2026-08-14 | First report of Rhinocladiella mackenziei osteomyelitis with CNS dissemination in a pediatric CGD patient post-HSCT: A case report and literature review.
Rhinocladiella mackenziei is a rare neurotropic dematiaceous fungus that causes cerebral phaeohyphomycosis, predominantly in immunocompetent adults with a geographical predilection to the Middle East. Pediatric infection is exceptionally rare, and to our knowledge, no cases of combined osseous and central nervous system involvement following hematopoietic stem cell transplantation (HSCT) have been reported. We report a male child with autosomal recessive chronic granulomatous disease (CGD) who developed traumatic forearm osteomyelitis due to R. mackenziei several months after haploidentical HSCT. Subsequent neuroimaging demonstrated intracerebral abscesses despite immune reconstitution. The infection persisted despite prolonged combination antifungal therapy with voriconazole and amphotericin B and ultimately required neurosurgical excision. The patient recovered without neurological sequelae and continues on long-term posaconazole therapy. This case highlights R. mackenziei as a cause of severe, invasive, disseminated fungal disease in pediatric post-bone marrow transplant patients and demonstrates extracerebral inoculation with subsequent CNS dissemination. It also underscores the importance of early recognition and a combined medical-surgical approach in management of refractory disease.
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2026-08-03 | Prospective Study of Targeted Busulfan-Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Genetic Rare Diseases.
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study. Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure. Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively. Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
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2026-07-25 | Gene therapy approaches for inborn errors of immunity: from bench to bedside.
Inborn errors of immunity (IEI) are rare genetic defects that disrupt immune function, often resulting in life-threatening infections, malignancies, and immune dysregulation. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative option for some diagnoses, is limited by donor availability and the risks of graft-versus-host disease. This review explores the 30-year evolution of autologous gene therapy as a vital alternative to allogeneic HSCT for IEIs. Literature search using PubMed for gene therapy for IEI in the last 20 years. We trace the transition from early gamma-retroviral gene addition, which successfully restored immunity in severe combined immunodeficiency (SCID) but carried high risks of insertional mutagenesis and leukemogenesis, to the adoption of safer self-inactivating lentiviral vectors. The field is rapidly advancing beyond viral gene addition toward highly precise gene‑editing technologies, including CRISPR/Cas9 and base/prime editing, which offer targeted correction with minimized genotoxicity. Recent milestones in diseases such as Wiskott -Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) highlight enormous scientific success, yet significant barriers to accessibility, manufacturing, and affordability remain. Overcoming this requires innovative regulatory frameworks and collaborative funding models. Streamlining development and ensuring equitable access are essential next steps to establishing gene therapy as a safe alternative.
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2026-07-19 | NADPH oxidase 2 (NOX2)-independent inducers of neutrophil extracellular traps promote resolution of chronic inflammation.
Reactive oxygen species (ROS) generated by NADPH oxidase 2 (NOX2) are essential for antimicrobial defense but also for the resolution of inflammation. NOX2 deficiency, as observed in chronic granulomatous disease (CGD), predisposes to persistent sterile inflammation. Current therapeutic strategies largely rely on nonspecific immunosuppression or require residual NOX2 activity, while systemic ROS-inducing therapies are limited by toxicity. Here, we present a NOX2-independent approach to restore inflammation-resolving ROS signaling using N-alkylaminoferrocene-based prodrugs (pro-NAAFs), which amplify pre-existing ROS rather than generating ROS indiscriminately. Among several candidates, prodrug 1 emerged as the most potent and well-tolerated ROS amplifier. In human neutrophils, prodrug 1 induced strong ROS production and neutrophil extracellular trap (NET) formation. These responses occurred independently of NOX2 and were maintained in CGD-derived neutrophils. Similar NOX2-independent ROS induction and NET formation were observed in immune cells from wild-type and NOX2-dysfunctional Ncf1∗∗ mice. Prodrug 1-induced NETs aggregated into high-density structures (aggNETs) capable of degrading pro-inflammatory mediators in vitro. Prodrug 1 also inhibited neutrophil inflammasome activation. In vivo, subcutaneous administration of prodrug 1 reduced inflammatory mediator levels in air pouches, promoted resolution of chronic arthritis in Ncf1∗∗ mice, and protected from bone destruction. Transcriptomic analyses indicated early suppression of inflammatory pathways and restoration of neutrophil maturation trajectories towards a wild-type-like state. While prodrug 1 increased protein oxidation markers, it shifted systemic oxysterol profiles towards an inflammation-resolving phenotype. These findings identify pro-NAAFs as NOX2-independent ROS amplifiers capable of restoring inflammatory resolution and highlight their therapeutic potential for chronic inflammatory conditions linked to NOX2-dysfunction.
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2026-07-09 | Clinical analysis and follow up study of chronic granulomatous disease with neonatal onset
Objective To address the existing gap in knowledge regarding the small subset of chronic granulomatous disease (CGD) patients who present during the neonatal period, this study aimed to characterize their clinical features, genetic profiles, and long-term prognosis. Methods This study retrospectively selected CGD patients with neonatal onset who were diagnosed using neutrophil respiratory burst tests and genetic analysis at the Guangzhou Women and Children's Medical Center, Guangzhou Medical University, between January 2018 and September 2024. Results This study included nine male patients diagnosed with CGD presenting with neonatal onset. The median age at onset was 20 days (7–23 days). Pneumonia was observed in eight patients (88.9%), with Aspergillus species detected in five of these cases (62.5%). The stimulation index (SI) in the neutrophil oxidative burst assay was significantly reduced. All nine patients exhibited hemizygous variants in the CYBB gene. The median hospital stay was 42 days (15.5–48 days). Three patients died due to disease progression during their initial hospitalization. Regarding long-term prognosis, one patient was lost to follow-up at six months of age, and three patients died from severe infections during infancy. The remaining two patients underwent hematopoietic stem cell transplantation (HSCT) and achieved complete clinical remission. Conclusion Patients with CGD presenting in the neonatal period predominantly harbor mutations in the CYBB gene, which are associated with severe clinical manifestations. Aspergillus species are the most common pathogens in these patients. Although the prognosis is generally poor, it may be improved by hematopoietic stem cell transplantation (HSCT).
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