in celiac disease. Various immune pathways are involved, such as autoimmune deregulation and chronic inflammatory responses, while drug-induced and environmental factors further complicate its clinical picture. These findings highlight significant diagnostic challenges and underscore the need to adapt diagnostic algorithms that combine clinical history, serologic evaluations, and histopathologic analysis. In conclusion, an in-depth understanding of the heterogeneous etiology of NCVA is critical to improving diagnostic accuracy and optimizing therapeutic strategies. Future research should prioritize the identification of specific biomarkers and the development of targeted interventions to address the unique mechanisms underlying NCVA, thereby improving patient management and outcomes.

PMID:40724600 | DOI:10.3390/life15071098

Nat Immunol. 2025 Jul 28. doi: 10.1038/s41590-025-02225-4. Online ahead of print.

ABSTRACT

Inborn errors of immunity (IEIs) are rare genetic anomalies that cause defective immune function. Over 500 IEIs have been identified to date, affecting millions of patients globally. These IEIs reveal the complex interplay between genetics, the environment and microorganisms that determine immune disease phenotypes. Progress in understanding the molecular and cellular mechanisms of IEIs provides a genetic framework for a functional understanding of the human immune system, disease pathogenesis and successful therapeutic interventions. This Review describes how IEIs impact infectious diseases, particularly coronavirus disease 2019, inflammatory bowel disease and cancer.

PMID:40721512 | DOI:10.1038/s41590-025-02225-4

Pediatr Infect Dis J. 2025 Jul 22. doi: 10.1097/INF.0000000000004904. Online ahead of print.

NO ABSTRACT

PMID:40720847 | DOI:10.1097/INF.0000000000004904

Nat Commun. 2025 Jul 25;16(1):6888. doi: 10.1038/s41467-025-62090-5.

ABSTRACT

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a fatal hyperinflammatory disorder distinct from self-limiting EBV-induced infectious mononucleosis (IM). However, the immunological mechanisms underlying the divergence between benign EBV infection and fulminant HLH-particularly in the absence of inherited immunodeficiency-remains unclear, and systematic comparisons of immune landscapes across EBV-associated disease spectra are lacking. In this study, by enrolling children with IM and healthy volunteers as controls, we utilize single-cell RNA sequencing to identify unique immunological characteristics of EBV-HLH. Our analysis indicates that patients with EBV-HLH exhibite widespread activation of NF-κB signaling pathway. Furthermore, excessive cytokine secretion by T and NK cells is observed, along with a shift in monocyte differentiation towards an inflammatory phenotype, and the aggregation of IDO1⁺ monocytes. Metabolic pathway analysis reveals that L-kynurenine, a downstream metabolite of IDO1, is specifically elevated in EBV-HLH and mediates the production of multiple pro-inflammatory cytokines. Collectively, our study maps the immune landscape in pediatric EBV-HLH at single-cell resolution, uncovering potential role of IDO1⁺ monocytes and L-kynurenine as biomarkers.

PMID:40715093 | DOI:10.1038/s41467-025-62090-5

BMC Immunol. 2025 Jul 26;26(1):54. doi: 10.1186/s12865-025-00739-y.

ABSTRACT

BACKGROUND: Complete complement factor I (CFI) deficiency is an inborn error of immunity (IEI) that results in heightened susceptibility to infections and immune dysregulatory disorders. This systematic review seeks to enhance our understanding of the clinical characteristics, genotype-phenotype correlations, and treatment outcomes in patients with complete CFI deficiency, including three novel cases. We conducted a comprehensive literature review of cases published from 1996 to November 2024, identifying 49 patients with homozygous or compound heterozygous mutations in the CFI gene.

RESULTS: Among the 49 patients, the mean age at initial presentation was 7.19 (± SD: 9.75) years. Most patients presented with infectious manifestations (n: 37, 75.5%), particularly sepsis (n: 18, 36.7%). The predominant pathogens were encapsulated organisms, particularly Neisseria meningitidis. Immune dysregulatory manifestations involved rheumatologic (n: 14, 28.57%), neurologic (n: 11, 22.4%), and renal (n: 8, 16.3%) disorders. Immunological evaluations showed low or absent levels of C3 and CFI in most patients. Genetic analysis identified 45 distinct mutations; less deleterious mutations, such as missense and splicing variants, were more common in those with immune dysregulation. Notably, three patients treated with eculizumab demonstrated significant clinical improvement.

CONCLUSION: Complete CFI deficiency presents a varied clinical spectrum, from asymptomatic to recurrent infections and immune dysregulation. Early diagnosis and targeted therapies, such as eculizumab, may improve patient outcomes. These findings underscore the necessity for further research into the nature of complete CFI deficiency and the development of optimal management strategies.

PMID:40713518 | DOI:10.1186/s12865-025-00739-y

J Clin Immunol. 2025 Jul 25;45(1):115. doi: 10.1007/s10875-025-01915-w.

ABSTRACT

BACKGROUND: The assessment of polysaccharide responsiveness via vaccination is pivotal in the evaluation of patients for primary immunodeficiency. However, the applicability of current guidelines provided by the American Academy of Allergy, Asthma & Immunology (AAAAI) has been subject to scrutiny.

METHODS: We conducted a prospective study involving 120 healthy Danish adult blood donors. Antibodies targeting pneumococcal capsular polysaccharide serotypes were quantified using a multianalyte bead immunoassay before and four to eight weeks post-vaccination. Polysaccharide responsiveness in donors was assessed according to AAAAI guidelines.

RESULTS: Remarkably, only a minority of participants (2.5%) demonstrated a normal polysaccharide response per AAAAI criteria. This finding prompted us to advocate for an alternative approach based on percentile rankings relative to a reference population. Polysaccharide Responsiveness Percentile (PRP) was not significantly associated with age, sex, vaccine batch, or the duration between vaccination and antibody measurements in our cohort supporting its robustness, generalizability, and potential for standardized clinical application.

CONCLUSION: Our study unveils significant limitations of the AAAAI guidelines, highlighting the imperative for a more robust and adaptable approach. By introducing a novel PRP assessment method, we aim to enhance the accuracy and reliability of immune function evaluations.

PMID:40711631 | DOI:10.1007/s10875-025-01915-w

Front Immunol. 2025 Jul 10;16:1593897. doi: 10.3389/fimmu.2025.1593897. eCollection 2025.

ABSTRACT

Primary immune deficiencies (PI) are rare diseases associated with frequent, severe infections, inflammatory and autoimmune diseases and/or cancer. Because of the variability in presentation, undiagnosed PI patients can be encountered by many different medical specialists. A lack of awareness of and the rarity of PI can lead to delayed diagnosis particularly among primary care physicians and non-immunology specialists. These delays can lead to irreversible sequelae, decreased quality of life and premature mortality. In this review, we describe two projects designed to decrease the time to diagnosis in PI patients: 1) the expert-driven PIDCAP project conducted in Spain to promote early diagnosis in the primary care setting, and 2) a multi-modal data-driven approach using artificial intelligence and machine learning to identify individuals at high risk for PI. Both approaches aim to create widely available tools to promote early diagnosis and treatment of PI. Initial results have been positive. Future directions include larger studies and potentially combining expert-driven and data-driven approaches.

PMID:40709193 | PMC:PMC12286987 | DOI:10.3389/fimmu.2025.1593897