Juvenile neuropsychiatric systemic lupus erythematosus: A specific clinical phenotype and proposal of a probability score.

OBJECTIVE: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic auto-immune disease involving several organs. Neuropsychiatric (NP) SLE (NPSLE) is frequent in j-SLE and associated with increased morbidity/mortality. Although NPSLE classification criteria exist, attributing NP features to j-SLE remains a major challenge. The study objective is to thoroughly describe j-NPSLE patients and assist in their diagnosis. METHODS: This is a 4-year retrospective monocentric study of j-SLE patients. NP events were attributed to j-SLE using standardised diagnostic criteria and multidisciplinary paediatric clinical expertise. Clinical features, brain magnetic resonance imaging (MRI)s and samples analysis including cerebrospinal fluid were assessed. A risk of j-NPSLE score was developed based on multivariable logistic regression analysis. RESULTS: Of 39 patients included, 44% were identified as having j-NPSLE. J-NPSLE diagnosis was established at the onset of j-SLE in 59% of patients. In addition to frequent kidney involvement (76%) and chilblains (65%), all j-NPSLE patients displayed psychiatric features: cognitive symptoms (82%), hallucinations (76%), depressed mood (35%), acute confused state (18%) and catatonia (12%). Neurological involvement was often mild and nonspecific, with headache (53%) in about half of the patients. The main features reported on brain MRI were nonspecific T2/FLAIR white matter hyperintensities (65%), and cerebral atrophy (88%). Upon immunosuppressive treatment, clinical improvement of NP features was observed in all j-NPSLE patients. The score developed to attribute j-NPSLE probability, guide further investigations and appropriate treatments is based on hallucinations, memory, sleep and renal involvement (Sensitivity: 0.95 Specificity: 0.85). Cerebrospinal fluid (CSF) neopterin assessment increases the score sensitivity and specificity. CONCLUSION: Physicians should carefully and systematically assess the presence of NP features at diagnosis and early stages of j-SLE. For j-NPSLE patients with predominant psychiatric features, a multidisciplinary collaboration, including psychiatrists, is essential for the diagnosis, management and follow-up.

The principles of curative antibiotic treatments.

Knowledge of infectious diseases and their treatments is constantly evolving. New infectious agents are regularly discovered, due mainly to improvement of identification techniques, especially the development of molecular biology and mass spectrometry. While changes in the epidemiology of infectious diseases are not always predictable or readily understood, several factors regularly enter into consideration, such as not only the natural history of diseases and the impact of vaccinations, but also the excessive and irrational use of antibiotics. Antibiotic resistance is now recognized as one of the major challenges for humanity, especially since few new molecules have been put on the market in recent years. These molecules are reserved for serious infections caused by bacteria resistant to other antibiotics and should be prescribed only by infectious disease specialists trained in their use. Rationalization of antibiotic therapy is therefore one of the keys to reducing antibiotic resistance and the spread of resistant bacteria. In this guide, with regard to each clinical situation, the bacterial target(s) of antibiotic treatment, the preferred antibiotic choice, and the therapeutic alternatives will be specified. Comments on diagnosis and treatment of the infection will be added if necessary.

Anti-infective treatment of gastro-intestinal tract infections in children.

Gastroenteritis is most often viral in origin and Rotavirus and Norovirus most frequently implicated in young children. Stool-based multiplex Polymerase Chain Reaction (PCR) can detect bacteria, viruses or parasites that may or may not be responsible for gastroenteritis (colonization). While the etiological profile of these digestive infections has greatly benefited from PCR, in the absence of underlying pathologies the presence of potential pathogens does not justify anti-infectious treatment. Indeed, very few bacterial causes require antibiotic treatment, apart from shigellosis, severe forms of salmonellosis and a few Campylobacter sp. infections. The development of antibiotic resistance in Salmonella sp., Shigella sp. and Campylobacter sp. is a cause for concern worldwide, limiting therapeutic options. The antibiotics proposed in this guide are in line with the joint recommendations of the European Society of Pediatric Infectious Diseases and the European Society of Pediatric Gastroenterology and Nutrition. Azithromycin is preferentially used to treat infections with Shigella sp. or Campylobacter sp. Ceftriaxone and ciprofloxacin are recommended for salmonellosis requiring antibiotic therapy. Empirical treatments without bacterial identification are not indicated except in cases of severe sepsis or in subjects at risk (e.g., sickle-cell disease). Metronidazole should be prescribed only for acute intestinal amebiasis after microbiological confirmation.

Invasive Bacterial Infections in Children With Sickle Cell Disease: 2014-2019.

BACKGROUND: Children with sickle cell disease (SCD) are at a high risk of invasive bacterial infections (IBI). Universal penicillin prophylaxis and vaccination, especially against Streptococcus pneumoniae, have deeply changed its epidemiology. Analysis of IBI in children with SCD in a post-13-valent pneumococcal vaccine era is limited. METHODS: Twenty-eight pediatric hospitals from 5 European countries retrospectively collected IBI episodes in SCD children aged 1 month to 18 years between 2014 and 2019. IBI was defined as a positive bacterial culture or polymerase chain reaction from a normally sterile fluid: blood, cerebrospinal, joint, or pleural fluid and deep surgical specimen. RESULTS: We recorded 169 IBI episodes. Salmonella spp. was the main isolated bacteria (n = 44, 26%), followed by Streptococcus pneumonia (Sp; n = 31, 18%) and Staphylococcus aureus (n = 20, 12%). Salmonella prevailed in osteoarticular infections and in primary bacteremia (45% and 23% of episodes, respectively) and Sp in meningitis and acute chest syndrome (88% and 50%, respectively). All Sp IBI occurred in children ≤10 years old, including 35% in children 5 to 10 years old. Twenty-seven (17%) children had complications of infection and 3 died: 2 because of Sp, and 1 because of Salmonella. The main risk factors for a severe IBI were a previous IBI and pneumococcal infection (17 Sp/51 cases). CONCLUSIONS: In a post-13-valent pneumococcal vaccine era, Salmonella was the leading cause of bacteremia in IBI in children with SCD in Europe. Sp came second, was isolated in children ≤10 years old, and was more likely to cause severe and fatal cases.

Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers.

INTRODUCTION: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. OBJECTIVES: To identify central nervous system (CNS) disease biomarkers of j-NPSLE. METHODS: A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. RESULTS: Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p < 0.0001, n = 23 paired samples). CONCLUSION: CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.

Incidence, kinetics, and risk factors for intra- and extracranial cerebral arteriopathies in a newborn sickle cell disease cohort early assessed by transcranial and cervical color Doppler ultrasound.

The risk of stroke in children with sickle cell disease (SCD) is detected by abnormal intracranial arterial time-averaged mean of maximum velocities (TAMVs ≥200 cm/s). Recently, extracranial internal carotid artery (eICA) arteriopathy has been reported, and a cross-sectional study showed that eICA-TAMVs ≥160 cm/s are significantly associated with eICA kinkings and stenosis. The cumulative incidence of and predictive risk factors for intracranial arteriopathy are well described in sickle cell anemia (SCA=SS/Sß0) but are lacking for SC/Sß+ children, as is the cumulative incidence of eICA arteriopathy. We report a prospective longitudinal cohort study including 493 children with SCD (398 SCA, 95 SC/Sß+), all assessed by transcranial and cervical color Doppler ultrasound. Cerebral MRI/MRA data were available in 375 children with SCD and neck MRA in 365 children. eICA kinkings were defined as eICA tortuosities on neck MRA, with an internal acute angle between the two adjacent segments <90°. The median follow-up was 10.6 years. The cumulative incidence of kinkings was significantly lower in SC/Sß+ children than in children with SCA, and no SC/Sß+ child developed intra- or extracranial stenotic arteriopathy. The 10-year KM estimate of cumulative incidence (95% CI) for eICA-TAMVs ≥160 cm/s revealed its development in the 2nd year of life in children with SCA, reaching a plateau of 17.4% (13.2-21.6%) by about 10 years of age, while the plateau for eICA stenosis was 12.3% (8.3-16.3%). eICA assessment identified 13.5% (9.3-17.7%) patients at risk of stroke who were not detected by transcranial color Doppler ultrasound. We also show, for the first time, that in addition to a congenital origin, eICA kinkings sin patients with SCD can develop progressively with aging as a function of eICA-TAMVs, themselves related to anemia severity. Ongoing hydroxyurea treatment was significantly associated with a lower risk of abnormal intracranial arteriopathy and eICA kinkings. After adjustment with hydroxyurea, baseline low hemoglobin, high reticulocyte, and WBC counts remained independent risk factors for intracranial arteriopathy, while low hemoglobin and SEN ß-haplotype number were independent risk factors for extracranial arteriopathy. The association between extracranial arteriopathy and SEN ß-haplotype number suggested a genetic link between the ethnic origin and incidence of eICA kinkings. This prospective cohort study shows the importance of systematically assessing the eICA and of recording biological parameters during the 2nd year of life before any intensive therapy to predict the risk of cerebral arteriopathy and treat patients with severe baseline anemia.

Shift in Clinical Profile of Hospitalized Pneumonia in Children in the Non-pharmaceutical Interventions Period During the COVID-19 Pandemic: A Prospective Multicenter Study.

Non-pharmaceutical interventions (NPIs) against coronavirus disease 2019 were implemented in March 2020. These measures were followed by a major impact on viral and non-viral diseases. We aimed to assess the impact of NPI implementation in France on hospitalized community-acquired pneumonia (hCAP) frequency and the clinical and biological characteristics of the remaining cases in children. We performed a quasi-experimental interrupted time-series analysis. Between June 2014 and December 2020, eight pediatric emergency departments throughout France reported prospectively all cases of hCAP in children from age 1 month to 15 years. We estimated the impact on the monthly number of hCAP using segmented linear regression with autoregressive error model. We included 2,972 hCAP cases; 115 occurred during the NPI implementation period. We observed a sharp decrease in the monthly number of hCAP after NPI implementation [-63.0% (95 confidence interval, -86.8 to -39.2%); p < 0.001]. Children with hCAP were significantly older during than before the NPI period (median age, 3.9 vs. 2.3 years; p < 0.0001), and we observed a higher proportion of low inflammatory marker status (43.5 vs. 33.1%; p = 0.02). Furthermore, we observed a trend with a decrease in the proportion of cases with pleural effusion (5.3% during the NPI period vs. 10.9% before the NPI; p = 0.06). NPI implementation during the COVID-19 (coronavirus disease 2019) pandemic led not only to a strong decrease in the number of hCAP cases but also a modification in the clinical profile of children affected, which may reflect a change in pathogens involved.

Impact of COVID-19 social distancing on viral infection in France: A delayed outbreak of RSV.

INTRODUCTION: COVID-19 pandemic and associated lockdown measures have deeply modified the natural course of seasonal viral infections, such as respiratory syncytial virus (RSV). METHODS: We analyzed French national data from three networks: emergency departments (ED) of French hospitals, general practitioners (GP), and hospital laboratories. We compared the number of ED or GP visits for bronchiolitis in children <2 years of age, and the percentage of RSV positive tests in the 2020 to 2021 season with those of the two previous seasons (2018-2019 and 2019-2020). We used time series of the previous 5 years to calculate epidemic thresholds. RESULTS: During the 2020-2021 season, the epidemic begun in February (Week 05) in the Ile de France (Paris and suburbs) region, 12 weeks later compared with the previous seasons and progressively spread across all the French metropolitan regions. The highest number of bronchiolitis cases in 2021 (Week 12) occurred 10-12 weeks after the previous seasonal peaks of previous seasons, but the number of cases remained lower than in the previous seasonal peaks. CONCLUSION: We identified a delayed RSV epidemic in the period that usually corresponds at the end of the epidemic season, raising concerns for the burden of RSV in the already strained healthcare systems during the COVID-19 pandemic.

Diagnostic Accuracy of SARS-CoV-2 Antigen Detection Test in Children: A Real-Life Study.

Naso-pharyngeal RT-PCR is the gold standard for the diagnosis of COVID-19, but there is a need for rapid and reliable tests. Some validation studies have used frozen aliquots mainly from adults. The aim of this real-life study was to test the performance of a SARS-CoV-2 rapid antigen test (SC2-RAT) in children. Symptomatic patients aged 0 to 17 years were recruited in the emergency department of the University Hospital of Creteil and in primary care pediatric practices from October 10, 2020 for 7 weeks. Each enrolled child had a SARS-CoV-2 RT-PCR test and a SC2-RAT from two distinct nasopharyngeal swabs. Among the 308 patients (mean [SD] age 4.9 [5.3] years), fever was the main symptom (73.4%), with no difference between COVID-19-negative and -positive groups. The prevalence of COVID-19 was 10.7% (95% CI 7.5-14.7). On the whole cohort, the sensitivity and specificity of the SC2-RAT compared to RT-PCR was 87.9% (95% CI 71.8-96.6) and 98.5% (95% CI 96.3-99.6). Considering samples with cycle threshold >25, the sensibility was lower: 63.6% (95% CI 30.8-89.1) and the specificity 99.6% (95% CI 98.0-100.0). The mean delay to obtain an SC2-RAT result was <15 min but was 3.2 h (SD 5.5) for an RT-PCR result. Contact with a COVID-19-positive person was more frequent for COVID-19-positive than -negative patients (n = 21, 61.6%, vs. n = 64, 24.6%; p < 0.01). In real life, SC2-RAT seems reliable for symptomatic children, allowing to detect contagious children.

Impact of Early Versus Late Antiretroviral Treatment Initiation on Naive T Lymphocytes in HIV-1-Infected Children and Adolescents - The-ANRS-EP59-CLEAC Study.

Background: The early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8TN), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (<6 months) versus late (≥24 months of age)). Methods: The ANRS-EP59-CLEAC study enrolled 27 children (5-12 years of age) and nine adolescents (13-17 years of age) in the early-treatment group, and 19 children (L-Ch) and 21 adolescents (L-Ado) in the late-treatment group. T lymphocytes were analyzed by flow cytometry and plasma markers were analyzed by ELISA. Linear regression analysis was performed with univariate and multivariate models. Results: At the time of evaluation, all patients were on ART and had a good immunovirological status: 83% had HIV RNA loads below 50 copies/mL and the median CD4 T-cell count was 856 cells/µL (interquartile range: 685-1236 cells/µL). In children, early ART was associated with higher CD8TN percentages (medians: 48.7% vs. 31.0%, P = 0.001), and a marginally higher CD4TN (61.2% vs. 53.1%, P = 0.33). In adolescents, early ART was associated with low CD4TN percentages and less differentiated memory CD8 T cells. CD4TN and CD8TN levels were inversely related to cellular activation and gut permeability. Conclusion: In children and adolescents, the benefits of early ART for CD8TN were clear after long-term ART. The impact of early ART on CD4TN appears to be modest, because pediatric patients treated late respond to HIV-driven CD4 T-lymphocyte loss by the de novo production of TN cells in the thymus. Our data also suggest that current immune activation and/or gut permeability has a negative impact on TN levels. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02674867.

Sexual health of French adolescents with sickle cell disease.

PURPOSE: Focussing on sickle cell disease (SCD), the objective of this study was to assess adolescents' sexual heath experience in the context of their chronic illness. MATERIALS AND METHODS: We included teenagers from 14 to 19 years old followed for SCD in a hospital located in Créteil (France) from March 2017 to February 2018. Their sexual health experience was assessed by a self-questionnaire with three key themes: contraceptive experience, awareness of sexuality with chronic disease and level of information on the genetic transmission of the disease. RESULTS: 99 questionnaires were analysed. Only six SCD adolescents (one girl and five boys) reported being sexually active. Despite a very regular follow-up of their illness, only 13% of the boys and girls had received information on contraception at the hospital. Most adolescents (85% of boys and 81% of girls) did not think that the disease would interfere with sexual intercourse. The genetic pattern was well known (85% of boys and 87% of girls). CONCLUSION: Young people with SCD need more information on contraception. Clinicians caring for them should be aware of the need for sexual health information in order to propose prevention actions adapted to these young people with chronic disease.

Identification of Clinical and Laboratory Parameters Associated with the Development of Acute Chest Syndrome during Vaso-Occlusive Episodes in Children with Sickle Cell Disease: A Preliminary Step before Assessing Specific and Early Treatment Strategies.

This prospective observational study sought to ascertain clinical and laboratory parameters associated with the development of acute chest syndrome (ACS) during vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD). It was performed at the pediatric department of the university Intercommunal Créteil hospital. All children with SCD (all sickle genotypes) consecutively admitted from November 2013 to December 2016 for painful VOEs and no evidence of ACS were included. Clinical and laboratory parameters collected at admission and within 48 h after admission were compared for children in whom ACS developed or not. Variables that were statistically significant on univariate analysis or considered to be clinically relevant were included in a multivariable model to ascertain the risk factors associated with the development of ACS during a VOE. The variables retained in the multivariate model were used to construct a predictive score for ACS. For each included child and during the study period, only data from the first VOE and/or the first ACS were analyzed. Among 191 hospitalizations for painful VOEs, for 176 children with SCD, ACS developed in 35 during hospitalization. Mean hospital stay was longer for children with ACS versus VOEs alone (7.6 (±2.3) vs. 3.3 (±1.8) days, p < 0.0001), and all children with ACS versus 28/156 (17.9%) with VOEs alone received red blood cell transfusion (p < 0.0001). The multivariate model retained pain score (≥9/10), pain localization (abdominal or spinal pain or involving more than two limbs), and high reticulocyte (≥260 × 109/L) and neutrophil (>10 × 109/L) counts, at admission, as independently associated with ACS development. The area under the receiver operating characteristic curve for the ACS predictive score was 0.82 (95% CI: 0.74-0.89), and the negative predictive value was 97.7%. The evolution profiles during the first 48 h differed between children with ACS and VOEs alone, with a more rapid decline of pain score and leucocytosis in children with VOEs. Clinical and laboratory measurements at admission may be simple parameters to identify children with increased risk of ACS development during VOEs and to facilitate early diagnosis of this respiratory complication. Also, the persistent elevation of leukocyte count on day 2 may be considered a sign of evolving ACS.

Serum Immunoglobulin Levels in Children with Sickle Cell Disease: A Large Prospective Study.

Over the past 3 decades, the pediatric department of the university Intercommunal Créteil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS and HbSß0 thalassemia) and 157 with milder genotypes (HbSC and HbSß+ thalassemia). We found consistent sickle genotype differences in levels of IgG and IgA, with increased levels of IgA and IgG in the severe versus milder genotype, from early childhood to late adolescence. Additionally, our results revealed a low serum IgM level, irrespective of sickle genotype. Finally, we found that IgA and IgG levels were significantly increased after therapeutic intensification with hydroxyurea but were stabilized in children receiving a transfusion program. The mechanisms contributing to these changes in Ig levels are unclear as is their clinical significance. We believe they should be further investigated.

Long-term Association of 13-Valent Pneumococcal Conjugate Vaccine Implementation With Rates of Community-Acquired Pneumonia in Children.

Importance: In several countries, 5 years after 13-valent pneumococcal conjugate vaccine (PCV13) implementation, serotype replacement has been reported for invasive pneumococcal disease, which raises concerns about the long-term outcome of PCV13 implementation. The long-term effect of vaccination on community-acquired pneumonia (CAP) remains unknown. Objective: To assess the long-term outcome of PCV13 implementation on CAP in children. Design, Setting, and Participants: This quasi-experimental, population-based, interrupted time-series analysis was based on a prospective multicenter study conducted from June 2009 to May 2017 in 8 French pediatric emergency departments. All patients 15 years and younger with chest radiography-confirmed CAP were included. Exposures: Community-acquired pneumonia. Main Outcomes and Measures: The number of CAP cases per 1000 pediatric emergency department visits over time, analyzed using a segmented regression model, adjusted for influenza-like illness syndromes. Results: We enrolled 12 587 children with CAP, including 673 cases of CAP with pleural effusion (5.3%), 4273 cases of CAP requiring hospitalization (33.9%), 2379 cases of CAP with high inflammatory biomarkers (18.9%), and 221 cases of proven pneumococcal CAP (1.8%). The implementation of PCV13 in 2010 was followed by a sharp decrease in the frequency of CAP (-0.8% per month [95% CI, -1.0% to -0.5% per month]), from 6.3 to 3.5 cases of CAP per 1000 pediatric emergency department visits until May 2014, then a slight increase since June 2014 (0.9% per month [95% CI, 0.4%-1.4% per month]), until 3.8 cases of CAP per 1000 pediatric emergency department visits in May 2017. There were marked immediate decreases in cases of CAP with pleural effusion (-48% [95% CI, -84% to -12%]), CAP requiring hospitalization (-30% [95% CI, -56% to -5%]), and CAP with high inflammatory biomarkers (-30% [95% CI, -54% to -6%]), without any rebound thereafter. Conclusions and Relevance: The changes associated with PCV13 use 7 years after implementation remain substantial, especially for CAP with pleural effusion, CAP requiring hospitalization, and CAP with high inflammatory biomarkers. Emerging non-PCV13 serotypes may be less likely involved in severe CAP than invasive pneumococcal disease.

Biological impact of α genes, ß haplotypes, and G6PD activity in sickle cell anemia at baseline and with hydroxyurea.

Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major ß-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of α genes, ß haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Créteil pediatric cohort with available α-gene and ß-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study. Homozygous ß-haplotype patients represented 74% of cases (37.4% CAR/CAR, 24.3% BEN/BEN, and 12.1% SEN/SEN). HU was given to 168 cohort SCA children. Hematological parameters were recorded when HbF was maximal, and changes (ΔHU-T0) were calculated. At baseline, CAR-haplotype and α-gene numbers were independently and negatively correlated with Hb and positively correlated with lactate dehydrogenase. HbF was negatively correlated with CAR-haplotype numbers and positively with BEN- and SEN-haplotype numbers. The BCL11A/rs1427407 "T" allele, which is favorable for HbF expression, was positively correlated with BEN- and negatively correlated with CAR-haplotype numbers. With HU treatment, Δ and HbF values were positively correlated with the BEN-haplotype number. BEN/BEN patients had higher HbF and Hb levels than CAR/CAR and SEN/SEN patients. In conclusion, we show that BEN/BEN patients have the best response on HU and suggest that this could be related to the higher prevalence of the favorable BCL11A/rs1427407/T/allele for HbF expression in these patients.

Non-invasive CT screening for pulmonary arteriovenous malformations in children with confirmed hereditary hemorrhagic telangiectasia: Results from two pediatric centers.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that is caused by mutations in mainly two genes, that is ENG, encoding endoglin (HHT1), or ACVRL1, encoding activin receptor-like kinase 1 (ALK-1/HHT2). HHT is characterized by recurrent epistaxis, mucocutaneous telangiectasia, and vascular visceral dysplasia responsible for visceral arteriovenous malformations (AVM). AIM: to report the experience of two university hospitals (Trousseau, Paris, and CHIC, Creteil) with screening children for HHT and pulmonary AVM (PAVM) using high resolution computed tomography (HRCT). METHODS: parents with confirmed HHT were offered to have their children screened for the mutation identified in their family, and informed consent was obtained. Children carrying the same mutation as their parents underwent HRCT of the chest without contrast. RESULTS: between 2008 and 2015, 99 children were screened for HHT mutations. Mutations were identified in 59 patients, that is 24 HHT1 and 35 HHT2. Radiologic and clinical screening was possible in 52 patients (21 HHT-1 and 31 HHT-2). Among those, PAVM was identified in 13 patients (25%; n = 8 HHT1; n = 5 HHT2), and four of them required embolization therapy. CONCLUSION: This study highlights the usefulness of genetic screening in children with known HHT family. It also suggests that a non-invasive protocol such as HRTC is an efficient approach to detect non-symptomatic lesions that are present early on in children carrying the ENG (HHT1), but also the ACVRL1 mutations (HHT2). Pediatr Pulmonol. 2017;52:642-649. © 2017 Wiley Periodicals, Inc.

Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities.

Stroke risk in sickle cell anemia (SCA), predicted by high transcranial Doppler (TCD) velocities, is prevented by transfusions. We present the long-term follow-up of SCA children from the Créteil newborn cohort (1992-2012) detected at risk by TCD and placed on chronic transfusions. Patients with normalized velocities and no stenosis were treated with hydroxyurea, known to decrease anemia and hemolytic rate. Trimestrial Doppler was performed and transfusions restarted immediately in the case of reversion to abnormal velocities. Patients with a genoidentical donor underwent transplant. Abnormal time-averaged maximum mean velocities (TAMMV) ≥200 cm/s were detected in 92 SCA children at a mean age of 3.7 years (range, 1.3-8.3 years). No stroke occurred posttransfusion after a mean follow-up of 6.1 years. Normalization of velocities (TAMMV < 170 cm/s) was observed in 83.5% of patients. Stenosis, present in 27.5% of patients, was associated with the risk of non-normalization (P< .001). Switch from transfusions to hydroxyurea was prescribed for 45 patients, with a mean follow-up of 3.4 years. Reversion, predicted by baseline reticulocyte count ≥400 × 10(9)/L (P< .001), occurred in 28.9% (13/45) patients at the mean age of 7.1 years (range, 4.3-9.5 years). Transplant, performed in 24 patients, allowed transfusions to be safely stopped in all patients and velocities to be normalized in 4 patients who still had abnormal velocities on transfusions. This long-term cohort study shows that transfusions can be stopped not only in transplanted patients but also in a subset of patients switched to hydroxyurea, provided trimestrial Doppler follow-up and immediate restart of transfusions in the case of reversion.

Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia.

Early transcranial Doppler (TCD) screening of the Créteil sickle cell anemia (SCA)-newborn cohort, and rapid initiation of transfusion programs, resulted in successful prevention of overt strokes, but a high cumulative risk of silent cerebral infarcts (SCI) remained, suggesting that TCD screening does not identify all patients with SCA at risk for SCI. We hypothesized that episodes of hypoperfusion/hypoxia, as observed during acute chest syndromes or acute anemic events (AAE), and extracranial internal carotid artery (eICA) stenoses, detectable via submandibular Doppler sonography and cervical magnetic resonance angiography (MRA), could also be risk factors for SCI. This study includes 189 stroke-free patients with SCA from the Créteil newborn cohort (1992-2010) followed longitudinally by magnetic resonance imaging/MRA, including cervical MRA at the last assessment. All patients with abnormal TCD and/or intracranial stenoses were placed on a transfusion program. Mean follow-up was 9.9 years (range, 2.2-19.9 years; 1844 patient-years). Annual rates of clinical events were calculated. The cumulative risk for SCI was 39.1% (95% confidence interval [CI], 23.5%-54.7%) by age 18 years, with no plateau. We confirm that baseline hemoglobin level lower than 7 g/dL before age 3 years is a highly significant predictive risk factor for SCI (hazard ratio, 2.97; 95% CI, 1.43-6.17; P = .004). Furthermore, we show that AAE rate (odds ratio, 2.64 per unit increase; 95% CI, 1.09-6.38; P = .031) and isolated eICA stenosis (odds ratio, 3.19; 95% CI, 1.18-8.70; P = .023) are significant and independent risk factors for SCI.