Publications by authors named "Antonio Marzollo"

31 Publications

IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.

Hum Genet 2021 Jun 29. Epub 2021 Jun 29.

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
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http://dx.doi.org/10.1007/s00439-021-02300-4DOI Listing
June 2021

Neonatal-Onset Familial Mediterranean Fever in an Infant with Human Parainfluenza Virus-4 Infection.

Neonatology 2021 31;118(3):359-363. Epub 2021 Mar 31.

Maternal and Child Health Department, Padua University, Padua, Italy.

Unusual, severe infections or inflammatory episodes in newborns and infants are largely unexplained and often attributed to immature immune responses. Inborn errors of immunity (IEI) are increasingly recognized as the etiology of life-threatening inflammatory and infectious diseases in infancy. We describe a patient with a unique neonatal-onset Familial Mediterranean Fever (FMF) due to compound heterozygous variants in MEFV, presenting as pleuritis following human parainfluenza virus-4 infection. Diagnostic challenges of FMF in infancy include the interpretation of the attacks as infectious episodes. Newborns and infants with acute, recurrent, or chronic, unusually severe infectious or inflammatory conditions should be screened for IEI, including both disorders with defective immunological responses and autoinflammatory disorders.
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http://dx.doi.org/10.1159/000514694DOI Listing
March 2021

Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease.

Sci Rep 2021 Mar 15;11(1):5945. Epub 2021 Mar 15.

SickKids Inflammatory Bowel Disease Centre, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.
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http://dx.doi.org/10.1038/s41598-021-85399-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960730PMC
March 2021

Fatigue perception in a cohort of children with chronic immune thrombocytopenia and their caregivers using the PedsQL MFS: Real-life multicenter experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP).

Pediatr Blood Cancer 2021 03 4;68(3):e28840. Epub 2020 Dec 4.

Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari "Aldo Moro", Bari, Italy.

Background: Fatigue is an important clinical and psychological aspect for a significant number of children affected by immune thrombocytopenia (ITP). To date, few studies have explored fatigue and its relationship with chronic ITP in pediatric age. The aim of the present multicentric pilot study is to determine fatigue perception in a large group of children with chronic ITP and their caregivers using the PedsQL Multidimensional Fatigue Scale (PedsQL MFS), and to compare the results with those of healthy control subjects.

Procedure: Children with chronic ITP aged 5-18 years and/or caregivers of children aged 2-18 years were enrolled. Child/adolescent self-report was used for patients aged 5-18 years, and parent proxy-report for patients aged 2-18 years. The questionnaire was offered as online survey. PedsQL MFS is composed of 18 items covering three dimensions: General Fatigue Scale, Sleep/Rest Fatigue Scale, and Cognitive Fatigue Scale.

Results: One hundred ninety-one patients affected by chronic ITP and 248 caregivers answered the PedsQL MFS. We have highlighted that lower values of PedsQL MFS scores are obtained in the 13-18 age group. Moreover, sleep/rest fatigue domain appears to be more compromised in all age groups. For all PedsQL MFS scores, pediatric patients with chronic ITP and their caregivers reported statistically significant worse fatigue than healthy children.

Conclusions: This study suggests that fatigue is relevant among children and adolescents affected by chronic ITP. The PedsQL MFS represents an adequate instrument for measuring fatigue in patients with chronic ITP. Therefore, symptoms of fatigue should be routinely assessed in clinical practice.
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http://dx.doi.org/10.1002/pbc.28840DOI Listing
March 2021

Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.

Int J Mol Sci 2020 Nov 15;21(22). Epub 2020 Nov 15.

"Lalla Seràgnoli", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in . A phenotype-genotype correlation has been attempted and variable expressivity of biallelic variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.
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http://dx.doi.org/10.3390/ijms21228604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696905PMC
November 2020

A mixed-methods study of the disease experience in hematopoietic stem cell transplantation survivors: the contribution of text analysis.

J Psychosoc Oncol 2020 Nov-Dec;38(6):728-745. Epub 2020 Sep 10.

Haematology-Oncology Division, Department of Woman's and Child's Health, University Hospital of Padua, Padua, Italy.

Objectives: Few studies have detected qualitative and quantitative aspects of patients who underwent HSCT during childhood. The aims of this study are to explore the most recurrent narrative themes of HSCT experience in families five years after the procedure, and to observe statistical correlations between meaning attributed to the experience and defined variables.

Methods: Thirty-five families of pediatric HSCT survivors participated in the research. Both survivors and their families were asked to write a brief composition about their disease experiences. Qualitative analysis of the texts was performed using the T-LAB software. Information about medical aspects and psychological problems in HSCT survivors were collected with interviews and administering the Child Behavior Checklist 6-18.

Results: HSCT survivor families that reported the presence of externalizing and internalizing symptoms focused on thematic areas concerning broken families with separation between parents and the affected child versus healthy children.

Conclusions: Long term psychological problems seem to be connected to the perception of family disruption. Specifically, family relationships seem to be the factor that protects from or enhances the risk of psychopathology in HSCT survivors. Moreover, the use of metaphoric terms to refer to HSCT presents higher associations with psychopathology. On the contrary, the possibility of referring directly to the transplantation is associated with psychological well-being. It is important to consider the family as a group in order to improve care.
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http://dx.doi.org/10.1080/07347332.2020.1814932DOI Listing
June 2021

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity.

J Allergy Clin Immunol 2020 11 19;146(5):967-983. Epub 2020 Aug 19.

Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Childrens' Hospital, Sapienza, University of Rome, Rome Italy.

Medical advances have dramatically improved the long-term prognosis of children and adolescents with inborn errors of immunity (IEIs). Transfer of the medical care of individuals with pediatric IEIs to adult facilities is also a complex task because of the large number of distinct disorders, which requires involvement of patients and both pediatric and adult care providers. To date, there is no consensus on the optimal pathway of the transitional care process and no specific data are available in the literature regarding patients with IEIs. We aimed to develop a consensus statement on the transition process to adult health care services for patients with IEIs. Physicians from major Italian Primary Immunodeficiency Network centers formulated and answered questions after examining the currently published literature on the transition from childhood to adulthood. The authors voted on each recommendation. The most frequent IEIs sharing common main clinical problems requiring full attention during the transitional phase were categorized into different groups of clinically related disorders. For each group of clinically related disorders, physicians from major Italian Primary Immunodeficiency Network institutions focused on selected clinical issues representing the clinical hallmark during early adulthood.
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http://dx.doi.org/10.1016/j.jaci.2020.08.010DOI Listing
November 2020

Prevalence of Immunological Defects in a Cohort of 97 Rubinstein-Taybi Syndrome Patients.

J Clin Immunol 2020 08 27;40(6):851-860. Epub 2020 Jun 27.

Departamento de Nefrología, Hospital Universitario de Santiago, Santiago de Compostela, Spain.

Although recurrent infections in Rubinstein-Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. Graphical Abstract.
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http://dx.doi.org/10.1007/s10875-020-00808-4DOI Listing
August 2020

The combined use of enzyme activity and metabolite assays as a strategy for newborn screening of mucopolysaccharidosis type I.

Clin Chem Lab Med 2020 11;58(12):2063-2072

Division of Inherited Metabolic Diseases, Regional Center for Expanded Neonatal Screening Department of Women and Children's Health, University Hospital of Padova, Via Orus 2/B, 35129 Padova, Italy.

Objectives Mucopolysaccharidosis type I (MPS I) was added to our expanded screening panel in 2015. Since then, 127,869 newborns were screened by measuring α-L-iduronidase (IDUA) enzyme activity with liquid chromatography tandem mass spectrometry (LC-MS/MS). High false positives due to frequent pseudodeficiency alleles prompted us to develop a second-tier test to quantify glycosaminoglycan (GAG) levels in dried blood spot (DBS). Methods Heparan-sulfate (HS) and dermatan-sulfate (DS) were measured with LC-MS/MS after methanolysis. DBSs were incubated with methanolic-HCl 3 N at 65 °C for 45 min. Chromatographic separation used an amide column with a gradient of acetonitrile and water with 10 mM ammonium acetate in a 9-min run. The method was validated for specificity, linearity, lower limit of quantification (LOQ), accuracy and precision. Results Intra- and inter-day coefficients of variation were <15% for both metabolites. Reference values in 40 healthy newborns were: HS mean 1.0 mg/L, 0-3.2; DS mean 1.5 mg/L, 0.5-2.7). The two confirmed newborn MPS I patients had elevated HS (4.9-10.4 mg/L, n.v. <3.2) and DS (7.4-8.8 mg/L, n.v. <2.7). Since its introduction in February 2019, the second-tier test reduced the recall rate from 0.046% to 0.006%. Among 127,869 specimens screened, the incidence was 1:63,935 live births. Both patients started enzyme replacement therapy (ERT) within 15 days of birth and one of them received allogenic hematopoietic stem cell transplantation (HSCT) at ht age of 6 months. Conclusions GAGs in DBS increased the specificity of newborn screening for MPS I by reducing false-positives due to heterozygosity or pseudodeficiency. Early diagnosis and therapeutical approach has improved the outcome of our patients with MPS I.
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http://dx.doi.org/10.1515/cclm-2020-0064DOI Listing
November 2020

Urogenital Abnormalities in Adenosine Deaminase Deficiency.

J Clin Immunol 2020 05 19;40(4):610-618. Epub 2020 Apr 19.

Pediatric Immunohematology and Stem Cell Program, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132, Milan, Italy.

Background: Improved survival in ADA-SCID patients is revealing new aspects of the systemic disorder. Although increasing numbers of reports describe the systemic manifestations of adenosine deaminase deficiency, currently there are no studies in the literature evaluating genital development and pubertal progress in these patients.

Methods: We collected retrospective data on urogenital system and pubertal development of 86 ADA-SCID patients followed in the period 2000-2017 at the Great Ormond Street Hospital (UK) and 5 centers in Italy. In particular, we recorded clinical history and visits, and routine blood tests and ultrasound scans were performed as part of patients' follow-up.

Results And Discussion: We found a higher frequency of congenital and acquired undescended testes compared with healthy children (congenital, 22% in our sample, 0.5-4% described in healthy children; acquired, 16% in our sample, 1-3% in healthy children), mostly requiring orchidopexy. No urogenital abnormalities were noted in females. Spontaneous pubertal development occurred in the majority of female and male patients with a few cases of precocious or delayed puberty; no patient presented high FSH values. Neither ADA-SCID nor treatment performed (PEG-ADA, BMT, or GT) affected pubertal development or gonadic function.

Conclusion: In summary, this report describes a high prevalence of cryptorchidism in a cohort of male ADA-SCID patients which could represent an additional systemic manifestation of ADA-SCID. Considering the impact urogenital and pubertal abnormalities can have on patients' quality of life, we feel it is essential to include urogenital evaluation in ADA-SCID patients to detect any abnormalities, initiate early treatment, and prevent long-term complications.
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http://dx.doi.org/10.1007/s10875-020-00777-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253380PMC
May 2020

Use of Eltrombopag in Children With Chronic Immune Thrombocytopenia (ITP): A Real Life Retrospective Multicenter Experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP).

Front Med (Lausanne) 2020 28;7:66. Epub 2020 Feb 28.

Pediatric Unit, Department of Biomedical Science and Human Oncology, University of Bari "Aldo Moro", Bari, Italy.

The thrombopoietin receptor agonist eltrombopag has been shown to be safe and effective for children with chronic immune thrombocytopenia (ITP). The aim of the present study was to characterize eltrombopag use in current clinical practice. This is a retrospective multicenter study conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). The primary objective of the study was to determine the prevalence of eltrombopag use in Italian children affected by chronic ITP, after EMA authorization for pediatric age. The secondary objective was to assess efficacy in the first 6 months and safety during the whole period of eltrombopag treatment in current clinical practice. A total of 386 children with chronic ITP were retrospectively enrolled and eligible for analysis. Among these patients, 71 received eltrombopag. The prevalence of eltrombopag use was 19% (95% CI 0.15-0.23). Thirty-one patients (44%) were male and 40 patients (56%) were female. The median age at the first dose of eltrombopag was 12 years (3-17 years). The median duration of eltrombopag treatment was 11 months (1-32 months) and the median starting dose was 50 mg/day (12, 5-75 mg/day). Thirty-two patients (45%) required one or more concomitant ITP medications during the first 6 months of treatment with eltrombopag. Thirty-nine patients (55%) never required concomitant medications. Median platelet counts and proportion of patients achieving the target platelet count of at least 30 × 10/L and 100 × 10/L significantly increased during the first 6 months of treatment ( < 0.0001). Additionally, eltrombopag has been proved effective in the absence of concomitant therapies. The most common Adverse Events were headache (7%) and thrombocytosis (6%). Our study highlighted the crucial role of eltrombopag as second line treatment in children with chronic ITP.
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http://dx.doi.org/10.3389/fmed.2020.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059456PMC
February 2020

Susceptibility to infection in early life: a growing role for human genetics.

Hum Genet 2020 Jun 13;139(6-7):733-743. Epub 2020 Jan 13.

School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

The unique vulnerability to infection of newborns and young infants is generally explained by a constellation of differences between early-life immune responses and immune responses at later ages, often referred to as neonatal immune immaturity. This developmental view, corroborated by robust evidence, offers a plausible, population-level description of the pathogenesis of life-threatening infectious diseases during the early-life period, but provides little explanation on the wide inter-individual differences in susceptibility and resistance to specific infections during the first months of life. In this context, the role of individual human genetic variation is increasingly recognized. A life-threatening infection caused by an opportunistic pathogen in an otherwise healthy infant likely represents the first manifestation of an inborn error of immunity. Single-gene disorders may also underlie common infections in full-term infants with no comorbidities or in preterm infants. In addition, there is increasing evidence of a possible role for common genetic variation in the pathogenesis of infection in preterm infants. Over the past years, a unified theory of infectious diseases emerged, supporting a hypothetical, age-dependent general model of genetic architecture of human infectious diseases. We discuss here how the proposed genetic model can be reconciled with the widely accepted developmental view of early-life infections in humans.
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http://dx.doi.org/10.1007/s00439-019-02109-2DOI Listing
June 2020

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

J Allergy Clin Immunol 2020 05 27;145(5):1452-1463. Epub 2019 Dec 27.

Department of Bone Marrow Transplantation, Hadassah, Hebrew University Medical Centre, Jerusalem, Israel.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.

Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.

Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.

Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.

Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
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http://dx.doi.org/10.1016/j.jaci.2019.12.896DOI Listing
May 2020

Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network.

Front Immunol 2019 13;10:1908. Epub 2019 Aug 13.

Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, Rome, Italy.

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.
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http://dx.doi.org/10.3389/fimmu.2019.01908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700292PMC
September 2020

Successful Treatment of an EBV-positive Diffuse Large B-Cell Lymphoma in a Patient With Trisomy 21.

J Pediatr Hematol Oncol 2020 08;42(6):e472-e474

Department of Women's and Children's Health, Pediatric Hematology-Oncology Unit, University of Padova.

Diffuse large B-cell Lymphoma (DLBCL) secondary to a chronic severe Epstein-Barr virus (EBV) infection has not been previously described in a patient with trisomy 21. Here we report the case of a 14-year-old girl with trisomy 21 with impaired control of EBV and DLBCL. She was cured with dose-adapted chemotherapy and hematopoietic stem cell transplantation without severe treatment-related toxicity. We describe the first case of EBV-positive DLBCL in a patient with trisomy 21 and we propose a treatment modality for this rare entity.
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http://dx.doi.org/10.1097/MPH.0000000000001502DOI Listing
August 2020

Cerebral Lymphoproliferation in a Patient with Kabuki Syndrome.

J Clin Immunol 2018 05 30;38(4):475-477. Epub 2018 May 30.

Pediatric Hematology-Oncology Unit, Department of Women's and Children's Health, Azienda Ospedaliera-University of Padova, Via Giustiniani 3, 35128, Padua, Italy.

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http://dx.doi.org/10.1007/s10875-018-0516-9DOI Listing
May 2018

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy.

Biol Blood Marrow Transplant 2018 06 2;24(6):1223-1231. Epub 2018 Feb 2.

Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy; Department of Pediatric Sciences, University of Pavia, Italy. Electronic address:

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34 cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.022DOI Listing
June 2018

Haploidentical stem cell transplantation cures autoimmune hepatitis and cerebrovascular disease in a patient with sickle cell disease.

Bone Marrow Transplant 2018 05 15;53(5):644-646. Epub 2018 Jan 15.

Pediatric Hematology-Oncology Unit, Department of Women's and Children's Health, Azienda Ospedaliera-University of Padova, Padova, Italy.

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http://dx.doi.org/10.1038/s41409-017-0065-5DOI Listing
May 2018

Quality of Life and Psychopathology in Adults Who Underwent Hematopoietic Stem Cell Transplantation (HSCT) in Childhood: A Qualitative and Quantitative Analysis.

Front Psychol 2017 8;8:1316. Epub 2017 Aug 8.

Haematology-Oncology Division, Department of Women's and Children's Health, University Hospital of PaduaPadua, Italy.

Patients who undergo pediatric Hematopoietic Stem Cell Transplantation (HSCT) may experience long-term psychological sequelae and poor Quality of Life (QoL) in adulthood. This study aimed to investigate subjective illness experience, QoL, and psychopathology in young adults who have survived pediatric HSCT. The study involved patients treated with HSCT in the Hematology-Oncology Department between 1984 and 2007. Psychopathology and QoL were investigated using the SCL-90-R and SF-36. Socio-demographic and medical information was also collected. Finally, participants were asked to write a brief composition about their experiences of illness and care. Qualitative analysis of the texts was performed using T-LAB, an instrument for text analysis that allows the user to highlight the occurrences and co-occurrences of lemma. Quantitative analyses were performed using non-parametric tests (Spearman correlations, Kruskal-Wallis and Mann-Whitney tests). Twenty-one patients (9 males) participated in the study. No significant distress was found on the SCL-90 Global Severity Index, but it was found on specific scales. On the SF-36, lower scores were reported on scales referring to bodily pain, general health, and physical and social functioning. All the measures were significantly ( < 0.05) associated with specific socio-demographic and medical variables (gender, type of pathology, type of HSCT, time elapsed between communication of the need to transplant and effective transplantation, and days of hospitalization). With regard to the narrative analyses, males focused on expressions related to the body and medical therapies, while females focused on people they met during treatment, family members, and donors. Low general health and treatment with autologous HSCT were associated with memories about chemotherapy, radiotherapy, and the body parts involved, while high general health was associated with expressions focused on gratitude (-Test ± 1.96). Pediatric HSCT survivors are more likely to experience psychological distress and low QoL in adulthood compared with the general population. These aspects, along with survivors' subjective illness experience, show differences according to specific medical and socio-demographic variables. Studies are needed in order to improve the care and long-term follow-up of these families.
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http://dx.doi.org/10.3389/fpsyg.2017.01316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550669PMC
August 2017

Eltrombopag use in a patient with Wiskott-Aldrich syndrome.

Pediatr Blood Cancer 2017 Dec 23;64(12). Epub 2017 Jun 23.

Department of Women's and Children's Health, Pediatric Onco-Hematology Unit, University of Padova, Padova, Italy.

Wiskott-Aldrich syndrome (WAS) is an inherited X-linked disorder characterized by microthrombocytopenia, immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice. Eltrombopag, a thrombopoietin receptor agonist, may be useful to prevent bleeding while awaiting HSCT. We present a case of a male with WAS, profound thrombocytopenia, and bleeding diathesis successfully managed with eltrombopag before HSCT. Eltrombopag was given for 32 weeks obtaining a stable platelet count without any platelet transfusion. The patient did not experience any bleeding symptom. Eltrombopag may be a suitable therapeutic option for patients with WAS and severe thrombocytopenia as "bridge" to definitive cure.
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http://dx.doi.org/10.1002/pbc.26692DOI Listing
December 2017

Risk Factors and Outcomes Related to Pediatric Intensive Care Unit Admission after Hematopoietic Stem Cell Transplantation: A Single-Center Experience.

Biol Blood Marrow Transplant 2017 Aug 28;23(8):1335-1341. Epub 2017 Apr 28.

Pediatric Hematology and Oncology, Department of Woman's and Child's Health, University-Hospital of Padua, Padua, Italy.

To describe incidence, causes, and outcomes related to pediatric intensive care unit (PICU) admission for patients undergoing hematopoietic stem cell transplantation (HSCT), we investigated the risk factors predisposing to PICU admission and prognostic factors in terms of patient survival. From October 1998 to April 2015, 496 children and young adults (0 to 23 years) underwent transplantation in the HSCT unit. Among them, 70 (14.1%) were admitted to PICU. The 3-year cumulative incidence of PICU admission was 14.3%. The main causes of PICU admission were respiratory failure (36%), multiple organ failure (16%), and septic shock (13%). The overall 90-day cumulative probability of survival after PICU admission was 34.3% (95% confidence interval, 24.8% to 47.4%). In multivariate analysis, risk factors predisposing to PICU admission were allogeneic HSCT (versus autologous HSCT, P = .030) and second or third HSCT (P = .018). Characteristics significantly associated with mortality were mismatched HSCT (P = .011), relapse of underlying disease before PICU admission (P < .001), acute respiratory distress syndrome at admission (P = .012), hepatic failure at admission (P = .021), and need for invasive ventilation during PICU course (P < .001). Our data indicate which patients have a high risk for PICU admission after HSCT and for dismal outcomes after PICU stay. These findings may provide support for the clinical decision-making process on the opportunity of PICU admission for severely compromised patients after HSCT.
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http://dx.doi.org/10.1016/j.bbmt.2017.04.016DOI Listing
August 2017

Psychopathological Aspects in Childhood Hematopoietic Stem Cell Transplantation (HSCT): The Perception of Parents and Adolescents.

Front Psychol 2017 5;8:272. Epub 2017 Apr 5.

Department of Developmental and Social Psychology, University of PaduaPadua, Italy.

Data about psychosocial sequelae of childhood Hematopoietic Stem Cell Transplantation (HSCT) are limited and the association with a specific donor type or other medical factors is largely unknown (Chang et al., 2012). The aim of the present study was to compare the psychological aspects of pediatric HSCT survivors with healthy peers. A secondary aim was to detect whether parents and children differed in the perception of mental health status. The influence of medical factors on psychological status was also examined. Thirty seven HSCT survivors (23 males) with a mean age of 14.4 years ( = 3.03; range 8.16-18.33) were recruited. Twenty-six patients underwent an allogenic HSCT (matched unrelated donor, = 20; matched sibling donor, = 6) and 11 patients received an autologous HSCT. The children psychological aspects were assessed using the Youth Self Report (YSR) (Achenbach and Rescorla, 2001) and compared to a group of matched healthy peers. At the same time, parents were requested to complete the Child Behavior Checklist 6-18 (Achenbach and Rescorla, 2001). Medical and socio-demographic data were also collected. HSCT survivors reported significantly higher levels of somatic complains ( = 3.14; = 0.004; mean = 3.1) when compared to healthy peers (mean = 1.5). The parent CBCL scores on "child total competence" exceeded the normative clinical cutoff in 48.6% cases. Inter-rater agreement between parent and patient reports was present only in three scales: total competence score ( = 0.06, = 0.002), somatic complaints ( = 0.21, = 0.003) and attention problems ( = 0.13; = 0.02). According to Ancova models, internalizing problems were more frequent in HSCT from family donors ( = 3.13; = 0.06) or in the presence of acute complications ( = 11.95; = 0.003). In contrast to the perception of parents, pediatric HSCT survivors reported good psychological health. However, they complained about more somatic problems as compared with healthy peers. Medical aspects such as donor source and the presence of acute complications should be taken into consideration for the psychological approach in order to improve pediatric HSCT survivor care.
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http://dx.doi.org/10.3389/fpsyg.2017.00272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380719PMC
April 2017

Treosulfan-Based Conditioning Regimen in Sibling and Alternative Donor Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease.

Mediterr J Hematol Infect Dis 2017 15;9(1):e2017014. Epub 2017 Feb 15.

Pediatric Hematology-Oncology Unit, Department of Women's and Children's Health, University of Padova, Italy.

Background And Objectives: Lack of suitable donors and regimen related toxicity are major barriers for hematopoietic stem cell transplantation (HSCT) in patients with sickle cell disease (SCD). The aim of the study is the assessment of efficacy and toxicity of Treosulfan-based conditioning regimen for SCD also when alternative donors such as mismatched unrelated donor and haploidentical donor are employed.

Methods: We report our single-center experience: 11 patients with SCD received HSCT with a Treosulfan/Thiotepa/Fludarabine/Anti-thymoglobulin conditioning regimen between 2010 and 2015. The donor was a matched sibling donor (n= 7), a haploidentical parent (n= 2), a matched unrelated donor (n= 1) or a mismatched unrelated donor (n=1). The haploidentical and mismatched unrelated donor grafts were manipulated by removing TCRαβ and CD19 positive cells.

Results: All patients survived the procedure and achieved stable engraftment. Stable mixed chimerism was observed in 5/11 patients. Grade III-IV regimen related toxicity was limited to mucositis and no grade III-IV graft-versus-host disease (GvHD) occurred. No SCD manifestation was observed post transplant and cerebral vasculopathy improved in 3/5 evaluable patients. Organ function evaluation showed no pulmonary, cardiac or renal toxicity but gonadal failure occurred in 1/4 evaluable patients.

Conclusion: Our data suggest that Treosulfan is associated with low toxicity and may be employed also for unrelated and haploidentical donor HSCT.
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http://dx.doi.org/10.4084/MJHID.2017.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333731PMC
February 2017

Can high dose methotrexate be continued after severe hypersensitivity reaction?

Pediatr Blood Cancer 2014 Jun 21;61(6):1139. Epub 2013 Nov 21.

Department of Woman's and Child's Health, Pediatric Hematology and Oncology Division, Padova, Italy.

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http://dx.doi.org/10.1002/pbc.24879DOI Listing
June 2014

Airways obstruction and pulmonary capillary blood volume in children with sickle cell disease.

Pediatr Pulmonol 2014 Jul 8;49(7):723. Epub 2013 Nov 8.

Pediatric Hematology and Oncology Division, Department of Woman's and Child's Health, Padova, Italy.

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http://dx.doi.org/10.1002/ppul.22948DOI Listing
July 2014
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