From the original SARS-CoV-2 strain to the Omicron variant: Predictors of COVID-19 in ambulatory symptomatic children.

OBJECTIVES: To determine the predictors of a positive SARS-CoV-2 test in a pediatric ambulatory setting. PATIENTS AND METHODS: We performed a cross-sectional prospective study (November 2020-February 2022) of 93 ambulatory settings in France. We included symptomatic children < 15 years old tested for SARS-CoV-2. For each period corresponding to the spread of the original strain and its variants (period 1: original strain; period 2: Alpha, period 3: Delta; period 4: Omicron), we used a multivariate analysis to estimate adjusted odds ratios (aORs) associated with COVID-19 among age, signs, symptoms or contact, and 95 % confidence intervals (95CIs). RESULTS: Of 5,336 children, 13.9 % (95CI 13.0-14.8) had a positive test. During the first three periods, the positivity rate ranged from 5.6 % (95CI 4.6-6.7) to 12.6 % (95CI 10.8-14.6). The main factors associated with a positive test were contact with an infected adult at home or outside the home (aOR 11.5 [95CI 4.9-26.9] to 38.9 [95CI 19.3-78.7]) or an infected household child (aOR 15.0 [95CI 4.8-47.1] to 28.4 [95CI 8.7-92.6]). By contrast, during period 4, aORs for these predictors were substantially lower (2.3 [95CI 1.1-4.5] to 5.5 [95CI 3.2-7.7]), but the positivity rate was 45.7 % (95CI 42.3-49.2). CONCLUSIONS: In pediatric ambulatory settings, before the Omicron period, the main predictor of a positive test was contact with an infected person. During the Omicron period, the odds of these predictors were substantially lower while the positivity rate was higher. An accurate diagnostic strategy should only rely on testing and not on age, signs, symptoms or contact.

Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience.

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

Childhood diagnosis of genetic thrombocytopenia with mutation in the ankyrine repeat domain 26 gene.

UNLABELLED: The most common diagnosis for pediatric thrombocytopenia is immune thrombocytopenia. Nevertheless, in atypical cases, the hypothesis of an inherited thrombocytopenia has to be investigated. We report a series of cases of a newly described entity, genetic thrombocytopenia with mutation in the ankyrine 26 gene, diagnosed from the exploration of five pediatric cases of thrombocytopenia. This entity is characterized by a moderate thrombocytopenia with normal mean platelet volume, and poorly bleeding. Its transmission is autosomal dominant. Final diagnosis is made by sequencing of a short DNA region of ANKRD26 gene. This pathology can be considered as an hematological malignancy predisposition syndrome. CONCLUSION: We report the first cohort of pediatric patients diagnosed with thrombocytopenia with mutation in the ankyrine 26. The aim is to underline the specificities of this entity in children and bring it to the knowledge of pediatricians who may be in first place to manage these patients. WHAT IS KNOWN: • Genetic thrombocytopenia with mutation in the ankyrine 26 gene is a recently described entity, which seems to be considered as a predisposition for hematologic malignancies. • The first cohort has been reported in 2011, by Noris et al., in 78 Italian adult patients. What is New: • We describe clinical and biological features of the first pediatric cohort diagnosed with genetic thrombocytopenia with mutation in the ankyrine 26 gene. • It seemed important to consider the pediatric specificities of this entity to enable pediatricians to investigate, diagnose, and manage pediatric patients and their families.

Non-invasive biological quantification of acute gastrointestinal graft-versus-host disease in children by plasma citrulline.

Clinical grading of GI involvement during acute GVHD remains a challenging issue, especially in children. Plasma citrulline, a non-protein amino acid selectively produced and released by enterocytes, is a suitable surrogate endpoint for small intestinal epithelial cell mass, irrespective of the underlying cause of cell loss. Children referred for allogeneic bone marrow transplantation who were free from chronic malabsorption or constitutional disease involving the GI tract were consecutively included in this prospective study. Plasma citrulline and albumin concentration was measured every week between day 7 and day 28 of BMT until resolution of the aGVHD or occurrence of chronic GVHD. In total, 31 children were included between 2008 and 2011. After a CR, citrulline levels fell to a minimum level on day 7 and then increased to reach the initial value on day 28. After day 28, plasma citrulline but not albumin was strongly linked to the occurrence of GI GVHD, the threshold being set at 10 µmol/L. The correlation with clinical grade of GI-aGVHD now needs to be assessed in larger populations. In pediatric patients, citrulline is valuable as a suitable non-invasive marker of GI involvement in acute GVHD.

[The alliance of the parent, child and the nurse to challenge medical error]. / L'alliance parents-enfant-soignants à l'épreuve de l'erreur médicale.

A group composed of parents, nurses, and physicians involved in pediatric cancerology has reflected on medical errors within the Espace Éthique de l'Assistance publique-Hôpitaux de Paris. Based on narratives and qualitative analysis of histories and testimonies, this discussion aimed at exploring the causes, circumstances, and impacts of medical errors on the relations between these individuals. The study demonstrated that some circumstances actually promote medical errors, such as hard working conditions, mistrust, unreliable control procedures, not listening to parents, and caring for children in extreme situations of pain and suffering. Errors almost always result from the accumulation of several shortcomings. The tensions raised by a medical error can be overcome, provided that parents and caregivers trust each other from the onset of disease and that the medical errors are disclosed in a sincere way, whatever the medical consequences. The feelings raised by the painful experience of a medical error do not solely depend on the severity of the consequences, since seemingly benign errors may lead to long-term trauma, whereas severe errors, even those leading to death, do not necessarily breach trust. The keyword here is permanent vigilance. The capacity of caregivers to question their practice, from both a technical and ethical point of view, will determine their ability to learn from an error for the future. The depth and quality of this questioning, in the best of times encouraged by the institution, may also help children affected by a medical error and their family to move forward in their personal history, beyond such painful experiences.

[Is there a risk of steroid-induced adrenal deficit after induction treatment of acute lymphoblastic leukemia?]. / Existe-t-il un risque de déficit corticotrope au décours du traitement d'induction d'une leucémie aiguë lymphoblastique ?

The occurrence of eight cases of adrenal deficit in children hospitalized for acute lymphoblastic leukemia (ALL) led us to conduct a prospective study from May 2006 to May 2007 to better characterize this corticoid-induced adrenal deficit. Forty of the 48 patients hospitalized for ALL were given a low-dose Synacthen test (1 µg), a mean 7 days after the induction phase. An adrenal deficit was diagnosed in 27 patients (67.5%). No significant clinical or hematological difference was identified between the "with deficit" (n = 27) and "without deficit" (n = 13) groups. The diagnosis of adrenal deficit was not more common for children who had received dexamethasone (13/19) or prednisone (14/21), or for those who had (19/29) or had not (8/11) experienced corticoid toxicity during induction. The clinical signs suggesting adrenal deficit were identical in the two groups and none of the children presented an acute episode. In biological terms, only hypoprotidemia was significantly more common in patients with adrenal deficit (p = 0.0004). Of 13 patients with a deficit at the end of the induction who had received a 2nd low-dose Synacthène(®) test before intensification no. 1, 3 weeks on average after the end of corticotherapy, only two still had a deficit. Thus, corticoid-induced adrenal deficit is a common complication in children treated for ALL, although it is not highly symptomatic. Most of these children recover normal adrenal function before intensification no. 1, but it does not eliminate the risk of a secondary deficit after other courses of corticotherapy. Systematic repeated Synacthène(®) tests in common practice among children treated for ALL does not seem justified. However, the results of this study encouraged us to propose a hydrocortisone substitution to children treated for ALL in the event of stress.

Parental comprehension and satisfaction in informed consent in paediatric clinical trials: a prospective study on childhood leukaemia.

OBJECTIVE: To evaluate the extent to which parents are satisfied with and understand the information they are given when their consent is sought for their child to participate in a phase III randomised clinical trial and the reasons for their decision. PATIENTS AND METHOD: The authors carried out a prospective study. The authors included all parents whose consent was sought for their child to participate in the FRALLE 2000A protocol (acute lymphoblastic leukaemia) at two centres. The parents were questioned twice by a qualified psychologist using a semidirected interview, 1 and 6 months after consent was sought. RESULTS: 43 first interviews were carried out. All the parents declared they were satisfied with the explanations provided by the physician. 35 (81%) parents felt that the information provided with the request for consent was appropriate. Eight (19%) parents did not realise that their child had been included in a research protocol. 16 (39%) parents did not understand the concept of randomisation. Half the parents could explain neither the aim of the clinical trial nor the potential benefit of inclusion to their child. Only one third of the parents were aware that they had an alternative. The principal factor underlying their decision, as stated by 29 parents (67%), was confidence in the medical team. CONCLUSIONS: The parents signed consent forms without having fully understood all the elements specific to the experimental protocol. Rather, the parents based their decision on their confidence in the medical team, even when their child's life was at risk.

Hematopoietic progenitor cell mobilization and harvesting in children with malignancies: do the advantages of pegfilgrastim really translate into clinical benefit?

Our purpose was to assess success rates in children of achieving optimal hematopoietic progenitor cells (HPCs) harvest after mobilization with 300 microg/kg pegfilgrastim. Between January 2005 and January 2007, 26 children with solid malignancies who were referred for HPC collection were consecutively included. Hematopoietic progenitor cell mobilization consisted of one s.c. injection of 300 microg/kg body weight (BW) of pegfilgrastim. The success criterion was defined as at least 5 x 10(6) CD34+ cells/kg during the first standard apheresis (less than 3 blood volumes processed (BVP)). After 26 inclusions, the Bayesian analysis gave a mean estimated success rate of 60.7% (95% credibility interval: 42.0-78.0%). The first apheresis allowed the collection of 8.3 x 10(6) CD34+ cells/kg BW (range 0.6-37.8), with a median of 2.8 BVP (range 1.4-3.0). Overall, the median of CD34+ cells collected was 12.4 x 10(6)/kg (range 2.7-37.8). The cumulative dose of anthracyclin was the only variable associated with the total number of CD34+ collected cells (P<0.05). Mobilization was clinically well tolerated in 20 patients. No drug-related adverse events of grade > or =3 occurred. We conclude that a single injection of 300 microg/kg pegfilgrastim in the hematological steady state is an efficient and well-tolerated method of HPC mobilization in children with solid malignancies.

Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification.

Whereas neuroblastoma (NB) with MYCN amplification presents a poor prognosis, no single marker allows to reliably predict outcome in tumours without MYCN amplification. We report here an extensive analysis of 147 NB samples at diagnosis, without MYCN amplification, by chromosomal comparative genomic hybridisation (CGH), providing a comprehensive overview of their genomic imbalances. Comparative genomic hybridisation profiles showed gains or losses of entire chromosomes (type 1) in 71 cases, whereas partial chromosome gains or losses (type 2), including gain involving 17q were observed in 68 cases. Atypical profiles were present in eight cases. A type 1 profile was observed more frequently in localised disease (P<0.0001), and in patients of less than 12 months at diagnosis (P<0.0001). A type 2 genomic profile was associated with a higher risk of relapse in the overall population (log-rank test; P<0.0001), but also in the subgroup of patients with localised disease (log-rank test, P=0.007). In multivariate analysis, the genomic profile was the strongest independent prognostic factor. In conclusion, the genomic profile is of prognostic impact in patients without MYCN amplification, making it a help in the management of low-stage NB. Further studies using higher-resolution CGH are needed to better characterise atypical genomic alterations.

[How to discuss death with a dying child: a story can help?]. / Comment parler de la mort à un enfant en fin de vie: un conte peut-il être une aide?

Is it necessary - and possible - to discuss death with a child in palliative phase? How should one approach the subject? A recent Swedish study demonstrated the benefits for parents who discussed with their child his or her imminent death, and raised the question of the role nursing can play to help parents. The mother of one child treated in our unit recently wrote a story 48 hours before the child's death. The story served to broach a number of recurrent questions often raised by dying children and their families: fear of the unknown, of being replaced, the inevitability of death, grief, and fear of being forgotten... The story was given to 13 families with dying children. In order to evaluate the story's impact on families and to determine whether a document which stimulates dialogue should continue to be given to parents, we asked that they fill out a questionnaire. Fifty-five percent of parents answered, and confirmed that the story was experienced as a positive thing and helped parents to talk with their children. This study raises many questions and should be part of a global accompaniment strategy. A review of medical, general and children's literature, as well the results of our study, lead us to conclude that the medical body should lend its full support to families who wish to engage in this dialogue with their children.

Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML).

In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBFalpha/beta genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in 17% patients. c-Kit exon 8 mutations were more frequent in inv(16) than in t(8;21) subset (20 versus 6%). Only one patient had FLT3-ITD but FLT3-D835 was as frequent as reported in AML population (7%). Ras mutations were significantly more frequent in inv(16) than in t(8;21) subset (36 versus 8%, P=0.001). RTK mutations were associated with a higher white blood cell count (WBC) (36 versus 21 G/L, P=0.05). FLT3 mutations were significantly associated with a shorter EFS and survival (P<0.0001 and P=0.0002) owing to an excess of early events. c-Kit mutations were associated with a shorter EFS and RFS (P=0.002 and P=0.003) in t(8;21) but not inv(16) patients. As previously observed, Ras mutations did not affect prognosis. Screening for RTK mutations may help to identify patients with a more adverse outcome and thus susceptible to benefit from intensified protocols or RTK inhibitors.

Survival in France after childhood acute leukaemia and non-Hodgkin's lymphoma (1990-2000).

This article describes the survival after childhood acute leukaemia (AL) and non-Hodgkin's lymphoma (NHL) of French population aged less than 15 years. The French National Registry of Childhood Leukaemia and Lymphoma recorded 3995 cases of acute lymphoblastic leukaemia (ALL), 812 of acute myeloid leukaemia (AML) and 1137 of NHL over the period from 1990 to 2000. Overall survival rates at 5 years were 82% (95% CI 80-83), 58% (95% CI 54-61) and 87% (95% CI 85-89) for ALL, AML and NHL, respectively. Survival after AL increased from 77% (95% CI 75-80) in 1990-1992 to 85% (95% CI 83-87) in 1997-2000 for ALL and from 47% (95% CI 41-54) to 61% (95% CI 55-67) for AML. Among AL cases, children aged 1-4 years had the most favourable prognosis. Down's syndrome was associated with poor survival after ALL. No gender-related variations in survival were in evidence. The results reported herein are similar to those reported by other European registries and clinical trials.

[Quality of life of adolescents surviving childhood acute lymphoblastic leukemia]. / Vécu des adolescents guéris d'une leucémie aiguë lymphoblastique.

PURPOSE: To evaluate how adolescents and young adults cured of acute lymphoblastic leukemia (ALL) treated during childhood have integrated the disease, and possible death related to cancer. Particularly, we have focused on experiences related to diagnosis announcement, hospitalisation and treatments and consequences on their social, psychological and somatic behaviour. PATIENTS: Forty-one patients cured of ALL have been enrolled in the study and answered one interview with clinical psychologist or research nurse. RESULTS: Although 60% of the patients argued that they think rarely of their disease, 10% thought about it every day. Traumatic evidence was detectable in most of them. Physical pain was the most reported stress, mainly during hospitalisation (93%), as well as psychological suffering (83%). Afterwards, the mostly often-reported stress was psychological pain (61%). Sixty-six percent declared that they still experience psychological and health consequences at the time of the interview, in some cases reported as a handicap in their life. In 83% of the cases they considered themselves as cured, nevertheless fear of relapse persisted in 1/3. Ninety percent said they have a pleasant life, 56% did not like to talk about leukaemia and 70% thought they could have died. For 85%, disease has been the most important event of their life and 75% testify to repercussions of the disease on their family (family relationship changes, overprotection, siblings difficulties). CONCLUSION: Most of these patients declared to be 'as the others' and developed life projects, but overcoming the pain experience of the disease remained difficult. This study emphasized the need for long-term continuous information and reinforces the importance of addressing treatment psychological and physical pain mainly after the initial hospitalisation period.

[Evans' syndrome: a retrospective study from the ship (French Society of Pediatric Hematology and Immunology) (36 cases)]. / Syndrome d'Evans: étude rétrospective de la société d'hématologie et d'immunologie pédiatrique (36 cas).

UNLABELLED: Evans' Syndrome (ES) is defined as the combination of immune thrombocytopenia (ITP) and autoimmune haemolytic anemia (AIHA), in the absence of any known underlying etiology. Pathophysiology, epidemiology and outcome remain unclear. POPULATION: Thirty-six children (20 male, 16 female), who were diagnosed in the SHIP french centres (Société d'hématologie et d'immunologie pédiatrique) between 1990 and 2002 with ES, were included in this retrospective study. RESULTS: Median age at diagnosis was 4 years. In 21 children, ES occurred in the setting of consanguinity, family history of autoimmune/inflammatory disease, associated autoimmune disorder or immunoregulatory abnormalities (serum imunoglobulins, peripheral blood lymphocytes subsets, low level of the C3-C4 complement components, nuclear antibodies). Several successive treatments were used in this serie (median: 3, range: 0-10) including corticosteroid therapy (35/36), intravenous immunoglobulins (32/36), immunosuppressive agents (14/36), splenectomy (9/36) and anti CD 20 monoclonal antibodies (6/36). Patients with a low level of serum immunoglobulins were more often non-responders to corticosteroidtherapy/intravenous immunoglobulins and required more frequently further therapy (P=0.03). Three patients died (intracranial bleeding, N=2, Guillain-Barre syndrome; N=1). CONCLUSION: ES was a severe, life-threatening disease, requiring aggressive immunosuppressive therapy in as many as half the patients. Our forthcoming study aims to (i) describe homogeneously-studied and prospectively-analysed cohort of childhood ES, (ii) separate ES from specific immune deficiency (especially fas gene mutations), generalised autoimmune/inflammatory disorders and genetic diseases, (iii) identify well-defined ES subsets, (iv) establish prognostic factors and optimal treatment within these subsets.

Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit--multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group.

From 1989 to 1998, 341 children were included in the French multicentric LAME (Leucémie Aiguë Myéloblastique Enfant) trials. A total of 309 children were registered in the LAME 89/91 protocol. This intensive regimen included an induction phase (mitoxantrone plus cytarabine), two consolidation courses, one containing timed-sequential high-dose cytarabine, asparaginase and amsacrine; 276 (90%) achieved a CR. The 5-year overall survival (OS) and event-free survival (EFS) were 60+/-4 and 48+/-4%, respectively. From 1997, timed-sequencing of the LAME SP induction chemotherapy led to an unacceptable frequency of consolidation delay; future improvements are unlikely to come from further increases in intensity. The role of allogenic bone-marrow transplantation from an HLA-identical sibling in CR1 was examined. The disease-free survival (DFS) was 52+/-4% for non-allografted patients and 57+/-7% for allografted patients (P=NS); a better OS for allografted patients was shown and could be related either to allo-BMT early in CR1 or to a second allo-BMT in CR2. For the complete responders after consolidation therapy, the 5-year OS was significantly better in patients randomized for no maintenance therapy (MT-) than in patients randomized for MT (77.6+/-8 vs 59+/-8%; P=0.05), while the 5-year DFS was not significantly different. Exposure to low-dose MT might contribute to clinical drug resistance and treatment failure in relapsing patients.

Listing of common HLA alleles and haplotypes based on the study of 356 families residing in the Paris, France, area: implications for unrelated hematopoietic stem cell donor selection.

In this study we have identified frequent human leukocyte antigen (HLA)-A, -B, -C,-DRB1, and -DQB1 alleles, frequent HLA-B/C, HLA-DRB1/DQB1 two-allele associations, and the most common HLA-A/B/C/DRB1/DQB1 five-locus haplotypes in a population residing in the Paris, France, area. The study was carried out in 356 families of children awaiting hematopoietic stem-cell transplantation (HSCT), with the selection criterion that haplotypes could be assigned with certainty to both the patient and at least one parent. Parental haplotypes were HLA-A, -B serologically typed, and HLA-C, -DRB1, -DQB1 broadly typed by polymerase chain reaction-sequence-specific oligonucleotide probe. The alleles of the most frequent haplotypes were subsequently defined at a high-resolution level by polymerase chain reaction-sequence-specific primer. The results on the distribution of common alleles and common allele associations demonstrated similarities with the previously published data in Caucasian populations, as expected from the geographic origin of the studied population. More importantly, this study provides the largest listing of common B/C and DRB1/DQB1 associations and of common five-allele haplotypes defined with certainty in a Caucasian population to date. These results can be used to help estimate the likelihood of finding a suitable donor in unrelated HSCT and to delineate search strategies for potential donors.

[Disseminated fusarium infection in two neutropenic children]. / Fusariose disséminée chez deux enfants neutropéniques.

UNLABELLED: Disseminated fusariosis in children is a rare and serious fungal infection, that occurs especially in neutropenic immunosuppressed patients, treated for malignant hemopathy, or bone marrow transplant recipient. Treatment is difficult and mortality is estimated between 50 and 70% in adult patients. CASE REPORT 1: A ten-year-old boy, treated for an acute lymphoblastic leukemia in second relapse, presented a disseminated fusarium spp infection, that occurred during neutropenia. He died due to fusariosis infection in spite of amphotericin B treatment. CASE REPORT 2: A ten-year-old neutropenic girl, treated for an acute myeloïd leukemia, presented disseminated fusariosis, uncontrolled by amphotericin B. Recovery was observed after voriconazole introduction and resolution of neutropenia. Ten months later, she presented a leukemia's relapse, treated by new intensive chemotherapy with secondary prophylaxis by voriconazole, without fusariosis's recurrence. CONCLUSION: Voriconazole, a new triazole agent, seems to be an alternative antifungal agent to amphotericin B for disseminated fusarium infection, either at the acute phase or for secondary prophylaxis.