Transition of adolescents living with HIV from pediatric to adult care, a retrospective 12-year Single Center Study from the Sahel Region in West-Africa.

ABSTRACTTransition is the next major hurdle in the field of HIV-infected youth, especially in sub-Saharan Africa. At St Camille Hospital in Ouagadougou, fully informed and compliant patients over 13-years-old were eligible for referral to the adult HIV/AIDS service, after completion of an individualized preparatory process. Transition consisted in at least two consecutive "joined-service" appointments in the respective facilities. We retrospectively compared immunological, clinical, and therapeutical data one year before transition, at transition and one year after transition. Between 2008 and 2019 73 patients (34 females, 39 males) were transitioned. All had been previously in pediatric care for at least 1 year and 66 were on HAART. Matched paired analysis of CD4 counts revealed a modest drop in CD4 cells over time (p < 0.05). Clinical data also showed strong fluctuation between WHO clinical stages over the three time points, with a clear trend towards increased severity especially post transfer. This large retrospective 12-year single-center experience from a Sahel country showed a 95.8% retention rate at one year. It demonstrates how a comprehensive plan, carefully implemented, can provide excellent retention, even in a low-resource setting. However, mild immunological decline was associated with a worrisome clinical deterioration, underlining the importance of assessing the latter after transition.

Possible Impact of COVID-19 on Children in Africa, Reflections from Italy and Burkina Faso.

Africa is the World Health Organization-region least affected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. Here, we compare the situation in severely hit Italy with that in less hit Burkina Faso, focussing on the differences in epidemiological, geographical, demographical, cultural and medical conditions to highlight how a full-blown war on the pandemic can impact on other, equally important aspects of global child health.

Clinical and Prognostic Role of 18F-FDG PET/CT in Pediatric Ewing Sarcoma.

Ewing sarcoma (ES) is one of the most common pediatric solid tumors with aggressive behavior and unfavorable survival. In this study, we evaluated the diagnostic accuracy of baseline and restaging fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scans and their possible prognostic role in pediatric ES. We evaluated 17 patients who underwent a total of 27 18F-FDG-PET/CT scans (10 for staging and 17 for restaging). The PET images were analyzed visually and semiquantitatively by measuring SUVmean, SUVmax, SUVlbm, SUVbsa, MTV, and TLG. Moreover, PET/CT results were compared with other conventional imaging (CI) results. Among 10 baseline PET/CT scan results, 9 were positive and 1 not valuable by interference; baseline PET/CT and CI were concordant in 7 cases and discordant in 2, with pulmonary micrometastases not detected by PET/CT. Among 17 restaging PET/CT scan results, 9 were positive and 8 negative; CI and restaging PET/CT were concordant in 9 cases and discordant in 8. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of restaging 18F-FDG-PET/CT were 73%, 83%, 89%, 62.5%, and 76%, respectively. After a median follow-up of 20 months, relapse/progression occurred in 8 patients and death in 5. A positive 18F-FDG-PET/CT at restaging was significantly associated with shorter overall survival compared with unremarkable PET/CT at the same timepoint, but not with progression-free survival. Instead, metabolic PET/CT features were not correlated with outcome. 18F-FDG-PET/CT showed a good diagnostic performance in pediatric ES; except for pulmonary micrometastases, PET/CT was better than CI at restaging. Only restaging PET/CT result was significantly correlated with overall survival.

Efficacy of a Solution Composed by Verbascoside, Polyvinylpyrrolidone (PVP) and Sodium Hyaluronate in the Treatment of Chemotherapy-induced Oral Mucositis in Children With Acute Lymphoblastic Leukemia.

The aim of this study was to assess the efficacy of a solution composed by verbascoside, polyvinylpyrrolidone, and sodium hyaluronate (Mucosyte) in the treatment of chemotherapy-induced oral mucositi (OM). Patients between 5 and 18 years receiving chemotherapy for acute lymphoblastic leukemia and with OM grade 1 or 2 were randomized in group A (treated with Mucosyte, 3 mouthwashes/d per 8 d) and group B (treated with placebo, ie, an inert water-based solution, 3 mouthwashes/d per 8 d). The OM scoring was performed at day 1 (diagnosis of OM-T0), after 3 days of treatment (T1), and at day 8 (T2). Pain was evaluated through the visual analog scale with the same timing of OM measurement. A total of 56 patients were included (28 patients per group). Group A experienced a statistically significant decline of OM at T2 (P=0.0038); a statistically significant difference in pain reduction between 2 groups both at T1 and at T2 (P<0.005) was observed. The use of Mucosyte mouthwashes in children with chemotherapy-induced OM may be recommended as supportive therapy.

Low-level laser therapy for treatment of chemotherapy-induced oral mucositis in childhood: a randomized double-blind controlled study.

The aim of this study was to verify if low-level laser therapy could be useful to reduce chemotherapy-related oral mucositis grading and pain in childhood undergoing chemotherapy. A randomized double-blind clinical trial was carried out. Patients from 3 to 18 years of age undergoing cancer therapy and presenting OM grade 2 or more were eligible for this study. Patients were randomly divided in two groups: group A received laser therapy from the day of OM diagnosis and other 3 consecutive days (830 nm wavelength, power 150 mW, spot size 1 cm(2), 30 s per cm(2), energy density 4.5 J/cm(2)); group B received sham therapy (placebo) with the same timing. Two blind clinicians performed OM scoring and pain evaluation at day 1 (immediately before the beginning of laser treatment-T0), day 4 (after finishing laser therapy cycle-T1) and at day 7 (T2) as follow-up. A total of 123 patients were included in the study. Group A was composed of 62 children while group B is 61; in both groups, there was a progressive reduction in grade of OM, and at day 7, not every mucosal lesion disappeared. The difference in the decline of OM grading between the two groups resulted not statistically significant (p = 0.07). A statistically significant difference in pain reduction between two groups both at T1 and at T2 (p < 0.005) was observed. This study demonstrated the efficacy of LLLT in reducing pain due to chemotherapy-induced oral mucositis in children, while no significant benefit was noted in reducing OM grade.

Taste dysfunction in patients undergoing hematopoietic stem cell transplantation: Clinical evaluation in children.

The aim of this study was to determine the variability of TD in children undergoing HSCT. Cases were identified as consecutively enrolled children in the period January 2011-January 2013 among patients attending the Paediatric Department of Spedali Civili of Brescia and all candidates to HSCT. The TST was conducted in two phases: identification of threshold values and identification of perceived stimulus intensity. Sixteen sapid solutions with four flavors (sucrose, sodium chloride, citric acid, and quinine hydrochloride) at four different concentrations were administered in a random sequence. The same protocol was administered at different time intervals: before starting the conditioning therapy (T0), during the conditioning therapy (T1) (two times), and every three months (two times) after engraftment post-HSCT (T2). A p-value < 0.05 was considered statistically significant. Fifty-one children (29 female and 22 male, mean age 5.2 ± 0.7 yr) were enrolled. Threshold value means for the four flavors increased during HSCT conditioning therapy (T1) (p < 0.01); intensity of perceived stimulus decreased during HSCT conditioning therapy (p < 0.01). At six months after engraftment (T2), both parameters had returned to starting values (T0). Changes in taste perception in children undergoing HSCT seem to occur especially during the conditioning therapy and resolve in about six months after engraftment post-HSCT.

Impact of COVID-19 on Outpatient Malnutrition Centers in Urban and Rural Burkina Faso.

Although the numbers of SARS-CoV-2 infections and related deaths are relatively low in sub-Saharan Africa, the pandemic might lead to a high indirect death toll there. We determined the impact of the COVID-19 pandemic on the management of malnourished children in urban and rural areas. We analyzed data from two Centers for Rehabilitation, Education & Nutrition (CRENs), one in the capital and one in a rural center, both run by the Camillian Fathers. We compared data from the year before the pandemic (2019) with the first 2 years during the pandemic (2020/2021). In the urban CREN, there was a sharp reduction in new patients enrolled, from 340 in the pre-pandemic year to 189 during the first pandemic year and 202 in the second year. The follow-up was significantly shorter during the first pandemic year, with a rebound in the second year (pre: 57 days versus 42 and 63 days for the first and second years, respectively). In the rural CREN, the situation was different: The numbers of patients did not show any significant variation between the pre-pandemic year (191) and the first and second pandemic years (223 and 179, respectively). Different perceptions of the pandemic in urban (high, more testing, more COVID) and rural (low, less information and testing) areas may partly explain this difference. The discrepancy between the decreasing numbers of malnourished children in specialized care during the pandemic-especially in the urban area-is contrary to the lockdown-induced increase in food insecurity and warrants attention to avoid an increase in the silent epidemic of malnourished children in Africa.

Clinical and molecular description of a Wilms tumor in a patient with tuberous sclerosis complex.

We report on a girl affected with tuberous sclerosis, carrying a germline de novo TSC2 mutation, c.4934-4935delTT, leading to a p.F1645CfsX7, who developed a unilateral Wilms tumor (WT). Molecular investigation of the tumor biopsy at diagnosis revealed the loss of the constitutional wild-type TSC2 allele, and loss of heterozygosity for the WT1 gene. Deletion of the WTX gene was also present, but it involved the functionally inactive X chromosome. No mutation affecting the remaining WT1 and WTX alleles, as well as the CTNNB1 gene was found. Pathological examination of the surgical specimen documented the presence of diffuse anaplasia and p53 immunoreactivity. To the best of our knowledge, this is the second report of a patient with tuberous sclerosis who developed a WT, and it represents the first case in which a detailed clinical and molecular description is provided.

Nonenteric Adenoviruses Associated with Gastroenteritis in Hospitalized Children.

The object of this study was to investigate the frequency of human adenovirus (HAdV) infections in hospitalized pediatric patients. Stool samples were collected during a 1-year period (February 2018 to January 2019). HAdV was detected by a broad-range PCR and genotyped by sequencing and phylogenetic analysis. Demographic characteristics and detailed clinical information were analyzed for each patient. HAdV was detected in 7.1% of stool samples (34/476). Among these patients, 23.5% were coinfected with other enteric viral or bacterial pathogens. The majority (85.2%) of HAdV positives were detected in children of <5 years of age. Two HAdV species (B and C) with three types were identified in this study population. HAdV species F was not detected. Genetic analysis shows that the isolates circulating in our region present high diversity and do not exhibit clonal expansion. The presence of nonenteric HAdV in subjects with gastrointestinal symptoms and in immunocompromised patients has already been reported by different studies and underlines the need to develop routine molecular assays that have wide reactivity for most types of adenovirus in order to obtain an optimal tool for their rapid and accurate diagnosis. IMPORTANCE Gastroenteritis is the second leading cause of death among infants and children worldwide. Our study shows that adenovirus types other than 40 and 41 might be related to acute gastroenteritis. Therefore, a novel approach using diagnostic methods able to detect all adenovirus types is desirable in order to overcome the limitations of the current techniques.

Impact of Ethnicity on COVID-19 Related Hospitalizations in Children During the First Pandemic Wave in Northern Italy.

There is increasing evidence that black people and other minorities have a higher incidence of severe COVID-19 disease, but little is known about the situation of children, especially in Europe. In general children are less infected and if so, frequently show mild or asymptomatic disease, making conclusions difficult. We collected data on SARS-CoV-2 associated hospitalizations in a well-defined population of 550,180 children up to 15 years in five hub-centers during the "first wave" at the heart of the pandemic in Northern Italy. Among the 451,053 Italian citizens 80 were hospitalized as compared to 31 out of 99,127 foreign citizens, giving a significantly higher risk (odds ratio 1.76; 95% CI: 1.16-2.66) for the foreign children. The risk was highest for children of African ethnicity as compared to Italians with an odds ratio of 2.76 (95% CI: 1.56-4.87). None of the patients deceased. There was no significant difference in age (thou infants regardless of ethnicity had a 10-fold higher risk), sex, length of hospitalization or comorbidities, namely overweight. As bureaucratic, cultural and information barriers mostly affect preventive and adult services and considering that in contrast to other countries, in Italy pediatric care is guaranteed free of (out-of-pocket) charge to all people <16 years, and hospitals are densely spaced, access to health care seems to be a minor problem. Thus, other possible root causes are discussed. We believe that this is an unbiased starting point to understand and overcome the reasons for the higher risk those children experience.

CD34+ Stem Cell Selection and CD3+ T Cell Add-Back from Matched Unrelated Adult Donors in Children with Primary Immunodeficiencies and Hematological Diseases.

Less than 25% of children who require hematopoietic stem cell transplantation (HSCT) for primary immunodeficiencies (PIDs) or genetic hematological diseases have an HLA-identical sibling. For them, a matched unrelated donor (MUD), although baring a greater risk of graft failure, delayed engraftment and immune reconstitution, and severe graft-versus-host disease (GvHD), represents a valid alternative. The stem cell source is also important, as unprocessed peripheral blood stem cells (PBSCs) contain 5 to 10 times more T cells than bone marrow (BM)-derived grafts, a major risk especially for small children with PID. A CD34+ positive selection can mitigate HLA compatibility issues, but the resulting CD3+ T cell depletion hampers engraftment and facilitates infections. To mitigate those problems, we decided to add back a certain number of T cells (30 × 106 cells/kg body weight [BW]) to the positive CD34+ selection derived from MUD BM or PBSCs and report the results in terms of time to engraftment and immune reconstitution, GvHD incidence, infections, and survival. Our aim was to show not only the feasibility and clinical efficacy of this addback but also that PBSC-derived CD34+ selected grafts with calibrated T cell addback would be equivalent to BM-derived grafts. We analyzed retrospectively our single-center cohort of 76 children (median age, 1.9 years) affected by PID (61) and hematological diseases (15) who received a total of 79 MUD HSCTs with CD34+ selection and addback of 30 × 106 CD3+ cells/kg BW between 2001 and 2019. We used descriptive and analytic statistics (chi-square, Student's t-test, Mann-Whitney U test, as appropriate) and constructed Kaplan-Meier curves using the log-rank test to compare patients grafted with BM or PBSC-derived inocula. The two groups showed no statistically significant differences in terms of age, sex, HLA-mismatch, or amount of CD3+ cells/kg BW added back to the CD34+ selection. However, the latter being higher in the PBSC group (P = .0001). Overall engraftment rate was 96% (73/76) and occurred faster in the PBSC group than in BM recipients: polymorphonuclear cells, 16 versus 21 days (P = .006); platelets, 15 versus 22 days (P = .001). GvHD incidence was low. No acute GvHD was diagnosed in 24 children, whereas grades I, II, III, and IV occurred in 19, 28, five, and three children, respectively (P not significant). Chronic GvHD was seen in only two children. The CD4+ count at six months after HSCT was higher in PBSC recipients as compared to those receiving BM (184 versus 88 CD4+ cells; P = .003). Overall survival for the whole cohort was 80% at 10 years, with no significant difference between the two stem cell sources (P not significant). Viral infections occurred among five of the PBSC grafted children and 14 in the BM group (P not significant), and no patient suffered from post-transplant lymphoproliferative disorder (PTLD). The results we present show that an addback of 30 × 106 donor CD3+ cells/kg recipient BW to a MUD BM or PBSC-derived CD34+ selection gives promising results in infants and young children undergoing HSCT for PID or hematological diseases. Furthermore, with this manipulation the inherent limits of PBSC-derived grafts can be overcome, allowing both swift engraftment and immune reconstitution without an increase in GvHD, infections, or PTLD.

Varicella zoster virus-induced hemolytic crisis in an infant with severe vitamin B 12 deficiency.

BACKGROUND: Vitamin B 12 deficiency is an uncommon disorder in infancy. Most cases are because of maternal deficiency resulting from insufficient storage and/or reduced intake and are generally seen in exclusively breast-fed infants. Accentuation of the hemolytic process has never been described in association with Varicella Zoster Virus (VZV) infections. OBSERVATION: We describe a 9-months-old breast-fed infant with megaloblastic anemia secondary to maternal vitamin B 12 deficiency. He presented severe pancytopenia and regression of motor functions and developed hemolytic crisis during a VZV infection. CONCLUSIONS: Nutritional cobalamin deficiency should be considered in anemic infants with a history of prolonged exclusive breastfeeding and delayed developmental milestones. VZV infection can trigger a hemolytic process in infants with severe megaloblastic anemia secondary to B12 deficiency. A normal mean corpuscular volume does not rule out megaloblastic anemia, when the condition is combined with severe hemolysis.

Primary Immunodeficiencies and Oncological Risk: The Experience of the Children's Hospital of Brescia.

Background and aims: Primary immunodeficiencies (PID) are characterized by recurrent infections and increased risk of malignancies because of the reduced immunological surveillance against cancer cells and oncogenic viruses. Methods: We report the incidence of tumors among 690 patients with PID, diagnosed from 1990 until 2017 in Brescia. Results: Out of 690 patients, 25 patients (3.6%) developed 33 tumors. Of the 25 affected patients, 8 patients suffered from common variable immunodeficiency (CVID), 5 from combined immunodeficiency (CID), 3 from Ataxia-telangectasia (AT), 2 from Hermanksy-Pudlak type 2 (HSP2), 2 from gammaglobulinemia X-linked (XLA), 2 from Wiskott-Aldrich syndrome (WAS), 2 from Hyper IgE syndrome (HIES), 1 from severe combined immunodeficiency (SCID). The age at diagnosis ranged from 1 to 52 years, with a median age of 19.6 years. The time between the diagnosis of PID and onset of tumor was short, often <1 year between diagnosis and the appearance of cancer in the case of CID. Moreover, in two cases of CID, the diagnosis of cancer was made before the diagnosis of PID, so cancer was the onset clinical manifestation. Hematological malignancies were prevalent (22/33, 66.7%) with a minority of solid tumors (11/33, 33.33%). In particular Non-Hodgkin lymphomas were the most frequent (16/33, 48.48%). In total 13 patients survived (52%) and tumor was the main cause of death (7 cases). Two patients underwent BMT once the disease was in remission. Conclusions: Therefore, the correct management of tumors that arise in patients with primitive immunodeficiency still represents a challenge in the pediatric field. For this reason now it is mandatory to collect in a unique international registry the cases of malignancies in PID that could lead to a better understanding of the etiopathogenesis and of the biological and clinical characteristics of these tumors, with the aim of defining adequate preventive measures and guaranteeing an early diagnosis which also creating a shared and specific therapeutic strategy, with the prospect of obtaining a better prognosis for these patients.

Persistent Infection with Rotavirus Vaccine Strain in Severe Combined Immunodeficiency (SCID) Child: Is Rotavirus Vaccination in SCID Children a Janus Face?

We report the first case, to our knowledge, in Italy, of a severe combined immunodeficiency patient with a persistent rotavirus infection due to a vaccine derived strain. Rotavirus was detected by enzyme immunoassays and RT-PCR in stool specimens for five months. The persistent infection was resolved after complete immune reconstitution achieved by hematopoietic stem cell transplantation. This case underlines the importance of neonatal SCID_screening.

A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia.

MYC-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent MYC-translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis. The University of Padua T-cell acute lymphoblastic leukemia 13 (UP-ALL13) cell line has all the main features of the above described MYC-translocated T-ALL. Interestingly, UP-ALL13 was found to harbor a heterozygous R882H DNMT3A mutation typically found in myeloid leukemia. Chromatin immunoprecipitation coupled with high-throughput sequencing for histone H3 lysine 27 (H3K27) acetylation revealed numerous putative super-enhancers near key transcription factors, including MYC, MYB, and LEF1. Marked cytotoxicity was found following bromodomain-containing protein 4 (BRD4) inhibition with AZD5153, suggesting a strict dependency of this particular subtype of T-ALL on the activity of super-enhancers. Altogether, this cell line may be a useful model system for dissecting the signaling pathways implicated in NOTCH1-independent T-ALL and for the screening of targeted anti-leukemia agents specific for this T-ALL subgroup.

BTK: 22 novel and 25 recurrent mutations in European patients with X-linked agammaglobulinemia.

X linked agammaglobulinemia (XLA) is an immunodeficiency disease caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK), that is involved in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B lineage lymphoid cells. XLA is a primary immunodeficiency disorder characterized by lack of mature, circulating B lymphocytes, and recurrent infections. Using Single Strand Conformation Polymorphism (SSCP) followed by direct sequencing we investigated 57 patients with XLA phenotype, with or without a positive family history, from 52 unrelated families enrolled in the Italian XLA Multicenter Clinical Study. We have identified 25 recurrent mutations, 22 novel mutations including one large deletion comprising the coding sequence from exon 11 to 18. Among the mutations identified, three were detected in different unrelated families, whereas all the others were private mutations.

Epstein-Barr virus-associated adrenal smooth muscle tumors and disseminated diffuse large B-cell lymphoma in a child with common variable immunodeficiency: a case report and review of the literature.

This article reports the clinical and the histological features in a 7-year-old girl affected by common variable immunodeficiency (CVID) who developed multiple Epstein-Barr virus-associated tumors, represented by bilateral adrenal smooth muscle tumors (EBV-SMT) and multifocal diffuse large B-cell lymphoma. The EBV-SMTs showed features compatible with a benign or at least a low-malignant potential neoplasm. A peculiar feature observed in both EBV-SMTs was the occurrence of numerous lymphocytes intermingled with the spindle cells, which consisted of CD3+ CD5+ T-cells, with a predominant cytotoxic CD8+ component. Interestingly, EBV status differed in the neoplasms, since the EBV-SMTs were negative for LMP1 and positive for EBER, whereas the B-cell lymphoma expressed both EBV markers. Furthermore, EBV-LMP1 deletion was positive only in the EBV-SMTs, thus indicating that these tumors were the consequence of 2 distinct, EBV-dependent transformations. Similarly, lymphocyte clonality assay also showed different clonal bands in different sites (skin and nasal cavity), suggesting the development of intratumoral mutations. Finally, the authors review all 127 previously reported EBV-SMT, with discussion of their clinical and pathological features.