Over the last few decades, screening for dysglycemia in transfusion-dependent β-thalassemia patients (β-TDT) using an oral glucose tolerance test (OGTT) with fasting (FPG) and 2-hour plasma glucose (2h-PG) samples was recommended at 10, 12, 14, and 16 years, and annually thereafter. The precise measurement of PG levels is the mainstay for accurate diagnosis of dysglycemia and for limiting the risk of false-positive (i.e., overdiagnosis) and false-negative (i.e., underdiagnosis), especially in patients with PG values near the recommended cutoff values. The primary objective of the survey was to describe the procedures of the preanalytical phase of screening for dysglycemia, using data from actual clinical practice at Centers caring for β-TDT patients. The collected data were compared to the international recommendations of the American Diabetes Association and the World Health Organization. This observational study was based primarily on an online questionnaire. All members of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) were officially invited to participate. The questionnaire consisted of 6 sections and 22 questions, with single-, multiple-choice, and open-ended descriptive answer options. 14 out of 18 invited Centers [Bulgaria, Cyprus, Greece, Iran (2), Italy (2), Oman, Qatar, Sri Lanka, Türkiye (3) and United Kingdom] accepted and completed the survey with a response rate of77.7 % The total number of β-TDT patients followed in the participating Centers was 3,372 with 2,932 (86.9 %)over the age of 10 years. A total of 549 patients were followed for thalassemia-related diabetes mellitus (Th-RDM). Furthermore, the survey across the 10 countries showed variable adherence to and deviations from current international guidelines. The lowest adherence rate was associated with the information and instructions given to patients prior to the OGTT and with how the blood samples were stored from collection to centrifugation and analysis. Differences in these factors may lead to unintended variations in the prevalence and severity of hyperglycemia, with important implications for clinical practice. To improve the quality of the pre-analytical phase across participating centers, the Standards for Reporting of Diagnostic Accuracy (STARD) statement was implemented. Based on the STARD statement, the pre-analytical blood sampling procedures for OGTT screening in thalassemia Centers require revision and standardization. To minimize preanalytical errors, a precise diagnostic approach, coupled with closer patient follow-up, is needed to reduce the risk of glucose measurement errors.
Thalassemia and sickle cell disease are now increasingly present as lifelong chronic conditions in high-income countries, with growing numbers of patients reaching their 50s and 60s. This demographic shift transforms hemoglobinopathies from childhood-threatening disorders into chronic, multisystem conditions with cumulative morbidity. However, data specifically focused on later-life hemoglobinopathy populations remain limited, fragmented, and often extrapolated from younger cohorts, leaving hematologists and internists relatively unprepared for the functional decline, vulnerability, and geriatric syndromes that can characterize later life in these populations. This expert opinion narrative review synthesizes available evidence on the intersection of disease-driven pathology (anemia, hemolysis, vasculopathy), long-term treatment burden (transfusion-related iron overload, chelation toxicities), and aging biology (declining physiologic reserve, sarcopenia, cognitive vulnerability) in adults beyond midlife. Given the historical survival patterns in hemoglobinopathies and the inconsistent definition of "older adult" across studies, particularly in sickle cell disease, we use a pragmatic age threshold of >=50 years for the main gerontological framing, while incorporating evidence from cohorts beginning at 40-49 years when that is how the literature defines older hemoglobinopathy populations. We distinguish disease-specific priorities: thalassemia faces myocardial and hepatic iron deposition and endocrine failure, while sickle cell disease confronts cerebrovascular disease, chronic pain, and cardiopulmonary complications. Critically, care targets in later life must extend beyond survival and organ-specific metrics to functional endpoints, disability prevention, cognitive health, and quality of life. A conceptual mapping links mechanisms of hemoglobinopathy to established gerontology constructs, including inflammaging, cellular senescence, and vascular aging, while acknowledging that direct mechanistic evidence in older hemoglobinopathy cohorts remains incomplete. Three adjustments are necessary in adults beyond midlife: monitoring should prioritize early detection of treatable complications and emerging functional impairment rather than only documenting cumulative organ damage; therapeutic decisions should weigh treatment benefit, treatment burden, comorbidity burden, and goals of care rather than defaulting to pediatric-era protocols; and care systems should embed shared decision-making, palliative principles, and multidisciplinary coordination within primary care networks, with specialist hemoglobinopathy centers functioning as disease-specific hubs rather than stand-alone primary care providers.
Thalassemia is a common hereditary hemoglobin disorder in Vietnam. Elucidating the epidemiological and genetic patterns in children is essential for developing screening and prevention strategies. A retrospective analysis of 1,240 children under 10 years of age with Thalassemia treated at the National Institute of Hematology and Blood Transfusion in Vietnam, between 2014 and 2023. The median age at treatment initiation was 1 year (range 0-9 years), with 94.5% of patients aged 0-5 years. Children born after 2020 were diagnosed and treated earlier than those born before 2020 (0 year (range 0-2 years) vs 1 year (range 0-9 years); p < 0.0001), concurrent with the implementation of the national prenatal screening program. β-thalassemia and β-thalassemia/HbE accounted for nearly 90% of cases, with subtype distribution varying by ethnicity and region. β-thalassemia/HbE predominated in the Northwest and North Central regions, particularly among the Thai and Muong populations. In contrast, β-thalassemia was more prevalent in the Northeast, notably among the Tay and Nung populations. Eight α-globin and thirteen β-globin mutated types were detected. The common β-globin variants (CD17, CD41/42, CD71/72, -28, and IVSI-1) and HbE (CD26) mirror patterns reported in neighboring Laos and Guangxi Province, China. For α-globin genotypes, --SEA (49.83%), Hb CS (31.53%), and -α3.7 (8.47%) were most frequent. Geography, ethnicity, and genetic background strongly shape Thalassemia epidemiology in Northern Vietnam. Targeted genetic counseling, early carrier screening, and region-focused community programs are urgently needed to reduce disease burden in high-risk populations.
The study aimed to compare the incidence and course of febrile neutropenia (FN) and factors affecting mortality in hematologic patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either fresh or cryopreserved grafts. The clinical data of 155 patients who underwent allo-HSCT at our hematology clinic between 2010 and 2023 were retrospectively analyzed. The incidence of bloodstream infection (BSI) and FN-related mortality was analyzed in these patients. Factors affecting FN-related mortality were examined using a logistic regression model. A total of 143 patients who developed FN were included in the study. Ninety-eight patients underwent transplantation with fresh stem cells, and 45 patients with cryopreserved stem cells. The duration of FN episodes was similar between groups (p = 0.077); however, the duration of deep neutropenia (neutrophils < 100/mm3) was significantly longer in the cryopreserved group (11.56 ± 4.84 vs. 7.78 ± 3.03; p < 0.001). GNB infections and invasive fungal infections were more frequent in the cryopreserved group (p = 0.009 and p < 0.001, respectively). In the logistic regression model, the most important determinants of FN-related mortality were duration of the FN episode (OR 1.18; 95% CI 0.99-1.41; p = 0.046) and higher hematopoietic cell transplantation comorbidity index (HCT-CI) score (score 1; p = 0.014 and score 2; p = 0.039). This study demonstrated that, regardless of graft type, prolonged FN duration and a high HCT-CI score are the primary determinants of mortality. Therefore, clinical management of patients should also address these risk factors.
The immunomodulatory drug thalidomide is a promising alternative therapy for transfusion-dependent β-thalassemia (TDT) due to its potent induction of fetal hemoglobin. To identify the efficacy and safety of thalidomide in TDT patients. A comprehensive search was conducted across MEDLINE, EMBASE, CENTRAL, Web of Science, CBM, CNKI, VIP, Wangfang Data, and OpenGrey, up to January 24, 2026. We included RCTs and observational studies involving more than 10 TDT patients treated with thalidomide for at least 3 months. Risk of bias was assessed using RoB 2 and MINORS tools. The certainty of evidence was evaluated with the GRADE approach. Twenty-six studies involving 2422 patients were included. No studies had a high risk of bias. The meta-analysis of RCTs demonstrated that, compared with the control group, thalidomide significantly increased the major response rate (MRR; low certainty), the overall response rate (ORR; low certainty), and hemoglobin level (Hb; moderate certainty), as well as fetal hemoglobin level (HbF; moderate certainty). There was no significant between-group difference in changes in serum ferritin (SF) levels (very low certainty). The pre-post meta-analysis showed the following pooled outcomes: MRR 62.91% (very low certainty), ORR 75.07% (very low certainty), a Hb level change of 1.94 g/dL, a HbF level change of 39.21%, and an SF level change of -1432.39 ng/mL. The pooled incidence of adverse drug events (ADEs) was 4.65 per 100 person months, and that of ADEs leading to drug discontinuation was 0.04 per 100 person months. Most reported events were mild and tolerable. Thalidomide may provide limited benefits for TDT patients. In clinical practice, its potential risks must be thoroughly weighed against these benefits. Therefore, future large-scale, globally diverse, and high-quality RCTs are warranted.
Screening for dysglycemia with an annual oral glucose tolerance test (OGTT) is recommended in transfusion-dependent β-thalassemia (β-TDT), but adherence in routine practice is low. Fasting surrogate indices of β-cell function and insulin sensitivity could offer a less burdensome alternative. To evaluate in adult β-TDT patients with normal fasting plasma glucose (FPG < 100 mg/dL): (i) the performance of fasting HOMA-2 indices (HOMA2-IR, HOMA2-%β, HOMA2-%S) and their disposition index as predictors of dysglycemia, and (ii) the comparative value of basal versus dynamic OGTT-derived markers (30-min and 1-h plasma glucose, insulinogenic index [IGI], IGI × ISI Matsuda index and IGI/HOMA2-IR), as predictors of hyperglycemia. A single-centre retrospective analysis of 42 β-TDT patients (19 males/23 females; mean age 29.2 ± 5.9 yr) with FPG < 100 mg/dL who underwent a standard 75-g 2-h OGTT between January 2011 and September 2025. Patients were classified as those with normal glucose tolerance (NGT; n = 19) or those with impaired glucose tolerance (IGT: n= 20) or thalassemia-related diabetes mellitus (Th-RDM: n = 3). Fasting and dynamic indices were compared by ANOVA and Mann-Whitney U test; associations were tested by Pearson/Spearman correlation and by three sequential exploratory multivariable linear regression models with 2-h plasma glucose as the dependent variable. ROC analysis with Youden's index identified optimal hypothesis-generating cut-offs. Fasting HOMA2-IR, HOMA2-%β and HOMA2-%S did not differ significantly between NGT and hyperglycemic patients and were not independent predictors of 2-h plasma glucose. In contrast, in the total group, 30-min PG, 1-h PG, IGI, IGI × ISI Matsuda index and IGI/HOMA2-IR all differed significantly between groups (p: ≤ 0.0082) and were inversely correlated with 2-h PG. Receiver operating characteristic (ROC) analysis and area under the curve (AUC-ROC) were used to assess diagnostic performance of the most significant variables. The ROC-AUC cut-offs for predicting dysglycemia were 122.5 mg/dL for 30-min PG (sensitivity 0.91, specificity 0.52), 134 mg/dL for 1-h PG (0.95, 0.10), 5.7 for IGI × ISI Matsuda index (0.87, 0.47) and 1.33 for IGI/HOMA2-IR (0.87, 0.57). Fasting HOMA-2 indices alone are not reliable predictors of dysglycemia in β-TDT patients with PG < 100 mg/dL. The dynamic IGI/HOMA2-IR ratio and the 30-min/1-h post-load plasma glucose may help risk-stratify patients with β-TDT and normal fasting glucose; however, the proposed cut-offs should be regarded as hypothesis-generating, and prospective multicenter validation is required before these indices can be used to modify current OGTT screening recommendations.
Transfusion-dependent thalassemia (TDT) is a transfusion-dependent anemia frequently associated with iron overload, which may disrupt liver function and glucose metabolism. This study aimed to evaluate glucose dysregulation and the effects of iron chelation therapy in pediatric TDT patients. This retrospective study included 31 children and adolescents (aged 7-23 years) with TDT who were followed at a tertiary-care pediatric hematology center with available oral glucose tolerance test (OGTT) data. Clinical and laboratory data were analyzed, including oral glucose tolerance test (OGTT), serum ferritin, alanine aminotransferase (ALT), glycated hemoglobin (Hb A1c), C-peptide, homeostatic model assessment for insulin resistance (HOMA-IR), abdominal ultrasonography (USG), and liver and cardiac magnetic resonance imaging (MRI). Diagnosis of diabetes mellitus (DM) and prediabetes was based on American Diabetes Association (ADA) criteria. OGTT was performed in 28 patients; impaired fasting glucose (IFG) was observed in 10.7%, impaired glucose tolerance (IGT) in 3.6%, and 85.7% had normal glucose regulation. All received consistent oral chelation with film-coated deferasirox. ALT showed significant correlation with age at chelation onset (r=0.49, p=0.00), C-peptide (r=0.45, p=0.02), and age at diagnosis (r=0.56, p=0.001). Duration of chelation correlated with hepatomegaly severity (r=0.61, p=0.00), 30-minute glucose (r=0.39, p=0.03), and insulin levels at 30 (r=0.37, p=0.04) and 90 minutes (r=0.39, p=0.03). No significant association was found between ferritin and OGTT values (p>0.05). Overt glucose metabolism disorders were uncommon and should be interpreted cautiously. These results highlight the critical role of adherence to chelation and metabolic monitoring to prevent DM in children with TDT.
Radiologic complications of pediatric Mycoplasma pneumoniae pneumonia (MPP), consolidation, and necrotizing pneumonia (NP) are difficult to anticipate early. We tested whether admission cytokines and short-term changes predict imaging outcomes. A retrospective cohort (Oct 2022-Sep 2024) of hospitalized children with PCR-confirmed MPP. Multiplex cytokines (including IL-6, IL-10, CXCL10/IP-10) were assayed from residual samples at admission (T0) and days 3-5 (T1). NP analyses were conditional on undergoing computed tomography (CT). Primary outcomes were WHO end-point CXR consolidation ≤14 days and CT-defined NP ≤28 days. Full-cohort 14-day CXR-consolidation risk (admission), post-T1 consolidation risk among event-free children (day 3-5 landmark), and 28-day NP risk conditional on being scanned. Penalized logistic models evaluated T0 and Δ(T0-T1) predictors among children event-free at T1, with AUC (bootstrap-corrected) and BH-FDR control. Of 286 enrollments, 268 were analyzed; consolidation occurred in 96/268 (35.8%), CT was performed in 124/268 (46.3%), and identified NP in 28/124 (22.6%; 10.4% overall). In the Admission model, IL-6 (adjusted OR [aOR] 1.45, 95% CI 1.16-1.83; q=0.01), IP-10 (1.52, 1.21-1.93; q<0.01), and IL-10 (1.28, 1.03-1.60; q=0.04) predicted consolidation (AUC 0.78, 95% CI 0.73-0.83). In event-free children at T1 (n=180), ΔIL 6 (1.40, 1.12-1.76) and ΔIP 10 (1.48, 1.18-1.88) improved discrimination (AUC 0.84, 0.79-0.88). In CT-subset models, T0 IL-6 (1.67, 1.09-2.58) and ΔIL-6 (1.89, 1.22-3.00) were associated with NP (AUC 0.79). Findings were robust in prespecified sensitivity analyses. Admission cytokines and early rises, especially IL-6 and IP-10, enable pragmatic early risk stratification for consolidation, with ΔIL-6 also signaling NP risk in the CT-scanned subset. These results support external validation of a cytokine-based tool to inform imaging and triage.
This study explores the impact of different immunoparesis states on early infection risk within 6 months of diagnosis in patients with newly diagnosed multiple myeloma (NDMM), aiming to inform clinical infection prevention strategies. A retrospective analysis was conducted on 213 NDMM patients (2016-2024). Immunoparesis was classified qualitatively (no, partial, and full immunoparesis) and quantitatively (with immunoglobulin reduction < 50% and ≥ 50%). Early infection rates and immunoparesis status were assessed using Kaplan-Meier survival curves. Cox regression models were applied to evaluate the independent prognostic effect of immunoparesis on infection risk. Immunoparesis significantly increased the risk of early infections. In the qualitative analysis, infection rates were 15.8% for no immunoparesis, 53.1% for partial, and 53.8% for full immunoparesis (Log-rank P = 0.017). In the quantitative analysis, infection rates were 51.9% for < 50% immunosuppression and 54.2% for ≥ 50% immunosuppression, compared to 15.8% for no immunoparesis (Log-rank P = 0.017). Cox regression analysis showed that partial and full immunoparesis increased the risk of infection by 8.9-fold (HR = 8.9, P = 0.004) and 7.8-fold (HR = 7.8, P = 0.006), respectively. Similarly, < 50% and ≥ 50% immunosuppression increased infection risk by 8.67-fold (HR = 8.67, P = 0.005) and 7.95-fold (HR = 7.95, P = 0.005), respectively. Immunoparesis significantly increases early infection risk in NDMM patients. However, no significant risk gradient was observed relative to the breadth or depth of immunoparesis within this cohort. Monitoring and timely intervention for immunoparesis are essential for infection prevention.
The gut microbiota, a vast community of symbiotic microorganisms inhabiting our gut, has been recognized as a key-lever for human health, shaping immune system resilience and being essential for immunological homeostasis throughout the life course. Gut microbiota composition may influence both initiation and/or perpetuation of intestinal inflammation, but recent research has highlighted its contribution to both rising and progression of protean non-intestinal inflammatory diseases: indeed, a perturbation of host-associated microbiota during critical developmental stages like early childhood can directly condition many cellular dynamics and impact long-term health. This narrative review explores the interactions among gut microbiota, physiologic healthy equilibrium, dysbiosis, and immune-mediated non-intestinal inflammatory diseases occurring in childhood, such as inflammasome-based disorders, juvenile idiopathic arthritis, Kawasaki disease, and IgA vasculitis, focusing on how microbial changes may alter disease outcomes and suggesting potentially novel therapeutic approaches. Additionally, this review examines the evolution of immune recognition mechanisms and their role in maintaining the gut microbiota-host mutualism as a result of millennia of human co-evolution with the microbial counterpart.
Refractory and severe evolution complicate pediatric Mycoplasma pneumoniae pneumonia (MPP), yet early risk stratification still relies largely on single-time admission biomarkers. We tested whether a prespecified 48-hour pre-admission fever-burden index (FBI48) predicts in-hospital outcomes and improves model performance beyond guideline-consistent clinical and laboratory predictors. We conducted a retrospective single-center cohort study of hospitalized children ≤14 years with laboratory-confirmed MPP. FBI48 was defined as the area under the temperature-time curve above 38.0 °C over -48 to 0 h (°C·h). Thresholds of 38.5 °C and 39.0 °C were evaluated in sensitivity analyses. Prespecified covariates, chosen based on prior RMPP/SMPP studies and pediatric CAP/MPP guidelines, included age, illness days, SpO2, imaging severity, prior macrolide exposure, antipyretic and steroid use, LDH, log2-transformed NLR, CRP, and PCT. Penalized logistic regression generated predicted risks, while unpenalized models provided adjusted odds ratios. Model performance (AUC, Brier score, calibration) and decision-curve analysis (DCA) net benefit were assessed for base (clinical + laboratory) and augmented (base + FBI48) models across 10-30% risk thresholds. Of 720 eligible hospitalizations, 648 were analyzed. The composite endpoint (RMPP and/or incident SMPP) occurred in 176/648 (27.2%; RMPP 24.7%; SMPP 8.0%). FBI48 was independently associated with the composite endpoint (adjusted odds ratio [aOR] 1.45, 95% CI 1.25-1.68 per 1 SD ≈22 °C·h) and with SMPP alone (aOR 1.58, 95% CI 1.21-2.06). Adding FBI48 to the base model improved AUC from 0.78 to 0.83 (ΔAUC 0.05, p<0.001), reduced the Brier score (0.176 to 0.164, p=0.006), and increased net benefit compared with the base model and a treat-none strategy across 10-30% thresholds. Alternative fever thresholds (38.5 °C/39.0 °C) yielded similar effect sizes. A simple 48-hour pre-admission fever-burden metric provides independent and incremental prognostic information on the risk of refractory or severe evolution in pediatric MPP, complementing guideline-based clinical and laboratory predictors and supporting admission-time risk stratification. External validation and prospective evaluation of dynamic, in-hospital updating are warranted.
In non-dialysis chronic kidney disease (ND-CKD), anemia, frailty, and cardiovascular (CV) complications intersect, yet the prognostic relevance of within-patient hemoglobin (Hb) change over time remains unclear. We tested whether distinct 12-month Hb trajectory patterns are associated with frailty worsening and CV events. Adults with stage 3-5 ND-CKD and renal anemia (men <13 g/dL; women <12 g/dL) were enrolled at a single center (June-December 2023) and followed monthly for 12 months. Hb was measured monthly. Latent-class mixed models were used to derive stable, declining, and fluctuating Hb trajectories from all available Hb measurements during follow-up. Frailty was assessed at baseline, 6 months, and 12 months. Frailty worsening was prespecified as a ≥1-point increase in the FRAIL score or new onset of weak grip or slow gait. Associations were evaluated using mixed-effects logistic regression (frailty worsening) and cause-specific Cox models (time-to-first composite CV event), adjusting for key clinical covariates. Follow-up at 12 months was available for 182 of 190 (95.8%) participants. Trajectory allocation was 39% stable, 41% declining (mean slope -0.18 g/dL/month), and 20% fluctuating (higher within-person variability). Frailty worsened in 57% of participants who declined, 45% of participants who fluctuated, and 25% of participants who remained stable. Adjusted odds ratios versus Stable were 2.8 (95% CI 1.6-5.0) for Declining and 1.9 (0.9-4.0) for Fluctuating. Over 185 person-years, 46 composite CV events occurred (24.9/100 person-years), and adjusted hazard ratios were 2.6 (1.4-4.9) for Declining and 1.7 (0.8-3.6) for Fluctuating. A declining 12-month hemoglobin trajectory was associated with increased risk of frailty worsening and cardiovascular events compared with a stable profile.
Sepsis-induced cardiomyopathy (SICM) is a common and serious complication of sepsis, and early identification remains challenging. Inflammatory and immune markers may provide complementary information to myocardial injury biomarkers. A total of 319 adult patients with a first diagnosis of sepsis between June 2022 and January 2025 were enrolled. Complete blood counts and high-sensitivity cardiac troponin T (hs-cTnT) were collected within 0-6 hours after diagnosis. SICM was determined based on clinical and imaging data. Peripheral blood inflammatory indices (PBIIs), including NLR, SII, SIRI, PLR, and PIV, were calculated from blood counts. Variable robustness was assessed using LASSO logistic regression combined with bootstrap resampling. Univariate and multivariate logistic regression analyses were then performed to construct predictive models, and model performance was evaluated using ROC curves, calibration curves, and decision curve analysis. Among 319 patients with sepsis, 115 (36.1%) developed SICM. Compared with the non-SICM group, patients with SICM had significantly higher hs-cTnT levels, indicating more severe myocardial injury. Peripheral inflammatory indices were also higher overall, with the largest between-group differences observed for SII and NLR. SIRI and PLR were also elevated, whereas PIV showed a smaller difference (all P<0.05). The baseline model including hs-cTnT achieved an AUC of 0.825; adding SII or NLR further improved discrimination, with AUCs of 0.856 and 0.860, respectively. Calibration and decision curve analyses showed consistent model performance. SII and NLR, as readily available peripheral inflammatory markers, were associated with improved early prediction of SICM when combined with hs-cTnT. This combined strategy may help refine early risk stratification in patients with sepsis.
An increased serum ferritin is a frequent finding in adults with β-thalassemia trait (BTT). However, whether such an increase is associated with a proportional increase in iron stores is unclear. We aimed to evaluate liver iron stores in a consecutive cohort of BTT with hyperferritinemia who underwent magnetic resonance imaging (LICMRI) for clinical purposes. Sixty-six BTT subjects with hyperferritinemia were studied. Clinical, biochemical, and genetic evaluations were done to assess the cause of hyperferritinemia. LICMRI was classified as: grade-1= ≤3 mg/g (normal/mild); grade-2= >3≤7 mg/g (moderate); grade-3= >7 (severe). 80.3% showed normal/mild (n=29, 43.9%) or moderate LICMRI (n=24, 36.4%), while 19.7% (n=13) showed values >7 mg/g. The latter had lower haemoglobin concentration (p=0.004) and higher transferrin saturation and ferritin compared to subjects with lower LICMRI (p<0.001), while steatotic liver disease was more frequent in subjects with lower LICMRI grades (p=0.012). Liver cirrhosis was significantly more frequent in subjects with moderate/severe than in those with lower LICMRI grades (p=0.001 and p=0.025, respectively). We found a higher frequency of HFE and non-HFE iron-related genotypes (risk genotypes) in LICMRI grades 2-3 compared to none in LICMRI grade 1 (p=0.003 and p<0.0001, respectively). A regression analysis identified risk genotypes, liver cirrhosis, and BMI as significantly associated with LICMRI. Hyperferritinemia is common in BTT subjects, but major iron overload is limited to a minority of cases. They present associated genetic and acquired causes of iron accumulation and increased risk of liver damage.
Febrile neutropenia (FN) remains a frequent and potentially life-threatening complication in pediatric oncology, where prompt recognition of bacteremia is critical for risk-adapted therapy and antimicrobial stewardship. Traditional biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) are widely used, yet their early predictive value is inconsistent across studies. Cellular activation markers measured by flow cytometry, particularly CD48, have been scarcely investigated in this setting. This study aimed to evaluate conventional, metabolic, and immune biomarkers for predicting bacteremia in children with FN and to assess the incremental diagnostic value of CD48. This prospective single-center cohort enrolled 38 pediatric oncology patients presenting with 46 FN episodes over 9 months. Clinical data, blood cultures, and serial measurements of CRP, PCT, lactate, interleukin-6, interleukin-8, MCP-1, sTREM-1, CD48, and CD64 were obtained at 0, 24, 48, and 72 hours. Bacteremia was defined by positive culture for a recognized pathogen. Receiver operating characteristic (ROC) analyses were performed to determine the area under the curve (AUC), sensitivity, and specificity. A multivariable logistic regression model evaluated the combined performance of biomarkers. Bacteremia occurred in 12 (26.1%) FN episodes. Sepsis, tachycardia, and elevated lactate were more common among bacteremic patients. CRP showed limited early discrimination (AUC 0.62 on day 2) but improved by day 4 (AUC 0.74). PCT was consistently higher in bacteremia (AUC 0.89 at day 4), and lactate demonstrated strong early predictive value (AUC 0.81). CD48 was significantly elevated from 0-24 h (AUC 0.78), outperforming CD64 (AUC 0.60) and preceding the rise in CRP. In combined modeling, PCT + CD48 + lactate achieved the highest discrimination (AUC 0.92; sensitivity 92%, specificity 85%). Post-hoc power analysis showed 82% power to detect AUC differences ≥0.15. Integration of CD4 with PCT and Lactate markedly improved diagnostic accuracy in this cohort; however, given the limited number of bacteremic episodes, these findings should be considered exploratory and require external validation in larger, multicenter studies before clinical implementation.
Relapse remains the principal cause of treatment failure after allogeneic hematopoietic stem cell transplantation (AHSCT) in acute leukemia. Post-transplant surveillance commonly relies on measurable residual disease (MRD) and donor chimerism monitoring; however, their relative predictive value and optimal timing remain uncertain. To compare the prognostic performance of MRD and donor chimerism in predicting relapse after AHSCT in adult patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). This retrospective cohort included 264 adults (186 AML, 78 ALL) who underwent AHSCT. MRD was assessed by multiparametric flow cytometry on day 28 and at months 3 and 12, and chimerism by short tandem repeat PCR. Cox regression identified independent relapse predictors. Relapse occurred in 95 patients (68 AML, 27 ALL). In AML, MRD positivity at month 3 (HR 3.69, p<0.001) and mixed total chimerism at month 3 (HR 2.47, p=0.029) independently predicted relapse and were associated with inferior overall and disease-free survival. MRD detected relapse earlier and with greater sensitivity than chimerism. In ALL, total mixed chimerism at month 3 was associated with relapse in univariate analysis, whereas MRD showed limited statistical power due to small sample size. Post-transplant MRD monitoring at month 3 provides superior risk stratification compared with chimerism in AML. In ALL, both approaches appear complementary, but conclusions are limited by cohort size. Disease-specific, risk-adapted surveillance strategies are warranted.
Reactivating fetal hemoglobin (HbF) has become a key therapeutic strategy for β-hemoglobinopathies. However, the regulatory networks controlling HbF are complex and have only recently been uncovered. This review integrates current knowledge of the genetic and epigenetic factors that influence HbF expression, including BCL11A, HBS1L-MYB, KLF1, and variants associated with HPFH, and shows how these pathways work together to regulate γ-globin levels. It also highlights recent advances in HbF-targeted treatments, including gene-editing technologies such as CRISPR-Cas9-based BCL11A enhancer disruption, promoter editing to mimic hereditary persistence of fetal hemoglobin (HPFH), and advanced tools like base and prime editing. By combining mechanistic understanding with therapeutic development, this review highlights how improvements in HbF regulation have transformed efforts to find cures for sickle cell disease and β-thalassemia, while also revealing new opportunities for targeted HbF induction across different patient groups.
In the ICU, distinguishing immune-mediated thrombotic thrombocytopenic purpura (iTTP) from sepsis-associated thrombotic microangiopathy (TMA) is time-critical. We tested whether serial ADAMTS-13 combined with targeted coagulation and inflammation markers improves iTTP risk stratification in a Sepsis-3 ICU cohort and whether a pragmatic rule-out is feasible. Prospective single-center study of adults meeting Sepsis-3 with thrombocytopenia and schistocytes ≥ 1% or LDH > 2× ULN within 24 h of ICU admission. ADAMTS-13 activity and VWF: Ag were assayed at 0/24/48/72 h alongside a thrombo-inflammatory panel. We derived a Dynamic ADAMTS-13 Index (DAI), a Coagulation Consumption Index (CCI) anchored to ISTH DIC and fibrinogen/antithrombin III, and an Inflammation Index (IL-6/HBP). The prespecified main rule-out required a ≥ 15% ADAMTS-13 rise by 48 h plus low CCI. A prespecified RCV-anchored sensitivity analysis required ≥ 35% relative rise or ≥ 10 absolute % points plus low consumption. For decision-making, pre-treatment (pre-plasma exchange, PEx) analyses are emphasized. Intent-to-diagnose (care-embedded) analyses are exploratory, and internal validation used a bootstrap optimism correction. Of 1,274 screened, 330 were included (iTTP = 34). Discrimination improved from baseline ADAMTS-13 (AUROC 0.78) to DAI (0.93), with smaller gains after adding CCI (0.95) and the Inflammation Index (0.96). With the main rule-out (≥ 15% + low CCI) in the intent-to-diagnose analysis, sensitivity was 97.1%, specificity was 86.1%, and NPV was 99.6%. The RCV-anchored sensitivity analysis preserved 100.0% sensitivity and NPV with 76.0% specificity. A 72-h phenotype (ADAMTS-13 < 10% with high IL-6/HBP) was associated with higher 28-day mortality (adjusted HR 2.6). In Sepsis-3 ICU patients with TMA features, serial ADAMTS-13 testing, along with targeted coagulation/inflammation markers, enhances early iTTP risk stratification and supports a pragmatic rule-out framework. External validation and implementation studies remain essential. These findings also support investment in rapid/automated ADAMTS-13 activity assays and decision-support workflows to enable timely adoption beyond tertiary centers.
The therapeutic landscape of hematological malignancies has expanded rapidly, increasing survival but also exposing patients to pharmacokinetic variability and clinically relevant drug-drug interactions. Therapeutic drug monitoring (TDM) offers a pharmacokinetics-informed strategy to individualize dosing, yet its real-world implementation across drug classes and healthcare settings remains insufficiently characterized. We conducted an international, cross-sectional online survey (December 2023-February 2024) assessing availability, utilization, and clinical impact of TDM in patients with hematological malignancies. Physicians from multiple specialties reported institutional practices, turnaround times, drug-specific monitoring strategies, and treatment modifications based on TDM results. A total of 209 physicians from 32 countries participated, predominantly from Europe (92%). TDM was widely accessible (97%), mainly performed onsite (79%), and perceived as beneficial by nearly all respondents (99%). Routine TDM was most frequently used for classical agents (methotrexate, cyclosporin A), antifungals, and antibiotics, but substantial interest was reported for targeted therapies, including BCL-2 inhibitors, BCR-ABL tyrosine kinase inhibitors, FLT3 inhibitors, and Bruton tyrosine kinase inhibitors. Treatment was modified based on TDM results by 71% of respondents, with faster turnaround times strongly associated with clinical action. Limited assay availability, delayed reporting, and insufficient clinical evidence were identified as key barriers to broader implementation. TDM is widely available and perceived as clinically useful in the management of hematological malignancies, frequently informing treatment decisions. While firmly established for classical agents and anti-infectives, clinicians express growing interest in extending TDM to targeted therapies. Optimizing turnaround times, expanding assay availability, and integrating pharmacokinetics-informed dosing into clinical trials may further clarify the role of TDM within precision medicine approaches in hematology.
Scrub typhus is a leading cause of febrile illness across the Asia-Pacific region. Doxycycline is the first-line therapy, with azithromycin as an alternative; sequential treatment (doxycycline followed by azithromycin) is used for nonresponders. However, comparative real-world effectiveness for sequential therapy remains uncertain. We conducted a single-center, non-interventional target-trial emulation at the 970th Hospital of the People's Liberation Army (January 2023 - June 2025). Consecutive patients ≥12 years receiving oral doxycycline, azithromycin, or sequential doxycycline/azithromycin treatment were included. The primary outcome was 48-hour defervescence sustained ≥24 h without antipyretics. Secondary outcomes were time to defervescence, Day 5 failure, complications, length of stay, 28-day mortality, and safety. Confounding was addressed using inverse probability weighting (generalized boosted models). The confirmatory comparison (doxycycline vs azithromycin) was limited to non-pregnant initiators (pregnancy excluded due to structural non-overlap) to satisfy positivity. The sequential pathway was explored descriptively with time-varying and 48-hour landmark analyses. We analyzed 512 patients (doxycycline 206, azithromycin 208, and sequential 98). Crude 48-hour defervescence was 82.0%, 78.8%, and 66.3%, respectively. In the confirmatory inverse probability of treatment weighting (IPTW) analysis, doxycycline vs azithromycin showed no difference (adjusted RR 1.03, 95% CI 0.95-1.12; p=0.34). Weighted time-to-event analysis was concordant (aHR 1.08, 95% CI 0.96-1.21; p=0.20). Secondary outcomes were similar between monotherapies (Day-5 failure aRR 0.83, 95% CI 0.56-1.24; complications aRR 0.94, 95% CI 0.66- 1.33; median length of stay 5 [IQR 4-7] days in both; 28-day mortality 1.6% overall). The sequential switch group had lower crude 48-hour defervescence, consistent with escalation after early non-response. Pairwise causal contrasts involving the sequential pathway were not presented due to structural bias. Oral doxycycline and azithromycin demonstrated comparable effectiveness and safety for early defervescence in routine care. Inferior crude outcomes with sequential therapy likely reflect clinical escalation. Multi-center validation and randomized trials are warranted.