Research

Open Forum Infect Dis. 2025 Dec 11;13(1):ofaf750. doi: 10.1093/ofid/ofaf750. eCollection 2026 Jan.

ABSTRACT

BACKGROUND: The increasing incidence of resistant invasive mold infections (IMIs) has highlighted the need for novel antifungal agents. Olorofim, a first-in-class orotomide, has shown promising efficacy in a recent phase II study, but clinical data remain limited.

METHODS: We conducted a retrospective multicenter cohort study in France, including all patients who received olorofim under compassionate use for proven or probable non-Mucorales IMIs. Eligible patients had IMIs refractory to or intolerance to standard antifungals or no effective treatment options. Efficacy was defined as mycological and clinical control of infection; safety was also assessed.

RESULTS: Between January 2020 and December 2023, 17 patients (median age, 39 years) received olorofim. Underlying conditions included primary immunodeficiency (n = 4) and lung transplantation (n = 5). Sites of infection included the lung (88.2%) and the central nervous system (23.5%), with 5 cases of disseminated disease. In total, 23 strains were identified, mostly Aspergillus fumigatus (34.8%) and Microascus spp (13%). The median duration of prior antifungal therapy was 9.1 months. Olorofim was used primarily for refractory IMIs (70.6%) and in combination with other antifungals in 82.4% of cases. Olorofim minimum inhibitory concentrations were ≤0.5 mg/L in the 8 available isolates. Among 15 evaluable patients, 5 (33.3%) achieved clinical and mycological success, 7 (46.7%) had partial responses, and 3 (20%) experienced treatment failure. The 3-month mortality rate was 29.4% (5 of 17). No severe adverse events were reported.

CONCLUSIONS: Olorofim exhibited potential efficacy and good tolerability in patients with refractory IMIs. Further data from ongoing clinical trials are needed to confirm these findings.

PMID:41531505 | PMC:PMC12794007 | DOI:10.1093/ofid/ofaf750

Pediatr Pulmonol. 2026 Jan;61(1):e71457. doi: 10.1002/ppul.71457.

ABSTRACT

BACKGROUND: The primary risk factor determining the progression of tuberculosis (TB) infection is the host’s immune status. However, reports of TB cases in children diagnosed with primary immunodeficiency (PID), also referred to as inborn errors of immunity (IEI), remain scarce. In this study, we describe the impact of PID/IEI on childhood TB disease.

METHODS: In this retrospective cohort study, data of patients aged 1 month to 18 years who were diagnosed with TB between January 2012 and January 2025 were collected. TB patients were compared according to PID status. Additionally, radiological, histopathological, and microbiological diagnostic findings, as well as clinical features and treatments of TB patients with PID, were evaluated.

RESULTS: A total of 217 TB patients were included, with a median age of 118 months (IQR: 42-169.5). PID was detected in 5.5% (n = 12) of the patients. In 6 (50%) of the PID patients, the immunodeficiency was not known before the TB diagnosis. The median age of patients with PID was 17 months (IQR: 10.3-58.5), which was significantly lower compared to other patients (p = 0.001). The diagnosis of extrapulmonary TB was significantly more common among PID patients (p = 0.049). Treatment durations in patients with PID ranged from 6 to 24 months, and no mortality was observed.

CONCLUSION: Investigating PID in children diagnosed with TB may be a critical step in enabling early diagnosis and treatment before the development of potentially fatal complications. We also believe that expanding immunological investigations will contribute to a better understanding of childhood TB pathogenesis.

PMID:41521825 | DOI:10.1002/ppul.71457

J Pediatr Nurs. 2026 Jan 10;87:112-117. doi: 10.1016/j.pedn.2025.12.027. Online ahead of print.

ABSTRACT

BACKGROUND: The study aimed to examine the predictive effect of having a child with primary immunodeficiency (PID) on the psychological resilience, general self-efficacy, and spiritual well-being of parents.

METHODS: A cross-sectional, correlational, and comparative study was conducted with parents of children with PID (N = 88) and healthy controls (n = 168) in Türkiye from June 2024 to February 2025. Study data were collected through the Connor-Davidson Resilience Scale Short Form, the General Self-Efficacy Scale, and the Spiritual Well-being Scale.

RESULTS: The mean general self-efficacy of parents of children with PID was significantly lower than that of parents of healthy controls (p < 0.05). However, no significant difference was found between the groups in psychological resilience or spiritual well-being (p > 0.05). There were significant positive relationships among psychological resilience, general self-efficacy, and spiritual well-being among parents of children with PID (p < 0.05). The disease has no statistically significant effect on spiritual well-being in parents (p > 0.05).

CONCLUSIONS: The mean general self-efficacy of parents of children with PID was lower than that of parents of healthy controls. Although no difference in psychological resilience was detected between the groups in the descriptive comparison, the multivariate analysis indicated that having a child with PID is a negative factor affecting parents’ resilience. Having a child with PID also had a statistically significant effect on the general self-efficacy of parents.

PRACTICE IMPLICATIONS: The findings will guide the planning of family-centred nursing interventions to enhance the psychological resilience, general self-efficacy, and spiritual well-being of parents of children with PID.

PMID:41520468 | DOI:10.1016/j.pedn.2025.12.027

J Clin Immunol. 2026 Jan 10;46(1):4. doi: 10.1007/s10875-025-01967-y.

ABSTRACT

We describe a 3-year-old patient with xeroderma pigmentosum (XP) and genetically confirmed XPA deficiency who presented with recurrent infections in early childhood. Immunological assessment revealed mild hypogammaglobulinemia with IgG2 and IgG3 subclass deficiencies, as well as impaired humoral immunity demonstrated by a reduced antibody response to repeated vaccinations against bacterial antigens. Flow cytometric analysis further showed an altered distribution of peripheral T helper (TH) cell subsets. In addition, we report a second case: a 33-year-old XP patient with ERCC4 deficiency who also exhibited IgG3 subclass deficiency and reduced response to booster vaccination. Functional studies revealed defective nucleotide excision repair (NER) following UV-C exposure, along with reduced B-cell activation capacity. These findings suggest a potential link between XP and immunoglobulin subclass deficiencies, indicating a susceptibility to infections in affected individuals. We therefore recommend that patients diagnosed with XP undergo comprehensive immunological evaluation to allow early detection of immunodeficiency and timely intervention, including booster vaccinations or prophylactic measures such as low-dose antibiotics or immunoglobulin replacement therapy when indicated.

PMID:41518476 | DOI:10.1007/s10875-025-01967-y

Int J Mol Sci. 2025 Dec 19;27(1):14. doi: 10.3390/ijms27010014.

ABSTRACT

Primary immune regulatory disorders (PIRDs) are a group of conditions characterised by a loss of immune tolerance. Two such disorders, CHAI and LATAIE, share common molecular mechanisms, leading to significant clinical overlap. Here, we report demographic, clinical, immunological, and molecular findings in 29 patients referred from different parts of India with a diagnosis of CHAI or LATAIE. LATAIE patients demonstrated a higher prevalence of consanguinity, while CHAI patients more often had a positive family history. Both disorders presented with overlapping clinical features, predominately autoimmune cytopenias, benign lymphoproliferation, and inflammatory bowel disease (IBD). However, the incidence of recurrent infections, otitis media, bronchiectasis, and hypogammaglobulinemia was higher among LATAIE patients as compared to CHAI. Flow cytometry analysis revealed significant differences in T cell subsets, particularly in percentages of CD4+ naïve cells and T regulatory cells (Treg), between the two disorders. B cell abnormalities were also observed. Molecular diagnosis was achieved using targeted or clinical exome sequencing, and specific protein expression was employed to validate the novel variants.

PMID:41515894 | DOI:10.3390/ijms27010014

J Clin Med. 2025 Dec 26;15(1):179. doi: 10.3390/jcm15010179.

ABSTRACT

Primary humoral immunodeficiencies are a heterogeneous group of disorders defined by quantitative and/or functional defects in one or more immunoglobulin classes, often with associated cellular immune abnormalities. Their link with bronchiectasis, whose prevalence varies across specific defects, is largely driven by recurrent respiratory infections. Selective Immunoglobulin-(Ig)A deficiency and IgG2 subclass deficiency are the most frequent forms, but common variable immunodeficiency (CVID) is the condition most often associated with bronchiectasis and is usually diagnosed earlier because of its characteristic phenotype. In contrast, the contribution of isolated IgA deficiency or selective IgG subclass deficiencies to bronchiectasis remains controversial. Other reported associations include X-linked agammaglobulinemia, selective IgM or IgG deficiency, and rarer entities such as selective IgE deficiency, unclassified hypogammaglobulinemia, specific antibody deficiency, specific polysaccharide antibody deficiency, and heavy- or light-chain deficiencies. Current bronchiectasis guidelines recommend measurement of serum immunoglobulins and IgG subclasses in patients with compatible features, recurrent infections, or no clear etiology before labeling disease as idiopathic. Identifying immunoglobulin defects is clinically important because they represent treatable traits. The potential role of emerging therapies such as the DPP1 inhibitor brensocatib in immunodeficiency-related bronchiectasis remains uncertain, and ongoing registries will be key to clarifying these relationships.

PMID:41517428 | DOI:10.3390/jcm15010179

Medicine (Baltimore). 2026 Jan 9;105(2):e47005. doi: 10.1097/MD.0000000000047005.

ABSTRACT

RATIONALE: Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the RMRP gene, which is extremely rare in the population, and its most common feature is disproportionately short limb shortness with short and thickened long bones, usually found in newborns, occasionally found in the prenatal stage, and other clinical features include a series of extracutaneous manifestations, such as hypoglycemia, gastrointestinal dysfunction, immunodeficiency, anemia and increased risk of malignant tumors, etc, the specific pathogenesis is unknown.

PATIENT CONCERNS: The case of a 1.5-year-old male patient with severe short stature (height 70 cm, <-3 SD), sparse scalp hair, and short limbs, without ligamentous laxity or anemia.

DIAGNOSES: Family-based whole-exome sequencing revealed compound heterozygous variants in RMRP: NR_003051.3: n.-21_-9dup and n.5C > T. Classified as pathogenic or likely pathogenic according to ACMG guidelines, these variants confirm the diagnosis of CHH.

INTERVENTIONS: Due to the elevated tumor predisposition associated with CHH, and because growth hormone therapy is currently contraindicated, no disease-specific interventions have been initiated.

OUTCOMES: We have confirmed that the child has been diagnosed with CHH, but no intervention has been given, and we will do further follow-up and look forward to finding a treatment for the disease.

LESSONS: This report describes a rare case of RMRP-associated CHH. This case broadens the clinical understanding of the RMRP mutational spectrum and phenotypic variability, providing new insights into genotype-phenotype correlations in RMRP-associated disorders. We were currently unable to take effective treatment measures for this child, and we hope that in the future, there will be treatments such as gene therapy to bring hope to children and their families.

PMID:41517791 | DOI:10.1097/MD.0000000000047005

Congenit Anom (Kyoto). 2026 Jan-Dec;66(1):e70040. doi: 10.1002/cga.70040.

ABSTRACT

Bloom syndrome (BS) is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, greatly increased risk of early-onset cancer, and the development of multiple malignancies. Few cases of BS diagnosed during the prenatal period have been reported. Here, I present the comprehensive clinical and genetic characterization of two unrelated fetuses diagnosed with BS. Two pregnant women with abnormal ultrasound findings underwent amniocentesis for karyotype analysis, copy number variation sequencing (CNV-seq), and trio-whole exome sequencing (Trio-WES). Both fetuses exhibited severe fetal growth restriction. One fetus had a pericardial effusion. The karyotype analysis and CNV-seq revealed no apparent abnormalities. Trio-WES revealed biallelically likely pathogenic or pathogenic BLM variants in the fetuses. All parents were BLM variant carriers. These cases indicate that affected fetuses are more likely to have severe fetal growth restriction and do not display significant chromosomal abnormalities before birth. Clarification of the molecular diagnosis had important implications for these parents because they carried a 25% risk of recurrence. They were recommended to plan future pregnancies with preimplantation genetic testing for monogenic disorders to avoid future offspring with BS.

PMID:41518008 | DOI:10.1002/cga.70040

Case Reports Immunol. 2026 Jan 7;2026:1817159. doi: 10.1155/crii/1817159. eCollection 2026.

ABSTRACT

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocyte oxidative burst and may present in early life with severe or recurrent infections. We report a female infant born at 38 weeks’ gestation (birth weight 2700 g) who developed fever and presumed sepsis at 5 days of life, followed by multiple recurrent hospitalizations for febrile illness with suspected meningitis, diarrhea, dehydration, and failure to thrive. Cerebrospinal fluid (CSF) evaluations across episodes demonstrated pleocytosis with elevated protein and normal-to-low glucose, while Gram stain and CSF cultures were repeatedly negative, consistent with recurrent culture-negative meningitis. Laboratory assessment showed intermittent anemia, thrombocytosis, and episodes of significant neutropenia. Complement and immunoglobulin levels were within reference ranges, and flow cytometry demonstrated preserved T- and B-lymphocyte compartments. A flow cytometric dihydrorhodamine (DHR) oxidative burst assay was markedly abnormal (phorbol 12-myristate 13-acetate stimulation index 13%; Escherichia coli stimulation index 22.3%), supporting the diagnosis of CGD. At ~4.5 months of age, a sterile catheter urine culture grew multidrug-resistant Klebsiella pneumoniae at ≥100,000 CFU/mL with susceptibility limited to aminoglycosides; the patient was treated with amikacin 15 mg/kg/dose intravenously once daily for 10 days, with defervescence within 48 h, clinical recovery, and a repeat urine culture showing no growth. Genetic testing was not performed due to financial and social constraints, and longer-term outcomes beyond early infancy were unavailable in the record extract. This case underscores that recurrent culture-negative meningitis in early infancy should prompt evaluation for primary immunodeficiency and that early DHR testing can expedite CGD diagnosis and guide timely preventive management and specialist referral.

PMID:41509559 | PMC:PMC12776254 | DOI:10.1155/crii/1817159

Transl Cancer Res. 2025 Dec 31;14(12):8418-8431. doi: 10.21037/tcr-2025-1255. Epub 2025 Dec 19.

ABSTRACT

BACKGROUND: Neuroblastoma (NB) is an embryonic cancer arising from neural crest cells. Long non-coding RNA (lncRNA) plays an important role in the development of tumors. Several studies have reported that LINC01296 and thyroid hormone receptor interacting protein 13 (TRIP13) acts as oncogenic regulators of cancer. However, their deep specific biological mechanisms in tumor metastasis are not known. Here, we aimed to elucidate whether LINC01296 or TRIP13 drives NB proliferation and progression, and to assess their potential as therapeutic targets.

METHODS: In this study, we utilized the NB cell line SK-N-SH to investigate the roles of LINC01296 and TRIP13 by bacterial transformation and polymerase chain reaction (PCR) verification. Cells were infected with lentivirus, and fluorescence expression was monitored. Total RNA was extracted for reverse transcription quantitative PCR (RT-qPCR). Cell proliferation was assessed by using Cell Counting Kit-8 (CCK-8) assay. Migration was evaluated using wound-healing assays, and invasion was tested via Transwell with Matrigel-coated chambers. Apoptosis was analyzed by flow cytometry. For in vivo studies, non-obese diabetic/severe combined immunodeficiency (NOD/scid) mice were subcutaneously injected with 1×10⁷ cells/mL suspended in Matrigel. Tumor growth was measured every 2 days for 23 days; tissues were harvested for paraffin sections or stored at -80 ℃. Immunohistochemistry (IHC) involved antigen retrieval, blocking with 5% normal serum, primary antibody incubation, and counterstaining. Confocal microscopy was used for imaging.

RESULTS: In this study, we found that compared with negative control (NC) group, overexpression of LINC01296 (OE-LINC01296) or TRIP13 (OE-TRIP13) both promoted the proliferation, migration and invasion of SK-N-SH cells, while inhibiting apoptosis; and vice versa. In addition, we further demonstrated that LINC01296 stabilised knockdown via short hairpin RNA (shRNA) (sh-LINC01296) + OE-TRIP13, and TRIP13 stabilised knockdown via shRNA (sh-TRIP13) + OE-LINC01296 decreased SK-N-SH cell proliferation, migration and invasion, while promoting apoptosis. We also established a subcutaneous transplantation tumor model in NB NOD/scid mice, and sh-LINC01296 or sh-TRIP13 inhibited tumor growth in mice, and the tumor growth in the sh-LINC01296 + OE-TRIP13 group and the sh-TRIP13 + OE-LINC01296 group was between the NC group and the sh-LINC01296 or sh-TRIP13 group.

CONCLUSIONS: These results suggest that LINC01296 may play a role as an oncogene in the development of tumorigenesis in NB by mediating TRIP13, and provide a marker for the prognosis of NB.

PMID:41510121 | PMC:PMC12776195 | DOI:10.21037/tcr-2025-1255