Efficacy of haematopoietic stem cell boost as a rescue for poor graft function after haematopoietic stem cell transplantation: A multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two-year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines.

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.

BACKGROUND: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.

Next-Generation Sequencing for Diagnosis and Tailored Therapy: A Case Report of Astrovirus-Associated Progressive Encephalitis.

A boy with X-linked agammaglobulinemia experienced progressive global motor decline, cerebellar syndrome, and epilepsy. All standard polymerase chain reactions for neurotropic viruses were negative on cerebrospinal fluid and brain biopsy. Next-generation sequencing allowed fast identification of a new astrovirus strain (HAstV-VA1/HMO-C-PA), which led to tailor the patient's treatment, with encouraging clinical monitoring over 1 year.

An update on pediatric invasive aspergillosis.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised adults and children, the number of which has been continuously increasing in the last decades. The purpose of our review was to provide epidemiological, clinical, and biological data and antifungal treatment options in the pediatric population. Several biological assays (galactomannan enzyme immunoassay, ß-D-glucan, detection of Aspergillus spp. DNA) have proven useful adjuncts for the diagnosis of IA in adult studies. However, data on these assays in children is limited by small sample sizes and sometimes conflicting results concerning their sensitivity/specificity. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. It is thus necessary to develop new antifungal formulations specifically adapted to the pediatric population and to evaluate their pharmacokinetic/pharmacodynamic profile, their safety, and their effectiveness in infants and children.

Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.

OBJECTIVE: To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. METHODS: A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. RESULTS: 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. CONCLUSIONS: Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.

[SFGM-TC recommendation on indications for allogeneic stem cell transplantation in children with congenital neutropenia]. / Indications d'allogreffe dans les neutropénies constitutionnelles : recommandation de la SFGM-TC.

In this report, we address the issue of allogeneic stem cell transplantation in children with congenital neutropenia. Constitutional disorders with neutropenia are exceptional. Treatment and prevention of severe infections are a major concern in the management of chronic neutropenia. These disorders, especially Kostmann's disease and Shwachman-Bodian-Diamond syndrome, are associated with an increased risk of leukemia. The role of allogeneic stem cell transplantation in these patients is still unclear. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

[Hurler syndrome: early diagnosis and treatment]. / Syndrome de Hurler : diagnostic et prise en charge précoces.

Hurler syndrome, the most severe form of mucopolysaccharidosis type I (MPS I), is a rare lysosomal storage disease. The overall incidence of MPS I is 0.99-1.99/100,000 live births. Accumulation of glycosaminoglycans causes the progressive dysfunction of multiple organs. We report the case of a 3-week-old newborn who was hospitalized in the Neonatal Intensive Care Unit for feeding problems. Coarse facial features and gingival hypertrophy, associated with axial hypotonia, upper airway obstruction, and moderate hepatomegaly, led to the early diagnosis of MPS I at 3 weeks of age and was confirmed by an abnormally elevated amount of dermatan and heparan sulphate in the urine and complete deficiency of alpha-L-iduronidase lysosomal enzyme activity. The child was homozygous for the p.W402X mutation, located on chromosome 4p16.3 of the alpha-L-iduronidase (IDUA) gene. The clinical condition gradually deteriorated until the age of 4 months, with thoracic and lumbar dysostoses, glaucoma, cerebral ventricular dilatation and cervical spinal stenosis, dilated cardiomyopathy, and umbilical hernia. Early diagnosis allowed enzyme replacement therapy (iaronidase, Aldurazyme(®), Genzyme) started at the age of 5 months, which provided stabilization of the heart disease, significant regression of rhinologic symptoms, and regression of hepatomegaly. Cord blood hematopoietic stem cell transplantation was performed at 11 months of age, allowing optimal preservation of cognitive development.

Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children.

Scarce data exist on allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in hepatitis B virus (HBV)-naïve recipients from HBV-experienced donors. Long-term follow-up is herein reported for 17 allogeneic HSCT performed in 13 HBV-naïve children from HBc-antibodies-positive donors between 2006 and 2012. Four donors were HBs-antigen-positive, with detectable but low viremia in 2 cases (<2 log10IU/ml). HBV-DNA was undetectable in all transplanted cell products. Recipients' HBV prophylaxis consisted of pre-transplant vaccination, polyvalent immune globulins, specific anti-HBV immune globulins, and/or oral lamivudine in 3, 12, 8, and 8 children, respectively. No case of HBV transmission occurred based on negative close monitoring of recipients' HBV serology and plasma HBV-DNA during a median follow-up of 22 months. In case of undetectable viremia in the donor, prophylaxis with vaccination and/or immune globulins in the recipient seems to be sufficient and lamivudine prophylaxis might be unnecessary to prevent viral transmission. In case of undetectable viremia in the donor, a systematic screening of HBV DNA in the stem cell product might be unnecessary to confirm the low risk of viral transmission. Prior exposure to HBV in the donor should not be considered a contraindication to HSCT.

Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder characterized by neonatal autoimmune enteropathy, diabetes and thyroiditis, food allergies and skin rash. IPEX syndrome is caused by mutations in FOXP3, a master control gene of regulatory T cells (Tregs), resulting in absent or dysfunctional Tregs. Data in the literature are scarce and the cutaneous manifestations are rarely depicted. OBJECTIVES: To evaluate the frequency and characteristics of cutaneous manifestations found in IPEX. METHODS: Retrospective single-centre study of a case series of IPEX. Patients' data were retrieved from medical files and numerous parameters concerning general and cutaneous characteristics of the disease were recorded. RESULTS: Ten children with IPEX were studied. Cutaneous involvement was present in seven of 10 children; age at onset was 0-4 months, median 1.5. All patients presented with atopic dermatitis (AD). Three presented more psoriasiform lesions. Eczema was severe; most affected areas were lower limbs, trunk and face. Pruritus was present in four of seven, and painful fissurary cheilitis in four of seven. Hyper-IgE was found in seven of 10 and hypereosinophilia in five of 10. Skin biopsies showed eczematiform or psoriasiform features. Affected patients were improved by dermocorticoids; no clear improvement was obtained with immunosuppressive regimens. Other features were urticaria secondary to food allergies and staphylococcal sepsis, mostly Staphylococcus aureus and catheter related. CONCLUSIONS: AD seems to be a frequent finding in IPEX syndrome, which is characterized by Treg anomalies. This hints to a possible role of Tregs in AD, which is then discussed in this study.

Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring.

INTRODUCTION: Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. PURPOSE: A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. METHOD: Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years). RESULTS: No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

Description of an adenovirus A31 outbreak in a paediatric haematology unit.

Adenovirus infections result in significant morbidity and mortality in allogeneic haematopoietic stem cell transplanted (hSCT) children. Adenovirus from species C and B account for more than 90% of adenoviruses recovered after hSCT. However, infections due to adenovirus A31 have been increasingly reported in recent years. Between April 2002 and April 2005, blood samples obtained every 2 weeks from 58 hSCT children were screened for adenovirus species A to C by quantitative real-time PCR. Phylogenetic analysis was realized after amplification and sequencing of the entire hexon gene. Fifteen cases of adenovirus infection with viraemia were recovered during this 3 years period. During spring/summer 2003, seven cases occurred and were due to an adenovirus species A. Phylogenetic analysis of the seven strains showed that they belonged to the A31 genotype and shared 100% homology. Clinical features of the seven HSCT children with A31 adenovirus viraemia are described. We describe here an epidemic spread of adenovirus genotype A31 in a paediatric haematology unit. Timing, location and hexon gene genotyping results highly suggested a nosocomial origin to this epidemic. The burden of adenovirus A31 infection needs to be further assessed in this context.

[Paediatric intervertebral calcifications: two cases report and review of the literature]. / Calcifications discales de l'enfant: à propos de deux observations et revue de la littérature.

UNLABELLED: Discal calcification in childhood is rare. Calcifications are occasionally discovered during routine examinations. Generally, the calcification process is confined to the nucleus pulposus of the intervertebral disc. CASES REPORT: We describe the cases of two children, five and seven years old who presented with acute low back pain. The patients underwent a CT scan, which demonstrated a posterolateral calcified disc hernia. DISCUSSION: Only a few cases with evidence of calcification of the herniated portion of the disc have been previously described. The clinical picture is composed of pain and functional limitation. The radiographic picture consists of the association of morphological and structural alterations of vertebral bodies adjacent to one or more disc calcifications usually centrally sited, sometimes associated with anterior or posterior herniations. The surgical decompression of the nerve root could be necessary.

Early balloon dilatation of the pulmonary valve in infants with tetralogy of Fallot. Risks and benefits.

BACKGROUND: Balloon dilatation, an established treatment for pulmonary valve stenosis, remains a controversial procedure in tetralogy of Fallot. METHODS AND RESULTS: Balloon dilatation of the pulmonary valve was performed in 19 infants with tetralogy of Fallot. Its effects on the severity of cyanosis, the growth of the pulmonary valve and pulmonary arteries, and the need for transannular patching were evaluated. Clinical, echographic, angiographic, hemodynamic, and operative data were analyzed. The procedure was safe in all, without significant complications. After balloon dilatation, systemic oxygen saturation increased from a mean value of 79% to 90%. This increase proved to be short-lasting in 4 patients, who required surgery before the age of 6 months. Balloon dilatation increased pulmonary annulus size in each case, from a mean value of 4.9 to 6.9 mm (P < .001). This gain in size remained stable over time, with a mean Z score of -4.8 SD before dilatation, -3.1 SD immediately after the procedure, and -2.7 SD at preoperative catheterization (P < .001). Pulmonary artery dimensions remained unchanged immediately after balloon dilatation but increased at follow-up from a Z score mean value of -2.5 to -0.06 SD and from -2.2 to 0.04 SD for right and left pulmonary arteries, respectively (P < .001). At the time of corrective surgery, the pulmonary annulus was considered large enough to avoid a transannular patch in 69% of the infants. This represented a 30% to 40% reduction in the need for a transannular patch compared with the incidence of transannular patch expected before balloon dilatation. CONCLUSIONS: Pulmonary valve dilatation in infants with tetralogy of Fallot is a relatively safe procedure and appears to produce adequate palliation in most patients. It allowed the growth of the pulmonary annulus and of the pulmonary arteries, resulting in a mean gain of 2 SD for those structures.