Manish Butte

J Clin Immunol. 2026 Feb 3. doi: 10.1007/s10875-025-01978-9. Online ahead of print.

ABSTRACT

PURPOSE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is successful in pediatric patients with inborn errors of immunity (IEI), but its use in adults is complicated by pre-existing organ damage and increased risk of treatment-related mortality. Ex vivo graft engineering using αβTCR/CD19 depletion has shown promising safety profiles in pediatric IEI, yet evidence in adults is limited. We assessed the feasibility and outcomes of αβTCR/CD19-depleted allo-HSCT in adults with IEI, focusing on engraftment, immune reconstitution, and clinical outcomes.

METHODS: We included 9 adults with IEI and 1 with VEXAS (age 21-51). IEIs included CTLA4HI, APDS, DOCK8, ALPS, DADA2, CVID2, and HA20, with Immune Deficiency and Dysregulation Activity (IDDA) scores of 17-92. αβTCR/CD19-depleted allografts from related, unrelated or haplo-identical donors were used after antithymocyte globulin (ATG) and myeloablative conditioning (thiotepa, melphalan, and fludarabine). Post-transplant immunoprophylaxis included mycophenolate mofetil; 4/10 patients received additional transplant-associated immunosuppression.

RESULTS: All patients achieved primary engraftment. One patient with secondary rejection successfully underwent a second allo-HSCT. 5 patients developed grade 2-4 acute GvHD; no chronic GvHD was observed. One patient with GvHD died from COVID-19. All remaining 9 patients were successfully tapered off immunosuppression and showed improved IDDA scores. At 6 months NK, γδT, B and CD8 + T cells normalized; CD4 + numbers reached 149 cells/µl at 1 year. Most patients were successfully vaccinated and could stop immunoglobulin substitution.

CONCLUSION: In conclusion, ex vivo graft engineering using αβTCR/CD19 depletion was feasible in adults with IEI. Clinical outcomes are encouraging, but need to be confirmed in larger studies.

PMID:41634270 | DOI:10.1007/s10875-025-01978-9

J Leukoc Biol. 2026 Feb 3:qiag020. doi: 10.1093/jleuko/qiag020. Online ahead of print.

ABSTRACT

Despite advances in engineered adaptive immune cell therapies, current options for innate immune cell therapies are sparse. In this work, we demonstrate the utility of a neutrophil progenitor-based cell therapy. Murine conditionally-immortalized neutrophil progenitors (NPs) overcome some of the hurdles of alternative cell therapies, such as granulocyte transfusion, by engrafting in the unconditioned host and undergoing substantial expansion in vivo. Here we demonstrate the therapeutic value of NPs using a murine model of the primary immunodeficiency chronic granulomatous disease (CGD). Those with CGD are highly susceptible to infection with Staphylococcus aureus because of genetic mutations that impair neutrophil antimicrobial function. We find that the prophylactic treatment of CGD mice with transfused NPs rescue them from an otherwise lethal S. aureus pulmonary infection. In investigating the mechanisms behind the improved clearance of S. aureus and survival of CGD mice, our data suggests that the antimicrobial function of host CGD neutrophils is rescued by the presence of donor-derived wild-type neutrophils. We also observe that survival is improved to >50% in the CGD model when mice receive NPs post-infection. This work highlights the application of NPs to improving outcomes to acute bacterial infection in CGD, demonstrating the translational potential of conditionally-immortalized myeloid progenitors as a cellular therapy.

PMID:41632796 | DOI:10.1093/jleuko/qiag020

Pediatr Int. 2026 Jan-Dec;68(1):e70342. doi: 10.1111/ped.70342.

ABSTRACT

BACKGROUND: Moraxella species are commensal organisms of the upper respiratory tract that only occasionally cause invasive infection. Pediatric Moraxella bacteremia is extremely rare, and its clinical features and optimal management remain poorly defined.

METHODS: We conducted a single-center, retrospective observational study at Tokyo Metropolitan Children’s Medical Center. Patients with blood cultures yielding Moraxella spp. between April 2010 and March 2024 were identified. Clinical and microbiological data were extracted from electronic medical records. The primary outcome was all-cause 28-day mortality.

RESULTS: Among 24 patients (28 episodes) with blood cultures positive for M. catarrhalis or M. osloensis, 13 episodes were excluded as contamination. Eleven patients (15 episodes) with confirmed bacteremia were analyzed: 8 episodes were due to M. osloensis and 7 to M. catarrhalis. Two patients had recurrent episodes (one patient with congenital nephrotic syndrome had four episodes of M. catarrhalis bacteremia). Overall, 10 of 11 patients (91%) had underlying immunodeficiency. Central venous catheters were present in 6 of 8 M. osloensis episodes, which were classified as catheter-associated bacteremia. In the M. catarrhalis group, pneumonia was the most likely focus in 2 of 7 episodes. Antimicrobial therapy commonly included cefepime or ampicillin-sulbactam for M. osloensis and cefotaxime or ampicillin-sulbactam for M. catarrhalis. The median duration of antimicrobial therapy was 14 days in both groups. No patients required pediatric intensive care unit (PICU) care and no 28-day mortality occurred.

CONCLUSION: The patients with bacteremia due to M. osloensis or M. catarrhalis had favorable clinical outcomes.

PMID:41630570 | DOI:10.1111/ped.70342

Genome Biol. 2026 Feb 2. doi: 10.1186/s13059-026-03974-7. Online ahead of print.

ABSTRACT

BACKGROUND: Beta-thalassemia is among the most common monogenic disorders, posing a major global health challenge. Editing of genetic modifiers, such as BCL11A erythroid enhancer and HBG promoters, enhances fetal hemoglobin expression and confers major therapeutic potential. Double-strand-break (DSB)-independent genome editing tools, such as base editors (BE), are potentially safer and better suited for multiplexed application than DSB-dependent CRISPR/Cas technology. However, harmful on- and off-target events remain a concern and must be excluded before clinical application, including chromosomal rearrangements invisible to standard detection technologies.

RESULTS: Using primary patient-derived CD34⁺ cells from three donors, we investigate simplex and duplex BE-based disruption of the BCL11A erythroid enhancer and the BCL11A binding site (-115 bp) on the HBG promoter for DNA-level and functional studies at the RNA, protein, and morphological level. Analyses include direct comparison to DSB-based editing, the current clinically applied standard, and CAST-seq to assess recombination events, allowing wider inferences on relative safety. RNA-seq analyses for clones of primary CD34⁺ cells across all treatments confirm peak HBG induction for duplex BE and comparable effects on apoptotic and immune response signatures. Overall, duplex BE produces robust γ-globin and fetal hemoglobin induction, improves functional correction over simplex editing and results in low incidence of genomic alterations in both target loci.

CONCLUSIONS: Duplex BE targeting both BCL11A erythroid enhancer and HBG promoter enables functional correction and genome integrity. Our study highlights the efficacy, safety, and therapeutic potential of the present duplex BE approach.

PMID:41629994 | DOI:10.1186/s13059-026-03974-7

Allergy Asthma Clin Immunol. 2026 Feb 2. doi: 10.1186/s13223-026-01016-2. Online ahead of print.

ABSTRACT

BACKGROUND: WHIM syndrome is a rare autosomal dominant primary immunodeficiency characterized by the classical tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. The majority of cases are associated with gain-of-function mutations in the CXCR4 gene. Recent studies have expanded the clinical spectrum of the disease, revealing that only a subset of patients present with all four hallmark features. This underscores the syndrome’s variable expression and the need for greater clinical awareness of its atypical forms.

CASE PRESENTATION: We report a case of a 6-year-old Saudi girl who presented with persistent neutropenia, recurrent upper respiratory infections, and an episode of thrombocytopenia following a dental procedure. She did not exhibit warts, hypogammaglobulinemia, or myelokathexis. Immunological workup revealed marked lymphopenia affecting T, B, and NK cells, while immunoglobulin levels remained within normal limits. Bone marrow findings were unremarkable. Whole-exome sequencing identified a heterozygous de novo CXCR4 frameshift mutation (c.1172_1173del), confirming the diagnosis of WHIM syndrome. The patient was clinically stable and managed conservatively with precautions.

CONCLUSION: This case contributes to the evolving understanding of the clinical variability in WHIM syndrome and highlights the importance of genetic testing in patients with unexplained neutropenia and recurrent infections, even in the absence of the complete clinical tetrad.

PMID:41629964 | DOI:10.1186/s13223-026-01016-2

Sci Rep. 2026 Feb 2. doi: 10.1038/s41598-026-35604-4. Online ahead of print.

NO ABSTRACT

PMID:41629504 | DOI:10.1038/s41598-026-35604-4

Zhonghua Jie He He Hu Xi Za Zhi. 2026 Feb 12;49(2):113-130. doi: 10.3760/cma.j.cn112147-20250729-00449.

ABSTRACT

The population of immunocompromised hosts has steadily increased in recent years. Clinical evidence indicates that these individuals are at a significantly higher risk of developing severe pneumonia following infection, with the mortality rates markedly higher than those observed in immunocompetent individuals. However, there is currently a lack of specific national or international guidelines or expert consensus addressing the management of severe pneumonia in this population. To address this unmet need, the Chinese Thoracic Society (CTS) of the Chinese Medical Association and the Oncology Respiratory Disease Committee of China Anti-Cancer Association (CACA) convened a multidisciplinary panel of experts from respiratory and critical care medicine, infectious diseases, and related fields in China to develop the present consensus.This consensus addresses 14 key clinical questions, covering topics such as the definition and classification of immunocompromised hosts, and the diagnosis and treatment of severe pneumonia in this high-risk group. The panel systematically reviewed evidence and formulated recommendations using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. The resulting consensus aims to standardize clinical practice, support evidence-based decision-making, and eventually improve outcomes for immunocompromised patients with severe pneumonia in China.Question 1: Definition and classification of immunocompromised Hosts.Recommendation 1: An immunocompromised host is defined as a patient with a significantly weakened or absent immune response to pathogens owing to various intrinsic or extrinsic factors. The immunocompromised status is categorized as either primary or secondary. This assessment should integrate the patient’s underlying conditions with available immunological parameters.Question 2: What are the diagnostic criteria for severe pneumonia in immunocompromised hosts, and which indicators are recommended for severity assessment?Recommendation 2: Severe pneumonia in immunocompromised hosts is diagnosed based on the criteria outlined by the 2016 Chinese guidelines for community-acquired pneumonia (CAP). Disease severity and immune status should be assessed at initial diagnosis to evaluate risk and guide treatment decisions. Hospitalization thresholds may be appropriately reduced in this population (1C).Question 3: What are the diagnostic and therapeutic workflows for severe pneumonia in immunocompromised hosts, and how should infectious pneumonia be distinguished from non-infectious pulmonary infiltrates?Recommendation 3: A multidimensional approach is recommended for differentiating severe pneumonia from non-infectious pulmonary infiltrates in immunocompromised hosts. Clinical, radiological, and microbiological data should be integrated. When necessary, histopathological biopsy and/or multidisciplinary team (MDT) consultation should be performed. The detailed diagnostic and therapeutic workflow are illustrated in Figure 1 (1A).Question 4: What are the major pathogens causing pneumonia in immunocompromised hosts, and how does pathogen distribution differ across immunosuppressive states?Recommendation 4: The core pathogens causing pneumonia in immunocompromised hosts are usually similar to those in immunocompetent hosts. However, pathogen distribution is more diverse, with immunocompromised hosts showing a higher prevalence of opportunistic pathogens and mixed infections (Table 5 and Figure 1A).Question 5: What are the recommended timings and methods for obtaining clinical specimens from immunocompromised hosts?Recommendation 5: High-quality clinical specimens are necessary for etiological diagnosis. Once infection is suspected, early sampling for microbiological testing is recommended. The sampling approach should be individualized based on the patient’s condition and the clinical team’s experience (1B).Question 6: How to choose diagnostic methods for pathogen identification in immunocompromised hosts with pneumonia?Recommendation 6: For immunocompromised hosts with severe pneumonia, comprehensive microbiological testing should be performed before or concurrently with empirical therapy to identify pathogens as early as possible and guide treatment strategies (1A).Question 7: What are the principles of anti-infective therapy for severe pneumonia in immunocompromised hosts?Recommendation 71. Initial empirical therapy should target drug-resistant Gram-negative and Gram-positive bacteria, with expansion of coverage when risk factors are present (1A).2. For ventilator-associated pneumonia (VAP), combination regimens that include β-lactams are recommended (1A).3. Echinocandins are preferred for treating invasive pulmonary candidiasis, and a switch to azoles may be considered when appropriate (1A).4. Empirical coverage for cytomegalovirus pneumonia is recommended for patients developing bilateral interstitial pneumonia shortly after lung transplantation or hematopoietic stem cell transplantation (1A).Question 8: What factors should be considered when selecting empirical anti-infective therapy for severe pneumonia in immunocompromised hosts?Recommendation 8: Empirical therapy should be selected based on the type and degree of immunodeficiency, healthcare exposure, risk of antimicrobial resistance, severity of infection, microbiological findings, treatment response, and preventive strategies (1A).Question 9: What are the recommended treatment durations for different pathogens in severe pneumonia among immunocompromised hosts?Recommendation 9: Treatment duration primarily depends on clinical presentation, radiographic changes, severity of infection, pathogen resistance profile, and the immune status of patients (1A).Question 10: Which respiratory support strategies should be prioritized for immunocompromised hosts with severe pneumonia complicated by respiratory failure?Recommendation 10: Noninvasive respiratory support is preferred for immunocompromised hosts with severe pneumonia and respiratory failure who do not require immediate intubation. High-flow nasal oxygen (HFNO) or noninvasive positive-pressure ventilation (NPPV) may be selected (1A).Question 11: When is tracheal intubation most appropriate for immunocompromised hosts with severe pneumonia?Recommendation 11: The timing of tracheal intubation in immunocompromised hosts is usually similar to that in immunocompetent hosts (1A).Question 12: When should extracorporeal membrane oxygenation (ECMO) be initiated in immunocompromised hosts with severe pneumonia and respiratory failure?Recommendation 12: The timing of ECMO initiation should be determined based on the same criteria as those used for immunocompetent hosts (1A).Question 13: For immunocompromised patients with severe pneumonia and respiratory failure, is early extubation followed by NPPV or HFNO a viable option?Recommendation 13: Early extubation followed by NPPV or HFNO can be actively considered for immunocompromised patients with severe pneumonia complicated by respiratory failure. In the absence of contraindications to NPPV, NPPV may be attempted as the initial post-extubation strategy (1A).Question 14: What recommendations are there for immunomodulatory therapy in immunocompromised hosts with severe pneumonia?Recommendation 14: Immunomodulation is an important component of therapy in immunocompromised hosts with severe pneumonia. Immune status should be assessed to guide individualized immunoregulatory strategies (1B).

PMID:41629088 | DOI:10.3760/cma.j.cn112147-20250729-00449

Life Med. 2025 Nov 25;4(5):lnaf030. doi: 10.1093/lifemedi/lnaf030. eCollection 2025 Oct.

ABSTRACT

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a primary immunodeficiency characterized by hyperactivated lymphocytes and recurrent infections. This study presents a 2.5-year-old patient with a novel PIK3CD gene mutation (c.1309C>T; p. R437C) derived from his mother. We explored the immunological consequences of this mutation in both the patient and his mother, revealing defects in T cell differentiation, B cell maturation, and mitochondrial function. Notably, we found that the elevated CD38 expression on B cells is a key factor driving B cell senescence, mitochondrial dysfunction, and increased transitional B cell proportion, contributing to the observed immunodeficiency, such as diminished serum antibodies. Further investigations of the PI3K/AKT/mTOR pathway highlight a preferential activation of mTORC2 over mTORC1. We also demonstrate that the transcription factor FOXO1, a downstream molecule of PI3K/AKT signaling, regulates CD38 expression by binding to the promotor of the CD38 gene, linking this pathway to B cell dysfunction. This novel mutation expands the spectrum of PIK3CD mutations associated with APDS and provides new insights into the molecular mechanisms underlying B-cell senescence and other immune dysregulation. Moreover, targeting the AKT-FOXO1 axis could offer therapeutic potential to reverse B-cell dysfunction and improve immune responses in patients with PIK3CD mutations.

PMID:41626283 | PMC:PMC12853000 | DOI:10.1093/lifemedi/lnaf030

Cureus. 2025 Dec 30;17(12):e100461. doi: 10.7759/cureus.100461. eCollection 2025 Dec.

ABSTRACT

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by the classic triad of microthrombocytopenia, recurrent infections, and eczema, with most cases diagnosed during infancy or early childhood. Adult presentation is uncommon and often leads to diagnostic delay or misdiagnosis. We report the case of a 28-year-old male who presented with multiple episodes of bleeding, petechiae, recurrent skin and respiratory infections, and chronic eczematous lesions. Over several years, he underwent repeated hospitalizations and was treated for immune thrombocytopenia (ITP) with prolonged courses of oral corticosteroids, resulting in features of iatrogenic Cushing’s syndrome, including moon facies and skin thinning. Despite steroid therapy, his symptoms worsened, and he continued to have intermittent respiratory tract infections, urinary tract infections, and recurrent skin ulcers. The patient’s family history revealed consanguinity and recurrent infections among female relatives, including his mother and maternal aunt, raising suspicion for an inherited immunodeficiency. On examination, he had diffuse eczematous lesions over the hands and feet, petechiae, and Cushingoid features. Laboratory investigations showed persistent thrombocytopenia with a low mean platelet volume, elevated inflammatory markers, and evidence of immune dysregulation. Given the constellation of symptoms, a primary immunodeficiency was suspected, prompting genetic evaluation. Whole-exome sequencing identified a hemizygous pathogenic nonsense variant in the WAS gene: NM_000377.3; chrX:48688689; c.961C>T; p.Arg321* in exon 10, confirming the diagnosis of WAS. This variant is predicted to result in the premature truncation of the WAS protein and is consistent with a classical WAS phenotype. This case highlights the challenges in diagnosing WAS in adulthood, especially when initial symptoms mimic more common hematological conditions such as ITP. Early recognition of syndromic features and consideration of inherited immunodeficiencies in persistent thrombocytopenia with eczema can prevent prolonged steroid exposure and facilitate timely, appropriate management.

PMID:41625929 | PMC:PMC12856365 | DOI:10.7759/cureus.100461

Front Immunol. 2026 Jan 15;17:1687549. doi: 10.3389/fimmu.2026.1687549. eCollection 2026.

ABSTRACT

XMEN disease (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a rare Inborn Error of Immunity (IEI)characterized by impaired magnesium ion transport due to mutations in the MAGT1 gene, which subsequently affects immune cell function. Timely diagnosis and prompt intervention are essential for improving patient outcomes. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential therapeutic approach to restore MAGT1 function. We report an infant with XMEN who acquired a novel mutation in the MAGT1 gene, presenting recurrent severe skin infections and neutropenia after 6 months of age, which was effectively managed following aggressive anti-infective treatment and HSCT.

PMID:41624006 | PMC:PMC12851993 | DOI:10.3389/fimmu.2026.1687549