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Cureus. 2024 Dec 4;16(12):e75128. doi: 10.7759/cureus.75128. eCollection 2024 Dec.

ABSTRACT

Chediak-Higashi syndrome (CHS) is a rare multisystem genetic disorder of childhood, caused by a defect in vesicular trafficking, which is an essential process for intracellular transport. This defect results in the formation of giant cytoplasmic granules in various cell types, including white blood cells, melanosomes, and Schwann cells. The presence of giant lysosomal granules in neutrophils and their precursors is a distinct and diagnostic feature of CHS, differentiating it from other childhood immunodeficiency disorders, such as Griscelli syndrome and Hermansky-Pudlak syndrome, which share common characteristics like albinism and increased susceptibility to fatal hemophagocytic lymphohistiocytosis. Diagnosing CHS is challenging for both clinicians and pathologists, requiring a high degree of suspicion. This case emphasizes the critical role of vigilant observation of subtle clinical and pathological features for an accurate diagnosis. We present a rare case of CHS in a six-month-old male child who presented with recurrent episodes of fever and failure to thrive. Physical examination revealed patchy gray hair on the scalp and hypopigmented patches on the lower limbs. Laboratory findings showed pancytopenia, with large, coarse cytoplasmic granules in neutrophils and their precursors on bone marrow examination – a finding diagnostic of CHS. This case highlights the importance of morphological assessment in diagnosing this rare and potentially fatal disorder, enabling early diagnosis and prompt treatment.

PMID:39759654 | PMC:PMC11700029 | DOI:10.7759/cureus.75128

Environ Pollut. 2025 Jan 2:125631. doi: 10.1016/j.envpol.2025.125631. Online ahead of print.

ABSTRACT

Allergic asthma is a significant international concern in respiratory health, which can be exacerbated by the increasing levels of non-allergenic pollutants. This rise in airborne pollutants is a primary driver behind the growing prevalence of asthma, posing a health emergency. Additionally, climatic risk factors can contribute to the onset and progression of asthma. Understanding the complex interplay between pollution, climate, and asthma induction is crucial to elucidate how environmental changes intensify asthma. In this study, we investigated the proteomic and metabolomic changes in the lungs of a mouse asthma model following co-exposure to carbon black nanoparticles and high humidity, which represent airborne and climatic factors, respectively. An asthma model was established using ovalbumin, and mice were intratracheally instilled with 15 or 30 μg/kg of carbon black and simultaneously exposed to either 70% or 90% relative humidity. Protein and metabolite profiles from the lung were used to analyze the most significantly changed clusters, and potential biomarkers and enriched pathways were identified to dissect the adverse effects of the two risk factors. The lung proteome and metabolome are significantly altered by the co-exposure, with the effects modulated by carbon black concentration and humidity level. This study proposes 10 proteins and 18 metabolites as candidate biomarkers. The significantly enriched KEGG pathways include one protein pathway (primary immunodeficiency) and six metabolic pathways (ABC transporters, nucleotide metabolism, Parkinson’s disease, purine metabolism, choline metabolism in cancer, and biosynthesis of cofactors). A joint proteomic and metabolomic analysis identifies five common pathways across both omics, namely, ABC transporters, central carbon metabolism in cancer, EGFR tyrosine kinase inhibitor resistance, glioma, and NF-kappa B signaling pathway, disturbed by the co-exposure. We provide a multi-omic basis for the health risk assessment and management of co-exposures to environmental risk factors.

PMID:39755354 | DOI:10.1016/j.envpol.2025.125631

Rev Alerg Mex. 2024 Dec 23;71(4):268-271. doi: 10.29262/ram.v71i4.1405.

ABSTRACT

BACKGROUND: Congenital neutropenia is a primary immunodeficiency characterized by quantitative anomalies in neutrophil counts. It is classified as mild, moderate, or severe. Hematopoietic stem cell transplantation stands as a potential therapeutic intervention; nevertheless, graft-versus-host disease emerges as a main complication.

CASE REPORT: We report the case of a 2-year-old female patient, with a history of congenital neutropenia. She had scalp abscesses and preseptal cellulitis, which were satisfactorily treated. After a multidisciplinary approach, a protocol was initiated to receive an allogenic hematopoietic progenitor cell transplant; graft versus host disease was subsequently diagnosed, ultimately resulting in death of the patient.

CONCLUSION: Graft-versus-host disease remains a significant complication in patients who undergo allogeneic hematopoietic stem cell transplants. Its recognition, management, and treatment are clinically relevant aspects given the substantial degree of associated morbidity and mortality.

PMID:39752270 | DOI:10.29262/ram.v71i4.1405

J Clin Immunol. 2025 Jan 2;45(1):61. doi: 10.1007/s10875-024-01855-x.

ABSTRACT

PURPOSE: Patients with inborn errors of immunity (IEI) have lifelong health complications including severe infections and physical impairments. Previous studies show that a patient’s perception of their health is an important predictor of health outcomes. The purpose of this study was to understand factors related to patient reported health status.

METHODS: We used data from the Immunodeficiency Foundation (IDF) 2017 National Patient Survey and analyzed factors which correlated with the reported health status (RHS). Among a cohort of 1139 self-reported IEI patients, we identified age at the time of diagnosis, time gap between symptom onset and diagnosis, number of physicians seen, and whether the diagnosis was made in the first 5 years of life as significant. We used a two-tailed t-test, single-factor ANOVA, and Tukey-Kramer post-hoc test to assess statistical significance in the observed difference.

RESULTS: Patients who received a diagnosis before the age of 12 had a significantly better mean RHS (n = 207 pre-12a vs. n = 900 post-12a; p < 0.0001). Patients who received a diagnosis within 10 years of symptom onset showed improved mean RHS (n = 413 pre-10 vs. n = 524 post-10; p < 0.0001). Among patients who had symptom onset within the first 5 years of life, those who received a diagnosis had a significantly improved RHS (3.5 ± 0.92, n = 275 undiagnosed vs. 2.8 ± 0.94, n = 108 diagnosed; p < 0.0001). Finally, RHS was significantly impacted by number of physicians(n ≥ 4) seen prior to diagnosis (3.1 ± 0.96 vs. 3.4 ± 0.80, p < 0.0001).

CONCLUSION: These findings shed light upon critical factors which impact IEI patient RHS. Specifically, we find that efficient, rapid and early-life IEI identification should improve patient reported health and relevant outcomes. These improvements appear to be independent of the clinician specialty ultimately making the IEI diagnosis.

PMID:39747782 | DOI:10.1007/s10875-024-01855-x

JAMA Oncol. 2025 Jan 2. doi: 10.1001/jamaoncol.2024.5636. Online ahead of print.

ABSTRACT

IMPORTANCE: The current standard-of-care salvage therapy in relapsed/refractory classic Hodgkin lymphoma (cHL) includes consolidation high-dose chemotherapy (HDCT)/autologous stem cell transplant (aSCT).

OBJECTIVE: To investigate whether presalvage risk factors and fludeoxyglucose-18 (FDG) positron emission tomography (PET) response to reinduction chemotherapy can guide escalation or de-escalation between HDCT/aSCT or transplant-free consolidation with radiotherapy to minimize toxic effects while maintaining high cure rates.

DESIGN, SETTING, AND PARTICIPANTS: EuroNet-PHL-R1 was a nonrandomized clinical trial that enrolled patients younger than 18 years with first relapsed/refractory cHL across 68 sites in 13 countries in Europe between January 2007 and January 2013. Data were analyzed between September 2022 and July 2024.

INTERVENTION: Reinduction chemotherapy consisted of alternating IEP (ifosfamide, etoposide, prednisolone) and ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients with low-risk disease (late relapse after 2 cycles of first-line chemotherapy and any relapse with an adequate response after 1 IEP/ABVD defined as complete metabolic response on FDG-PET and at least 50% volume reduction) received a second IEP/ABVD cycle and radiotherapy (RT) to all sites involved at relapse. Patients with high-risk disease (all primary progressions and relapses with inadequate response after 1 IEP/ABVD cycle) received a second IEP/ABVD cycle plus HDCT/aSCT with or without RT.

MAIN OUTCOMES AND MEASURES: The primary end point was 5-year event-free survival. Secondary end points were overall survival (OS) and progression-free survival (PFS). PFS was identical to event-free survival because no secondary cancers were observed. PFS data alone are presented for simplicity.

RESULTS: Of 118 patients analyzed, 58 (49.2%) were female, and the median (IQR) age was 16.3 () years. The median (IQR) follow-up was 67.5 (58.5-77.0) months. The overall 5-year PFS was 71.3% (95% CI, 63.5%-80.1%), and OS was 82.7% (95% CI, 75.8%-90.1%). For patients in the low-risk group (n = 59), 41 received nontransplant salvage with a 5-year PFS of 89.7% (95% CI, 80.7%-99.8%) and OS of 97.4% (95% CI, 92.6%-100%). In contrast, 18 received HDCT/aSCT off protocol, with a 5-year PFS of 88.9% (95% CI, 75.5%-100%) and OS of 100%. All 59 patients with high-risk disease received HDCT/aSCT (and 23 received post-HDCT/aSCT RT) with a 5-year PFS of 53.3% (95% CI, 41.8%-67.9%) and OS of 66.5% (95% CI, 54.9%-80.5%).

CONCLUSION AND RELEVANCE: In this nonrandomized clinical trial, FDG-PET response-guided salvage in relapsed cHL may identify patients in whom transplant-free salvage achieves excellent outcomes. HDCT/aSCT may be reserved for primary progression and relapsed cHL with inadequate response.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00433459.

PMID:39745682 | DOI:10.1001/jamaoncol.2024.5636

Eur Ann Allergy Clin Immunol. 2025 Jan 2. doi: 10.23822/EurAnnACI.1764-1489.383. Online ahead of print.

ABSTRACT

Background. Children with milk and egg allergies have outcomes in which, three-quarters are tolerant to baked forms of the allergenic food. Identifying predictors of tolerance to baked foods for IgE-mediated immediate-type reactions may guide the early introduction of baked allergens to diet and tolerance development. This study explores factors associated with early tolerance to baked foods. Methods. We retrospectively analysed patients with IgE-mediated immediate-type food allergy in infancy who either became tolerant to the baked form before two years or remained reactive after two years. Results. We examined 143 patients solely with IgE-mediated immediate-type egg and/or milk allergies excluding the ones having atopic dermatitis, 76 (42 egg-allergics; 34 milk-allergics) achieved tolerance, and 67 (38 egg-allergics; 29 milk-allergics) were reactive beyond the age of two. Independent markers favoring tolerance to baked forms at two years included the absence of anaphylaxis during the first reaction, applicable to milk and egg allergens. The absence of familial atopy and concomitant egg allergy were also independent predictors for milk-allergic subjects. Receiver operating characteristic analysis determined cut-off values for specific-Immunoglobulin E (sIgE) levels (kU/L) predicting mild phenotype at first admission: egg white-sIgE ≤ 7.39, milk-sIgE ≤ 5.99, and casein-sIgE ≤ 4.99, with AUC values of 0.703, 0.716, and 0.749, respectively. Conclusions. This study identifies key prognostic for tolerance of baked allergen for IgE-mediated immediate-type reactions, providing valuable insights to determine the patients who need more intensive care versus the ones who don’t need baked allergen avoidance early in their life from their initial admission at infancy.

PMID:39745421 | DOI:10.23822/EurAnnACI.1764-1489.383

Pulm Circ. 2025 Jan 1;15(1):e70034. doi: 10.1002/pul2.70034. eCollection 2025 Jan.

ABSTRACT

Common variable immunodeficiency (CVID) is a type of primary immunodeficiency that presents as a heterogenous disorder characterized by hypogammaglobinemia, poor response to vaccines, recurrent sinopulmonary infections, and can have noninfectious systemic manifestations. We performed a single-center, retrospective, observational study of five patients with noninfectious complications of CVID. All patients had CVID as defined by the European Society of Immunodeficiencies criteria and had received intravenous immunoglobulin therapy. There were multiple pulmonary manifestations of CVID including frequent pneumonias, bronchiectasis, granulomatous lung disease, and pulmonary hypertension. All our patients were treated with pulmonary vasodilators for severe precapillary pulmonary hypertension along with individualized immunosuppression regimen for interstitial lung disease. Despite treatment for interstitial lung disease and PH, their conditions worsened over 2-3 years with all patients progressing toward organ transplant evaluation. Idiopathic thrombocytopenia and non-cirrhotic portal hypertension were common, with three patients probably suffering from nodular regenerative hyperplasia. Noninfectious complications of CVID can affect different organs and progress despite advanced therapies. Single or multiorgan transplantation is a treatment option for patients with end-stage organ involvement refractory to medical therapy.

PMID:39744645 | PMC:PMC11688575 | DOI:10.1002/pul2.70034

PLoS One. 2024 Dec 31;19(12):e0315446. doi: 10.1371/journal.pone.0315446. eCollection 2024.

ABSTRACT

The vascular endothelium is vital for cardio-pulmonary homeostasis and, thus, plays a crucial role in preventing life-threatening lung diseases. The transcription factor GATA2 is essential for hematopoiesis and maintaining vascular integrity. Heterozygous mutations in GATA2 can lead to a primary immunodeficiency syndrome with pulmonary manifestations. Some GATA2 haploinsufficient patients develop pulmonary hypertension (PH), characterized by vascular remodeling and occlusion of small pulmonary arteries. However, the mechanism underlying pulmonary vascular remodeling in GATA2 haploinsufficient patients remain unclear. To understand how GATA2 deficiency affects pulmonary artery homeostasis, we applied a chronic hypoxia-mediated PH model using inducible systemic Gata2 conditionally deficient (G2-CKO) mice. The G2-CKO mice exhibited augmented pulmonary vascular remodeling, with enhanced α-smooth muscle actin accumulation and increased apoptotic cells in the vascular wall upon chronic hypoxia. Transcript analysis and chromatin immunoprecipitation assays using mouse pulmonary vascular endothelial cells revealed that GATA2 directly regulates the expression of G6pdx (a crucial cytoprotective enzyme) and Bmp4 (a growth factor that mediates vascular homeostasis). These results suggest that GATA2-deficient lungs are vulnerable to the hypoxic stress due to a diminished cellular protective response, making G2-CKO mice more prone to vascular remodeling upon chronic hypoxia. These findings provide insights into the mechanisms underlying GATA2-haploinsufficiency-related pulmonary hypertension.

PMID:39739870 | DOI:10.1371/journal.pone.0315446

J Pediatr Hematol Oncol. 2025 Jan 1;47(1):e74-e76. doi: 10.1097/MPH.0000000000002965. Epub 2024 Nov 15.

ABSTRACT

Nijmegen breakage syndrome (NBS) is a rare primary immunodeficiency disease due to a pathogenic variant in the NBN gene causing impaired DNA repair and increased predisposition for lymphoid malignancy. By contrast, solid tumors have been rarely reported. Neuroblastoma (NB) is a rare childhood solid tumor, associated with the worse outcome if MYCN oncogene is amplified. We describe 2 young pediatric patients with NBS who developed high-risk NB. The first patient died shortly after chemotherapy was introduced. The second patient successfully received modified chemotherapy resulting in clinical remission lasting 2 years after an initial diagnosis of NB.

PMID:39737638 | DOI:10.1097/MPH.0000000000002965

Front Immunol. 2024 Dec 16;15:1490593. doi: 10.3389/fimmu.2024.1490593. eCollection 2024.

ABSTRACT

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by an overactive immune response, particularly involving excessive production of type I interferons. This overproduction is driven by the phosphorylation of IRF7, a crucial factor in interferon gene activation. Current treatments for SLE are often not very effective and can have serious side effects.

METHODS: Our study introduces clobenpropit, a histamine analogue, as a potential new therapy targeting the CXCR4 receptor to reduce IRF7 phosphorylation and subsequent interferon production. We employed various laboratory techniques to investigate how clobenpropit interacts with CXCR4 and its effects on immune cells from healthy individuals and SLE patients.

RESULTS: Clobenpropit binds effectively to CXCR4, significantly inhibiting IRF7 phosphorylation and reducing interferon production. Additionally, clobenpropit lowered levels of pro-inflammatory cytokines in a mouse model of lupus, demonstrating efficacy comparable to the standard treatment, prednisolone.

DISCUSSION: These results suggest that clobenpropit could be a promising new treatment for SLE, offering a targeted approach with potential advantages over current therapies.

PMID:39737176 | PMC:PMC11682962 | DOI:10.3389/fimmu.2024.1490593