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Giorgio Costagliola,1 Emanuela De Marco,1 Francesco Massei,1 Giulia Roberti,2 Fabrizio Catena,1 Gabriella Casazza,1 Rita Consolini3 1Section of Pediatric Hematology and Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, 56126, Italy; 2Pediatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, 56126, Italy; 3Section of Clinical and Laboratory Immunology, Pediatric Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, 56126, ItalyCorrespondence: Giorgio Costagliola, Section of Pediatric Hematology and Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, 56126, Italy, Tel +39-050992841, Email giorgio.costagliola@hotmail.com; giorgio.costagliola@ao-pisa.toscana.itAbstract: Lymphoproliferation is defined by lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytic organ and tissue infiltration. The most common etiologies of lymphoproliferation are represented by infectious diseases and lymphoid malignancies. However, it is increasingly recognized that lymphoproliferative features can be the presenting sign of rare conditions, including inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Among IEI, lymphoproliferation is frequently observed in autoimmune lymphoproliferative syndrome (ALPS) and related disorders, common variable immunodeficiency (CVID), activated phosphoinositide 3-kinase δ syndrome, and Epstein-Barr virus (EBV)-related disorders. Gaucher disease and Niemann-Pick disease are the most common IEMs that can present with isolated lymphoproliferative features. Notably, other rare conditions, such as sarcoidosis, Castleman disease, systemic autoimmune diseases, and autoinflammatory disorders, should be considered in the differential diagnosis of patients with persistent lymphoproliferation when infectious and malignant diseases have been reasonably ruled out. The clinical features of lymphoproliferative diseases, as well as the associated clinical findings and data deriving from imaging and first-level laboratory investigations, could significantly help in providing the correct diagnostic suspicion for the underlying etiology. This paper reviews the most relevant diseases associated with lymphoproliferation, including infectious diseases, hematological malignancies, IEI, and IEM. Moreover, some practical indications to orient the initial diagnostic process are provided, and two diagnostic algorithms are proposed for the first-level assessment and the approach to persistent lymphoproliferation, respectively.Keywords: lymphadenopathy, splenomegaly, Hodgkin lymphoma, common variable immunodeficiency, autoimmune lymphoproliferative syndrome, gaucher disease

Unlabelled: The recently improved diagnostics have widened, in children, the spectrum of clinical manifestations recognisable as Bartonella henselae infection. We report here the clinical features of 20 (14 males) consecutive children with serologically proved B. henselae infection observed within 12 months in the Paediatric Department of the University of Pisa. The patients had a mean age of 7 years 4 months (range 1.1-14.1 years). All children but one had a history of contact with kittens. Clinical manifestations included regional lymphadenopathy in 14 patients, representing in five the only clinical manifestation at onset, infectious mononucleosis-like syndrome in six, erythema nodosum in three, and Parinaud oculoglandular syndrome in one. In five patients a severe disorder was first suspected: fever of unknown origin in two with multiple hepatosplenic granulomatosis in one; osteolytic lesion suggesting bone neoplasm, marked inguinal lymph-node enlargement, suggesting Burkitt lymphoma, and an acute encephalopathy in one each. Bartonella henselae IgG antibody was positive in all patients with a titre ranging from 1:128 to 1:8590. IgM antibody was present in all except one child with an IgG titre of 1:2048. All patients recovered, some spontaneously.Conclusion: Bartonella henselae infection is frequent in Tuscany and probably underdiagnosed due to the high frequency of atypical onset of the clinical manifestations. An accurate clinical history and a reasonably wide use of the serological test may allow a rapid and accurate diagnosis, reassuring the family of the patient and avoiding invasive and expensive diagnostic procedures. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this cross-sectional study was to investigate the association of left atrial (LA) strain parameters with demographics, clinical data, cardiovascular magnetic resonance (CMR) findings, and cardiac complications (heart failure and arrhythmias) in a cohort of patients with β-thalassemia major (β-TM)., Materials and Methods: We considered 264 β-TM patients (133 females, 36.79 ± 11.95 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. Moreover, we included 35 sex- and age-matched healthy controls (14 females, mean age 37.36 ± 17.52 years). Reservoir, conduit, and booster LA functions were analysed by CMR feature tracking using dedicated software., Results: Compared to the healthy control group, β-TM patients demonstrated lower LA reservoir strain and booster strains, as well as LA reservoir and booster strain rates. However, no differences were found in LA conduit deformation parameters. In β-TM patients, ageing, sex, and left ventricle (LV) volume indexes were independent determinants of LA strain parameters. The number of segments with late gadolinium enhancement (LGE) significantly correlated with all LA strain parameters, with the exception of the LA conduit rate. Patients with cardiac complications exhibited significantly impaired strain parameters compared to patients without cardiac complications., Conclusion: In patients with β-TM, LA strain parameters were impaired compared to control subjects, and they exhibited a significant correlation with the number of LV segments with LGE. Furthermore, patients with cardiac complications had impaired left atrial strain parameters. Clinical relevance statement In patients with β-thalassemia major, left atrial strain parameters were impaired compared to control subjects and emerged as a sensitive marker of cardiac complications, stronger than cardiac iron levels., Key Points: • Compared to healthy subjects, β-thalassemia major patients demonstrated significantly lower left atrial reservoir strain and booster strains, as well as left atrial reservoir and booster strain rates. • In β-thalassemia major, ageing, sex, and left ventricular volume indexes were independent determinants of left atrial strain parameters, while left atrial strain parameters were not correlated with myocardial iron overload. • An independent association between reduced left atrial strain parameters and a history of cardiac complications was found in β-thalassemia major patients., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

We evaluated the association of vitamin D and parathormone (PTH) levels with cardiac iron and function in beta-thalassemia major (β-TM) patients. Two-hundred and seventy-eight TM patients (39.04 ± 8.58 years, 56.8% females) underwent magnetic resonance imaging for the assessment of iron overload (T2* technique), biventricular function parameters (cine images), and replacement myocardial fibrosis (late gadolinium enhancement technique). Vitamin D levels were deficient (<20 ng/dL) in 107 (38.5%) patients, insufficient (20-30 ng/dL) in 96 (34.5%) patients, and sufficient (≥30 ng/dL) in 75 (27.0%) patients. Deficient vitamin D patients had a significantly higher frequency of myocardial iron overload (MIO; global heart T2* < 20 ms) than patients with sufficient and insufficient vitamin D levels and a significantly higher left ventricular end-diastolic volume index and mass index than patients with sufficient vitamin D levels. PTH was not associated with cardiac iron, function, or fibrosis. In the multivariate regression analysis, vitamin D, serum ferritin, and pancreatic iron levels were the strongest predictors of global heart T2* values. In receiver operating characteristic curve analysis, a vitamin D level ≤ 17.3 ng/dL predicted MIO with a sensitivity of 81.5% and a specificity of 75.3% ( p < 0.0001). In TM, the periodic and regular assessment of vitamin D levels can be beneficial for the prevention of cardiac iron accumulation and subsequent overt dysfunction., Competing Interests: The authors declare no conflict of interest.

We evaluated pattern and clinical correlates of renal T2* measurements in adult β-thalassemia major (β-TM) patients. Ninety β-TM patients (48 females, 38.15 ± 7.94 years), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network, underwent T2* magnetic resonance imaging (MRI) for quantification of iron overload (IO) in kidneys, liver, pancreas, and heart. Ten (11.1%) patients showed renal IO (T2* < 31 ms). Global kidney T2* values did not show a correlation with gender, age, splenectomy, regular transfusions or chelation starting age, pre-transfusion hemoglobin, and serum ferritin levels. Global kidney T2* values showed an inverse correlation with MRI liver iron concentration (LIC) values (R = - 0.349; p = 0.001) and a positive correlation with global pancreas T2* values (R = 0.212; p = 0.045). Frequency of renal IO was significantly higher in patients with cardiac IO than in patients without cardiac IO (50.0% vs. 6.3%; p = 0.001). A significant inverse association was detected between global kidneys T2* values and lactate dehydrogenase (LDH) (R = - 0.529; p < 0.0001). In multivariate regression analysis, MRI LIC and LDH were the strongest predictors of global kidney T2* values. A MRI LIC > 4.83 mg/g dw predicted the presence of renal IO (sensitivity = 90.0%; specificity = 61.2%). Global kidney T2* values were inversely correlated with uric acid (R = - 0.269; p = 0.025). In conclusion, in adult β-TM patients, renal iron deposition is not common and is linked to both hemolysis and total body iron overload., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: We measured myocardial T2 values by a segmental approach in thalassaemia major (TM) patients, comparing such values against T2* values for the detection of myocardial iron overload (MIO), evaluating their potential in detecting subclinical inflammation, and correlating with clinical status., Methods and Results: One-hundred and sixty-six patients (102 females, 38.29 ± 11.49years) enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network underwent magnetic resonance imaging for the assessment of hepatic, pancreatic, and cardiac iron overload (T2* technique), of biventricular function (cine images), and of replacement myocardial fibrosis [late gadolinium enhancement (LGE)]. T2 and T2* values were quantified in all 16 myocardial segments, and the global value was the mean of all segments. Global heart T2 values were significantly higher in TM than in a cohort of 80 healthy subjects. T2 and T2* values were significantly correlated. Out of the 25 patients with a decreased global heart T2* value, 11 (44.0%) had reduced T2 values. No patient with a normal T2* value had a decreased T2 value.Eleven (6.6%) patients had a decreased global heart T2 value, 74 (44.6%) a normal global heart T2 value, and 81 (48.8%) an increased global heart T2 value. Biventricular function was comparable amongst the three groups, whilst LGE was significantly more frequent in patients with reduced vs. increased global heart T2 value. Compared with the other two groups, patients with reduced T2 values had significantly higher hepatic and pancreatic iron deposition., Conclusion: In TM, T2 mapping does not offer any advantage in terms of sensitivity for MIO assessment but detects subclinical myocardial inflammation., Competing Interests: Conflict of interest: AP received speakers’ honoraria from Chiesi Farmaceutici S.p.A. The remaining authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We evaluated the feasibility and reproducibility of bone marrow T2* values and established the lower limit of normal in a cohort of healthy subjects. We investigated the clinical correlates of bone marrow T2* values in patients with thalassemia major (TM)., Material and Methods: Thirty healthy subjects and 274 consecutive TM patients (38.96 ± 8.49 years, 151 females) underwent MRI at 1.5T. An axial slice in the upper abdomen was acquired by a T2* gradient-echo multiecho sequence and the T2* value was calculated in a circular region of interest defined in the visible body of the first or second lumbar vertebra. In patients, also liver and heart T2* values were assessed., Results: In healthy subjects bone marrow T2* values were independent of age and gender. The lower limit of normal for bone marrow T2* was 13 ms. In both healthy subjects and 30 randomly selected patients, the coefficient of variation for inter-operator-reproducibility was < 10%. TM patients exhibited significantly lower bone marrow T2* values than healthy subjects (7.47 ± 5.18 ms vs. 17.08 ± 1.89 ms; p < 0.0001). A pathological bone marrow T2* was detected in 82.8% of TM patients. In TM, the female sex was associated with reduced bone marrow T2* values. Bone marrow T2* values were inversely correlated with mean serum ferritin levels (R = -0.431; P < 0.0001) and hepatic iron load (R = - 0.215; P < 0.0001). A serum ferritin level > 536 ng/ml predicted the presence of a pathological bone marrow T2*. A positive correlation was found between bone marrow and heart T2* values (R = 0.143; P = 0.018). A normal bone marrow T2* showed a negative predictive value of 100% for cardiac iron., Conclusion: Bone marrow T2* measurements can be easily obtained using the same sequences acquired for liver iron quantification and may bring new insights into the pathophysiology of iron deposition; hence, they should be incorporated into clinical practice., (© 2022. Italian Society of Medical Radiology.)