Gut microbiota diversity before allogeneic hematopoietic stem cell transplantation as a predictor of mortality in children.

The correlation existing between gut microbiota diversity and survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has so far been studied in adults. Pediatric studies question whether this association applies to children as well. Stool samples from a multicenter cohort of 90 pediatric allo-HSCT recipients were analyzed using 16S ribosomal RNA amplicon sequencing to profile the gut microbiota and estimate diversity with the Shannon index. A global-to-local networking approach was used to characterize the ecological structure of the gut microbiota. Patients were stratified into higher- and lower-diversity groups at 2 time points: before transplantation and at neutrophil engraftment. The higher-diversity group before transplantation exhibited a higher probability of overall survival (88.9% ± 5.7% standard error [SE] vs 62.7% ± 8.2% SE; P = .011) and lower incidence of grade 2 to 4 and grade 3 to 4 acute graft-versus-host disease (aGVHD). No significant difference in relapse-free survival was observed between the 2 groups (80.0% ± 6.0% SE vs 55.4% ± 10.8% SE; P = .091). The higher-diversity group was characterized by higher relative abundances of potentially health-related microbial families, such as Ruminococcaceae and Oscillospiraceae. In contrast, the lower-diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae. Network analysis detected short-chain fatty acid producers, such as Blautia, Faecalibacterium, Roseburia, and Bacteroides, as keystones in the higher-diversity group. Enterococcus, Escherichia-Shigella, and Enterobacter were instead the keystones detected in the lower-diversity group. These results indicate that gut microbiota diversity and composition before transplantation correlate with survival and with the likelihood of developing aGVHD.

SARS-CoV-2 Infection in the Pediatric Oncology Population: The Definitive Comprehensive Report of the Infectious Diseases Working Group of AIEOP.

OBJECTIVE: The objective of this study was to assess the clinical impact and outcome of the SARS-CoV-2 infection on children with cancer or those who received a hematopoietic stem cell transplantation. METHODS: AIEOP (Italian Association of Pediatric Hematology and Oncology) performed a nationwide multicenter observational cohort study, including consecutive patients between April 2020 and November 2022. RESULTS: Twenty-five Italian centers participated and 455 patients were enrolled. We reported a significant increasing trend of symptomatic cases over the years, while the number of nonmild infections remained stable. Early infection after oncologic diagnosis (<60 days) and severe neutropenia were identified as independent risk factors for developing moderate, severe, or critical infections. The percentage of patients who were asymptomatic and mildly symptomatic and who stopped chemotherapy reduced over the years of the pandemic. Nine patients died, but no death was attributed to SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infection presented a self-limiting benign course in the Italian pediatric oncohematology population during the pandemic, and its main consequence has been the discontinuation of cancer-directed therapies. The rate of patients who were asymptomatic and stopped chemotherapy reduced over the years, suggesting that the continuation of chemotherapy is a feasible option.

Use of music therapy in pediatric oncology: an Italian AIEOP multicentric survey study in the era of COVID-19.

Music therapy (MT) is a complementary therapy offered to children, young adults, and their families in pediatric oncology and palliative care. We performed a survey to collect information about MT in pediatric oncology in Italy. The outbreak of COVID-19 unavoidably changed the scenario of MT, suggesting some considerations presented in this survey. 27/32 (84.4%) centers belonging to the Infections and Supportive Therapy Working Group of Association of Pediatric Hematology and Oncology (AEIOP) completed in 2 different time points (T1 and T2) an online survey on MT, before and after COVID-19 pandemia. Different kinds of music approach were used taking care of patients in 21/27 centers, while in 14/21 (66%), a specific project of MT conducted by a music therapist was present. In 6/14 centers, MT activities were delivered for < 3 h/week, in 3 centers for > 3 and < 10 h/week, and in the remaining 5 for > 3 h/week. MT sessions were in different areas, day hospital, or ward (patient rooms, operating rooms, waiting rooms), on an individual basis or by groups. Patients were invited to MT by psychologists, caring physician, or nurse, or on equipé decision. MT was evaluated with tools self-made by music therapist in 11/14 centers. After COVID-19, MT has been withdrawn in 3 centers, sessions in the waiting rooms were reduced, individual sessions were preferred, and enrollment by multidisciplinary teams increased. CONCLUSION: This survey represents the starting platform to compare and discuss different experience of MT in AIEOP centers, to implement MT in pediatric oncology for a more qualified assistance to patients, and to improve quality of care. WHAT IS KNOWN: • Music therapy in pediatric oncology and palliative care can be used for the management and prevention of various somatic and psychological symptoms of patients and often is provided to children together with their families. • In Italy the application of Music therapy in the AIEOP pediatric oncology centers is constantly increasing, but due to the outbreak of Covid-19 Pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures. WHAT IS NEW: • Although the majority of Centres did not abrogate MT interventions, judgment about limitation should be carefully taken since MT helps children and even more adolescents in their fight against cancer. • The best practice of Music therapy in pediatric oncology requires communication and collaboration among qualified music therapists and multidisciplinary care team, using a model of family-centered care that actively involves parents/ caregivers in assessment, treatment planning, and care delivery.

Outdoor Air Pollution and Childhood Respiratory Disease: The Role of Oxidative Stress.

The leading mechanisms through which air pollutants exert their damaging effects are the promotion of oxidative stress, the induction of an inflammatory response, and the deregulation of the immune system by reducing its ability to limit infectious agents' spreading. This influence starts in the prenatal age and continues during childhood, the most susceptible period of life, due to a lower efficiency of oxidative damage detoxification, a higher metabolic and breathing rate, and enhanced oxygen consumption per unit of body mass. Air pollution is involved in acute disorders like asthma exacerbations and upper and lower respiratory infections, including bronchiolitis, tuberculosis, and pneumoniae. Pollutants can also contribute to the onset of chronic asthma, and they can lead to a deficit in lung function and growth, long-term respiratory damage, and eventually chronic respiratory illness. Air pollution abatement policies, applied in the last decades, are contributing to mitigating air quality issues, but more efforts should be encouraged to improve acute childhood respiratory disease with possible positive long-term effects on lung function. This narrative review aims to summarize the most recent studies on the links between air pollution and childhood respiratory illness.

Immunological Evaluation of Patients Affected with Jacobsen Syndrome Reveals Profound Not Age-Related Lymphocyte Alterations.

PURPOSE: Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited. METHODS: Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected. RESULTS: Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naïve CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/- cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients' age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time. CONCLUSIONS: Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.

Favorable outcome of SARS-CoV-2 infection in pediatric hematology oncology patients during the second and third pandemic waves in Italy: a multicenter analysis from the Infectious Diseases Working Group of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP).

COVID-19 has a mild clinical course with low mortality rate in general pediatric population, while variable outcomes have been described in children with cancer. Infectious diseases working party of the AIEOP collected data on the clinical characteristics and outcomes of SARS-CoV-2 infections in pediatric oncology/hematology patients from April 2020 to May 2021, including the second and the third waves of the pandemic in Italy. Factors potentially associated with moderate, severe, or critical COVID-19 were analyzed. Of the 153 SARS-Cov2 infections recorded, 100 were asymptomatic and 53 symptomatic. The course of COVID-19 was mild in 41, moderate in 2, severe in 5, and critical in 5 children. A total of 40.5% of patients were hospitalized, ten requiring oxygen support and 5 admitted to the intensive care unit. Antibiotics and steroids were the most used therapies. No patient died due to SARS-CoV-2 infection. Infections occurring early (< 60 days) after the diagnosis of the underlying disease or after SCT were associated to moderate, severe, and critical disease compared to infections occurring late (> 60 days) or during maintenance therapy. In the patients on active chemotherapy, 59% withdrew the treatment for a median of 15 days. SARS-CoV-2 presented a favorable outcome in children with cancer in Italy during the pandemic. Modification of therapy represents a major concern in this population. Our findings suggest considering regular chemotherapy continuation, particularly in patients on maintenance therapy or infected late after the diagnosis.

Brentuximab vedotin in the treatment of paediatric patients with relapsed or refractory Hodgkin's lymphoma: Results of a real-life study.

BACKGROUND: Brentuximab vedotin (BV) is an antibody drug-conjugated anti-CD30 approved for the treatment of adult classical Hodgkin's lymphoma (HL), whereas it is considered as off-label indication in paediatrics. The aim of the study was to evaluate the safety and efficacy of BV to treat patients aged less than 18 years with refractory/relapsed HL. MATERIALS AND METHODS: In this multicentre, retrospective study, 68 paediatric patients who received at least one dose of BV between November 2011 and August 2020 were enrolled. A median of nine doses of BV were administered as monotherapy (n = 31) or combined with other therapies (n = 37). BV was administrated alone as consolidation therapy after stem cell transplantation (SCT) in 12 patients, before SCT in 18 patients, whereas in 15 patients it was used before and after SCT as consolidation therapy. Median follow-up was 2.8 years (range: 0.6-8.9 years). RESULTS: The best response was observed in the 86% of patients; the overall response rate was 66%. The 3-year progression-free survival was 58%, whereas the overall survival was 75%. No statistically significant differences between patients treated with BV monotherapy or combination were highlighted. In multivariate analysis, patients with non-nodular sclerosis HL and not transplanted had an increased risk of failure. Overall, 46% of patients had grade 3-4 adverse events that led to BV discontinuation in five of them. CONCLUSION: In conclusion, our study confirms that BV was a safe and effective drug, able to induce complete remission, either as monotherapy or in association with standard therapy.

Refractory immune thrombocytopenia successfully treated with bortezomib in a child with 22q11.2 deletion syndrome, complicated by Evans syndrome and hypogammaglobulinemia.

Treatment of refractory autoimmune cytopenias (AICs) and Evans syndrome (ES) represent a great challenge in pediatric setting, where an underlying primary immunodeficiency is recurrent. Frequently, second or third line treatments are employed, with an increased risk of toxicity and infections. The advent of novel drugs is the object of research in order to modify the management of these patients.We report a case of successful use of bortezomib in a child with 22q11.2 deletion syndrome and CVID-like phenotype with a multi-refractory severe ES. Last flares were prolonged and dominated by severe and symptomatic ITP, refractory to different courses of high dose steroid and IVIG, mofetil mycophenolate, thrombopoietin receptor agonists, sirolimus, and rituximab. Persistence of AICs in subjects with depletion of CD20 + B-cells and IgG strengthens the hypothesis about the production of autoantibodies by terminally differentiated plasma-cells, not targetable from immunosuppressants and rituximab.In the attempt to enhance plasma-cells inhibition, the child was addressed to bortezomib, with a good response at 6 month follow-up without side effects. Nowadays, the use of bortezomib in ES/AICs is based only on small retrospective studies and case reports. Despite the lack of long term follow-up, our work highlights the potential role of bortezomib in the management of pediatric patients with multi-resistant AICs secondary to immune-system impairment.

Invasive aspergillosis in relapsed/refractory acute myeloid leukaemia patients: Results from SEIFEM 2016-B survey.

BACKGROUND: In patients with relapsed/refractory acute myeloid leukaemia (R/R AML) who received salvage chemotherapy, limited and not updated studies explored the incidence of invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP). The aims of this multicentre retrospective 'SEIFEM 2016-B' study were as follows: (1) to evaluate the current rate and the outcome of proven/probable IA and (2) to assess the efficacy of AP, in a large 'real life' series of patient with R/R AML submitted to salvage chemotherapy. RESULTS: Of 2250 R/R AML patients, a total of 74 cases of IA (5.1%) were recorded as follows: 10 (0.7%) proven and 64 (4.3%) probable. Information about AP were available in 73/74 (99%) patients. Fifty-eight (79%) breakthrough infections occurred, mainly during AP with posaconazole [25 (43%)]. The patients who received AP during salvage chemotherapy showed a benefit from antifungal therapy (AT) than patients who did not received AP [43 (86%) vs 7 (14%); p < .033]. In a multivariate analysis, AP and absence of severe mucositis had a significant favourable effect on overall response rate. CONCLUSION: Our data demonstrated that the incidence of IA during the salvage chemotherapy is similar to the past. Nevertheless, the attributable mortality rate (AMR) appears to be lower than that previously reported in R/R AML. Further prospective studies should be performed to confirm our preliminary observation and understand and the why a decreased AMR is reported in this setting of high-risk patients.

Treatment with rapamycin can restore regulatory T-cell function in IPEX patients.

BACKGROUND: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS: Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

Microbiome-Derived Metabolites in Allogeneic Hematopoietic Stem Cell Transplantation.

The gut microbiome has emerged as a major character in the context of hematopoietic stem cell transplantation. The biology underpinning this relationship is still to be defined. Recently, mounting evidence has suggested a role for microbiome-derived metabolites in mediating crosstalk between intestinal microbial communities and the host. Some of these metabolites, such as fiber-derived short-chain fatty acids or amino acid-derived compounds, were found to have a role also in the transplant setting. New interesting data have been published on this topic, posing a new intriguing perspective on comprehension and treatment. This review provides an updated comprehensive overview of the available evidence in the field of gut microbiome-derived metabolites and hematopoietic stem cell transplantation.

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

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.

The gut microbiome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

The gut microbiome (GM) has been associated with different clinical outcomes in the context of allogeneic hematopoietic stem cell transplantation (HSCT). Large multicenter cohort studies in adults have found significant correlations with overall survival, relapse, and incidence of complications. Moreover, GM is already a promising target for therapeutic interventions. However, few data are available in children, a population presenting unique features and challenges. During childhood, the GM evolves rapidly with large structural fluctuations, alongside with the maturation of the immune system. Furthermore, the HSCT procedure presents significant differences in children. These considerations underline the importance of a specific focus on the pediatric setting, and the role of GM and its age-dependent trajectory in influencing the immunity reconstitution and clinical outcomes. This review provides a comprehensive overview of the available evidence in the field of GM and pediatric HSCT, highlighting age-specific issues and discussing GM-based therapeutic approaches.

Enteral nutrition protects children undergoing allogeneic hematopoietic stem cell transplantation from blood stream infections.

Enteral Nutrition (EN) is recommended as first line nutritional support for patients undergoing Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), but only few studies exist in the literature which compare EN to Parenteral Nutrition (PN) in the paediatric population.Forty-two consecutive paediatric patients undergoing allo-HSCT at our referral centre between January 2016 and July 2019 were evaluated. Post-transplant and nutritional outcomes of patients receiving EN for more than 7 days (EN group, n = 14) were compared with those of patients receiving EN for fewer than 7 days or receiving only PN (PN group, n = 28). In the EN group, a reduced incidence of Blood Stream Infections (BSI) was observed (p = 0.02) (n = 2 vs. n = 15; 14.3% vs. 53.6%). The type of nutritional support was also the only variable independently associated with BSI in the multivariate analysis (p = 0.03). Platelet engraftment was shorter in the PN group than in the EN group for a threshold of > 20*109/L (p = 0.04) (23.1 vs 35.7 days), but this correlation was not confirmed with a threshold of > 50*109/L. The Body Mass Index (BMI) and the BMI Z-score were no different in the two groups from admission to discharge.Our results highlight that EN is a feasible and nutritionally adequate method of nutritional support for children undergoing allo-HSCT in line with the present literature. Future functional studies are needed to better address the hypothesis that greater intestinal eubyosis maintained with EN may explain the observed reduction in BSI.

Posaconazole delayed-release tablets in paediatric haematology-oncology patients.

BACKGROUND: To date, there are few studies that describe pharmacokinetics, safety and efficacy of posaconazole delayed-release tablet (DRT) formulation in the paediatric population. OBJECTIVES: We evaluated retrospectively posaconazole plasma concentrations and safety of posaconazole DRT in paediatric haematology-oncology patients. PATIENTS AND METHODS: Posaconazole DRT was assessed in 28 haematological paediatric patients with a median age 15 of years (range 5-18) and a median body weight of 50 kg (range 22-83 kg). Twenty-one patients received posaconazole DRT as prophylaxis and 7 patients as therapy. RESULTS: As prophylaxis, the median daily dose was 5.5 mg/kg/day (range 2.2-22.2) with posaconazole trough level ≥ 0.7 µg/mL in 80% by first week, 62.5% by second week and 87.5% by fourth week. As therapy, the median daily dose was 4 mg/kg/day (range 3.3-4.5) with trough level ≥ 1 µg/mL 100% by first week, 80% by second week and 33.4% by fourth week. CONCLUSIONS: Posaconazole DRT is feasible in paediatric patients capable to swallow tablets. Specific pharmacokinetic studies are needed.

Longitudinal evaluation of liver stiffness in three pediatric patients with veno-occlusive disease.

Liver stiffness measurement by transient elastography is a non-invasive ultrasound-based technique used mainly for the evaluation of liver fibrosis in patients with chronic liver diseases. Some authors have suggested that it could be useful in the assessment of hepatic complications during hematopoietic stem cell transplant (HSCT), especially veno-occlusive disease (VOD) or sinusoidal obstructive syndrome (SOS). Here, we present the evaluation of liver stiffness in three patients who developed severe hepatic VOD/SOS after HSCT. Liver stiffness measurement values were normal before transplant and afterward until the diagnosis of VOD/SOS when a dramatic increase was observed. After the VOD/SOS specific treatment, the values of stiffness showed a similar pattern of progressive reduction in all the three patients, with normalization after two weeks. In this report, we discuss the role of LSM in the management of patients after the diagnosis of VOD/SOS.

A survey on hematology-oncology pediatric AIEOP centres: The challenge of posterior reversible encephalopathy syndrome.

OBJECTIVES: Posterior reversible encephalopathy syndrome (PRES) is one of the most common neurological complications in hematology-oncology pediatric patients. Despite an increasingly recognized occurrence, no clear consensus exists regarding how best to manage the syndrome, because most cases of PRES have reported in single-case reports or small series. Aim of this paper is to identify incidence, clinical features, management, and outcome of PRES in a large series of hematology-oncology pediatric patients. METHODS: The cases of PRES occurred in twelve centers of the Italian Association of Pediatric Hematology and Oncology were reported. RESULTS: One hundred and twenty-four cases of PRES in 112 pediatric patients were recorded with an incidence of 2.1% and 4.7%, respectively, in acute lymphoblastic leukemia in first complete remission and hematopoietic stem cell transplantation (HSCT). The majority of cases occurred after a cycle of chemotherapy rather than after stem cell transplant. PRES after chemotherapy significantly differs from that after HSCT for diagnosis, time of presentation, risk factors, management, and outcome. CONCLUSIONS: This study demonstrates that PRES is a common neurological complication and occurring preferentially in course of induction treatment of some hematologic malignancies, as ALL and after HSCT. It also highlights great clinical differences in the management and outcome in patients with PRES occurring after chemotherapy or after HSCT.

A New Formulation of an Old Drug: A Potential New Therapy in the Management of Oral cGvHD.

Oral chronic graft versus host disease (cGVHD) is often refractory to systemic therapies. Additional topical treatment is commonly required. The potency of the agent, the vehicle and formulation in which it is delivered are all critical factors in determining the effectiveness of topical therapies. High potency of budesonide, combined with its very low bioavailability when absorbed through mucosal surfaces, increased the potential role in topical application for oral cGVHD. Viscous formulation increases mucosal contact time resulting in a greater decrease in mucosal inflammation. This short communication suggests that oral viscous budesonide should be considered as a potential new therapy in the management of oral cGVHD.