Recommendations for the management of acute immune thrombocytopenia in children. A Consensus Conference from the Italian Association of Pediatric Hematology and Oncology.

BACKGROUND: Immune thrombocytopenia (ITP) is an acquired immune-mediated bleeding disorder characterized by isolated thrombocytopenia. Its estimated yearly incidence in the pediatric population is 1.9-6.4/100,000. ITP in children is usually a self-limiting and benign disorder. The clinical management of children with ITP often remains controversial, as robust randomized trials on the management of this disorder are lacking. Treatments vary widely in clinical practice and existing guidelines from hematology societies on clinical management offer indications based largely on expert opinion rather than strong evidence. MATERIALS AND METHODS: The Coagulative Disorder Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) developed this document to collect shared expert opinions on the management of newly diagnosed ITP, updating previous guidelines and providing recommendations to pediatricians. Each statement has been given a score expressing the strength of evidence, appropriateness and agreement among participants. RESULTS: Clear-cut definitions of the clinical phases of the disease and clinical response are stated. Recommendations are given regarding the classification of bleeding symptoms, evaluation of bleeding risk, diagnosis, and prognostic factors. Specific recommendations for treatment include indications for first-line (intravenous immunoglobulins, steroids) and second-line (combined therapy, thrombopoietin receptor agonists, immunosuppressive drugs, rituximab) therapeutic agents, as well as hemorrhagic emergency and supportive treatment, including emergency splenectomy. The optimal follow-up schedule, the relation between ITP and vaccines and health-related quality-of-life issues are also discussed. DISCUSSION: The panel achieved broad consensus on issues related to how to treat children with newly diagnosed ITP, providing a comprehensive review of all relevant clinical aspects.

Sirolimus Restores Erythropoiesis and Controls Immune Dysregulation in a Child With Cartilage-Hair Hypoplasia: A Case Report.

Cartilage-hair hypoplasia (CHH) is a syndromic immunodeficiency characterized by metaphyseal dysplasia, cancer predisposition, and varying degrees of anemia. It may present as severe combined immunodeficiency in infancy, or slowly progress until fully manifesting in late adolescence/adulthood. No targeted treatment is currently available, and patients are usually managed with supportive measures, or are offered a bone marrow transplant if the clinical phenotype is severe and a suitable donor is available. We report the case of a young girl presenting with transfusion-dependent erythropoietic failure and immunological features resembling autoimmune lymphoproliferative syndrome who responded well to empirical sirolimus. She later developed a marked growth delay, which was ultimately attributed to metaphyseal dysplasia. A diagnosis of CHH was reached through whole-genome sequencing (WGS), after a less sensitive genetic diagnostic strategy failed. The patient eventually underwent a haploidentical bone marrow transplant due to progressive combined immunodeficiency manifested as cryptococcal meningoencephalitis. This case illustrates the potential role of sirolimus in correcting anemia and partially controlling the immune aberrations associated with CHH, and serves as a reminder of the invaluable role of WGS in diagnosing patients with complex and atypical presentations.

Hemolysis and Neurologic Impairment in PAMI Syndrome: Novel Characteristics of an Elusive Disease.

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare early-onset autoinflammatory disease associated with various hematologic findings, including chronic neutropenia and pancytopenia. We report a unique case of PAMI syndrome in a toddler with transfusion-dependent hemolytic anemia, hepatosplenomegaly, failure to thrive, developmental delay, and multiple malformations. Because of acute inflammatory-driven decompensation, anakinra was started with dramatic improvement of both the hematologic and neurologic involvement. A customized next-generation sequencing panel later identified a de novo pathogenic variant in the PSTPIP1 gene, confirming the diagnosis. Our case illustrates the broad spectrum of phenotypes associated with PAMI syndrome, which should be considered in any case of unexplained cytopenias associated with autoinflammatory stigmata. It is also one of the few reports of neurologic involvement in PSTPIP1-associated inflammatory diseases. Increased awareness of this rare disease and early performance of genetic testing can correctly diagnose PAMI syndrome and prevent disease complications.

SARS-COV-2-associated coagulopathy and thromboembolism prophylaxis in children: A single-center observational study.

BACKGROUND: Multiple investigators have described an increased incidence of thromboembolic events in SARS-CoV-2-infected individuals. Data concerning hemostatic complications in children hospitalized for COVID-19/multisystem inflammatory syndrome in children (MIS-C) are scant. OBJECTIVES: To share our experience in managing SARS-CoV-2-associated pro-coagulant state in hospitalized children. METHODS: D-dimer values were recorded at diagnosis in children hospitalized for SARS-CoV-2-related manifestations. In moderately to critically ill patients and MIS-C cases, coagulation and inflammatory markers were checked at multiple time points and median results were compared. Pro-thrombotic risk factors were appraised for each child and thromboprophylaxis was started in selected cases. RESULTS: Thirty-five patients were prospectively enrolled. D-dimer values did not discriminate COVID-19 of differing severity, whereas were markedly different between the COVID-19 and the MIS-C cohorts. In both cohorts, D-dimer and C-reactive protein levels increased upon clinical worsening but were not accompanied by decreased fibrinogen or platelet values, with all parameters returning to normal upon disease resolution. Six patients had multiple thrombotic risk factors and were started on pharmacological thromboprophylaxis. No deaths or thrombotic or bleeding complications occurred. CONCLUSIONS: COVID-19 pediatric patients show mildly altered coagulation and inflammatory parameters; on the other hand, MIS-C cases showed laboratory signs of an inflammatory driven pro-coagulant status. Universal anticoagulant prophylaxis in hospitalized children with SARS-CoV-2-related manifestations is not warranted, but may be offered to patients with other pro-thrombotic risk factors in the context of a multi-modal therapeutic approach.

New insights into pediatric community-acquired pneumonia gained from untargeted metabolomics: A preliminary study.

BACKGROUND: Available diagnostics often fail to distinguish viral from bacterial causes of pediatric community-acquired pneumonia (pCAP). Metabolomics, which aims at characterizing diseases based on their metabolic signatures, has been applied to expand pathophysiological understanding of many diseases. In this exploratory study, we used the untargeted metabolomic analysis to shed new light on the etiology of pCAP. METHODS: Liquid chromatography coupled with mass spectrometry was used to quantify the metabolite content of urine samples collected from children hospitalized for CAP of pneumococcal or viral etiology, ascertained using a conservative algorithm combining microbiological and biochemical data. RESULTS: Fifty-nine children with CAP were enrolled over 16 months. Pneumococcal and viral cases were distinguished by means of a multivariate model based on 93 metabolites, 20 of which were identified and considered as putative biomarkers. Among these, six metabolites belonged to the adrenal steroid synthesis and degradation pathway. CONCLUSIONS: This preliminary study suggests that viral and pneumococcal pneumonia differently affect the systemic metabolome, with a stronger disruption of the adrenal steroid pathway in pneumococcal pneumonia. This finding may lead to the discovery of novel diagnostic biomarkers and bring us closer to personalized therapy for pCAP.