Conjugate Haemophilus influenzae type b vaccines for sickle cell disease.

BACKGROUND: People affected with sickle cell disease are at high risk of infection from Haemophilus influenzae type b. Before the implementation of Haemophilus influenzae type b conjugate vaccination in high-income countries, this was responsible for a high mortality rate in children under five years of age. In African countries, where coverage of this vaccination is still extremely low, Haemophilus influenzae type b remains one of the most common cause of bacteraemias in children with sickle cell disease. The increased uptake of this conjugate vaccination may substantially improve the survival of children with sickle cell disease. OBJECTIVES: The primary objective was to determine whether Haemophilus influenzae type b conjugate vaccines reduce mortality and morbidity in children and adults with sickle cell disease.The secondary objectives were to assess the following in children and adults with sickle cell disease: the immunogenicity of Haemophilus influenzae type b conjugate vaccines; the safety of these vaccines; and any variation in effect according to type of vaccine, mode of administration (separately or in combination with other vaccines), number of doses, and age at first dose. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group\u27s Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also contacted relevant pharmaceutical companies to identify unpublished trials.Date of last search: 23 November 2015. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials comparing Haemophilus influenzae type b conjugate vaccines with placebo or no treatment, or comparing different types of Haemophilus influenzae type b conjugate vaccines in people with sickle cell disease. DATA COLLECTION AND ANALYSIS: No trials of Haemophilus influenzae type b conjugate vaccines in people with sickle cell disease were found. MAIN RESULTS: There is an absence of evidence from randomised controlled trials relating to the subject of this review. AUTHORS\u27 CONCLUSIONS: There has been a dramatic decrease in the incidence of invasive Haemophilus influenzae type b infections observed in the post-vaccination era in people with sickle cell disease living in high-income countries. Therefore, despite the absence of evidence from randomised controlled trials, it is expected that Haemophilus influenzae type b conjugate vaccines may be useful in children affected with sickle cell disease, especially in African countries where there is a high prevalence of the disease. The implementation of childhood immunisation schedules, including universal Haemophilus influenzae type b conjugate vaccination, may substantially improve the survival of children with sickle cell disease living in low-income countries. We currently lack data to evaluate the potential effect of Haemophilus influenzae type b vaccination among unvaccinated adults with sickle cell disease. Further research should assess the optimal Hib immunisation schedule in children and adults with sickle cell disease

Mutation Analysis of NR5A1 Encoding Steroidogenic Factor 1 in 77 Patients with 46, XY Disorders of Sex Development (DSD) Including Hypospadias

BACKGROUND: Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein. CONCLUSIONS/SIGNIFICANCE: Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations

Mastocytes, basophiles et substance P dans la drépanocytose

La drépanocytose est une hémoglobinopathie autosomique récessive sévère, reconnue comme la première maladie monogénique dans le monde avec plus de 300 000 naissances par an. Bien qu’elle soit la conséquence d’une mutation ponctuelle parfaitement caractérisée du gène de bêta-globine, conduisant à la polymérisation de la desoxyhémoglobine S et à la falciformation des hématies, sa physiopathologie complexe impliquant de nombreuses cellules du système immunitaire inné n’est pas encore parfaitement comprise et les options thérapeutiques validées restent limitées. Un rôle des mastocytes a été récemment suggéré par la mise en évidence de signes clinico-biologiques de syndrome d’activation mastocytaire chez un nombre restreint de patients ainsi que par la démonstration de l’implication des mastocytes et de la substance P dans l’inflammation neurogénique de la souris drépanocytaire. L’objectif de ce travail était d’explorer le rôle des mastocytes, des basophiles et de la substance P dans la physiopathologie de la drépanocytose et notamment dans la pathogénie de la crise vaso-occlusive (CVO) et du syndrome thoracique aigu (STA). Nous avons mis en évidence dans une large cohorte enfants-adultes une élévation majeure à l’état basal, et encore d’avantage pendant les CVO/STA, des taux plasmatiques des deux principaux médiateurs des mastocytes et des basophiles que sont l’histamine et la substance P. Les valeurs de substance P étant maximales au cours du STA, nous avons testé l’hypothèse que la substance P pourrait induire le STA. Chez les souris transgéniques drépanocytaires, à la différence des souris contrôles, l’injection intra-veineuse de substance P a été à l’origine de crises létales associées à des lésions pulmonaires histologiques de STA et corrélées à la dose de substance P injectée. Des résultats similaires ont été obtenus avec le MAR-1 (anti-FcεRIα), suggérant un rôle de l’activation/dégranulation des mastocytes/basophiles. L’administration préventive d’un stabilisateur de membrane des mastocytes/basophiles a permis de prévenir la survenue des crises et des lésions histologiques de STA induites par la substance P chez les souris drépanocytaires. Les analyses de cytométrie en flux réalisées dans le sang des patients drépanocytaires ont permis la mise en évidence d’un phénotype activé des basophiles ainsi que d’une augmentation de leur nombre à l’état basal avec diminution pendant les CVO, suggérant leur recrutement hors du compartiment vasculaire. Des résultats similaires ont été observés chez les souris drépanocytaires après injection intra-veineuse de substance P. L’étude immunohistochimique des poumons des souris drépanocytaires a alors révélé la présence d’un grand nombre de mastocytes et de basophiles, avec une possible augmentation de ces derniers pendant le STA. Par ailleurs, des valeurs de substance P extrêmement élevées ont été retrouvées dans les expectorations de patients en STA, reflétant la probable dégranulation des mastocytes/basophiles. Nous avons également mis en évidence une surexpression de différents récepteurs de cytokines/chémokines à la surface des basophiles circulants des patients drépanocytaires, dont le récepteur de la substance P et de la morphine, MRGPRX2, suggérant une activation/dégranulation accrue pendant les crises et un possible rôle délétère de la morphine dans la survenue du STA. D’autre part, les études in vitro portant sur les mécanismes d’activation des mastocytes/basophiles dans la drépanocytose ont permis la mise en évidence d’un rôle de l’hémoglobine S (HbS) via le récepteur TLR4 avec une inhibition de cette activation en présence de l’inhibiteur de TLR4, TAK-242. Ce nouveau mécanisme d’activation cellulaire impliquant l’HbS mais pas l’hémoglobine A (HbA) ni l’hème a pu être validé sur d’autres cellules majeures du système immunitaire inné que sont les monocytes et les macrophages. (...)Sickle cell disease (SCD) is a severe autosomal recessive hemoglobinopathy, considered the first monogenic disease in the world with more than 300,000 births per year. Although it is the consequence of a well characterized point mutation of the beta-globin gene, leading to deoxyhemoglobin S polymerization and sickling of red blood cells, its complex pathophysiology, involving many innate immune cells, is not yet fully elucidated and therapeutic options remain restricted. A role of mast cells has been suggested by the description of clinico-biological signs of mast cell activation in a limited number of patients. Likewise, in an SCD mouse model, substance P released from mast cells was shown to promote neurogenic inflammation and pain. The aim of this work was to explore the role of mast cells, basophils and substance P in SCD pathophysiology, especially in the pathogenesis of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS). In a large cohort of children and adults affected with SCD, we observed a significant elevation in plasma levels of histamine and substance P, two major mediators of mast cells and basophils, with further enhancement during VOC. Since plasma substance P levels were maximal during ACS, we tested the hypothesis that substance P could induce ACS. In SCD transgenic mice, unlike control mice, intravenous injection of substance P caused dose-dependent lethal crises with acute lung injuries. Similar effects were obtained with MAR-1 (anti-FcεRIα), reflecting a likely role of mast cell or basophil activation/degranulation. Pretreatment of sickle mice with the mast cell and basophil stabilizer, cromolyn sodium, prevented lethal crises and substance P-induced lung injuries. Flow cytometric analyses revealed an activated phenotype of circulating basophils from SCD patients, as well as increased number in steady state. By contrast, blood basophil count decreased during VOC, suggesting their recruitment outside the vascular compartment. Similar results were observed in sickle mice after intravenous substance P injection. Immunohistochemistry revealed the presence of a large number of mast cells and basophils in the lungs of sickle mice, unlike control mice, with further recruitment after intravenous substance P injection. In addition, we observed extremely high levels of substance P in the sputum of SCD patients during ACS, consistently with mast cell and basophil degranulation in the lungs. We also found an overexpression of several cytokines and chemokine receptors on circulating basophils from SCD patients, including the substance P and morphine receptor MRGPRX2, which may promote activation/degranulation during VOC with a possible deleterious effect of morphine in ACS. Furthermore, in vitro studies on mast cell/basophil activation mechanisms in SCD revealed a role for hemoglobin S (HbS) through the TLR4 receptor, which was inhibited by TLR4 inhibitor, TAK-242. This novel mechanism of cellular activation involving HbS, but not hemoglobin A (HbA) or heme, was subsequently validated on two other major innate immune cells, namely monocytes and macrophages. These results should allow the forthcoming clinical trials of innovative treatments modulating the activity of innate immune cells in SCD, including tyrosine kinase inhibitors as well as molecules inhibiting HbS-TLR4 interaction (patent pending)

Hepatobiliary Complications in Children with Sickle Cell Disease: A Retrospective Review of Medical Records from 616 Patients

Hepatobiliary complications in children with sickle cell disease (SCD) are rarely reported but can be life-threatening. We retrospectively assessed their prevalence in a cohort of 616 children followed in a French university-hospital SCD reference center. Eligibility criteria were the following: age <18 years, seen at least twice with an interval of more than 6 months from January 2008 to December 2017, with all genotypes of SCD. Patients with hepatobiliary complications were identified via the local data warehouse and medical files were thoroughly reviewed. At least one hepatobiliary complication was reported in 37% of the children. The most frequent was cholelithiasis, in 25% of cases, which led to systematic screening and elective cholecystectomy in the case of gallstones. Overall, 6% of the children experienced acute sickle cell hepatic crisis, sickle cell intra-hepatic cholestasis, or acute hepatic sequestration, with severity ranging from mild liver pain and increased jaundice to multiple organ failure and death. Emergency treatment was exchange transfusion, which led to normalization of liver tests in most cases. Five children had chronic cholangiopathy, associated with auto-immune hepatitis in two cases. One needed liver transplantation, having a good outcome but with many complications. Transfusion iron load and infectious hepatitis cases were mild. Hepatotoxicity of an iron chelator was suspected to contribute to abnormal liver test results in five patients. We propose recommendations to prevent, explore, and treat hepatobiliary complications in SCD children. We underline the need for emergency exchange transfusion when acute liver failure develops and warn against liver biopsy and transplantation in this condition

Presentation of 493 consecutive girls with idiopathic central precocious puberty: a single-center study.

BACKGROUND:Despite the number of reported data concerning idiopathic central precocious puberty (CPP) in girls, major questions remain including its diagnosis, factors, and indications of gonadotropin releasing hormone (GnRH) analog treatment. METHODS:A retrospective, single-center study was carried out on 493 girls with CPP. RESULTS:Eleven girls (2.2%) were aged less than 3 years. Breast development was either isolated (Group 0, n = 99), or associated with one sign, pubic hair development, growth rate greater than 2 standard deviation score (SDS) or bone age (BA) >2 years above chronological age, (Group 1, n = 187), two signs (Group 2, n = 142) or three signs (Group 3, n = 65). The interval between onset of puberty and evaluation, body mass index (BMI) SDS, plasma luteinising hormone (LH) concentrations (basal and peak) and LH/ follicle-stimulating hormone (FSH) peak ratio after GnRH test, plasma estradiol and uterus length were significantly greater in Groups 2 and 3 than in Groups 0 and 1 respectively. 211 (42.8%) patients were obese and/or had excessive weight gain during the year before puberty. Obese girls more often had BA advance of >2 years (p = 0.0004) and pubic hair development (p = 0.003) than the others. BMI did not correlate with LH or with LH/FSH peak ratio. Girls with familial history of early puberty (41.4%) had greater frequencies of pubertal LH/FSH peak ratios (p = 0.02) than the others. During the 31 years of the study, there was no increase in the frequency of CPP or variation in its characteristics. CONCLUSION:Obesity is associated with a higher BA advance and higher frequency of pubic or axillary hair development but not with LH secretion, suggesting that obesity accelerates adrenarche but not the maturation of the hypothalamic-pituitary-ovarian axis. The LH/FSH peak ratio was more frequently pubertal in girls with a familial history of early puberty, suggesting that this maturation depends on genetic factors

Clinical, biological and genetic analysis of anorchia in 26 boys.

BACKGROUND: Anorchia is defined as the absence of testes in a 46,XY individual with a male phenotype. The cause is unknown. METHODS: We evaluated the clinical and biological presentation, and family histories of 26 boys with anorchia, and sequenced their SRY, NR5A1, INSL3, MAMLD1 genes and the T222P variant for LGR8. RESULTS: No patient had any associated congenital anomaly. At birth, testes were palpable bilaterally or unilaterally in 13 cases and not in 7; one patient presented with bilateral testicular torsion immediately after birth. The basal plasma concentrations of anti-Müllerian hormone (AMH, n = 15), inhibin B (n = 7) and testosterone (n = 19) were very low or undetectable in all the patients evaluated, as were the increases in testosterone after human chorionic gonadotropin (hCG, n = 12). The basal plasma concentrations of follicle stimulating hormone (FSH) were increased in 20/25, as was that of luteinising hormone in 10/22 cases. Family members of 7/26 cases had histories of primary ovarian failure in the mother (n = 2), or sister 46,XX, together with fetal malformations of the only boy with microphallus and secondary foot edema (n = 1), secondary infertility in the father (n = 2), or cryptorchidism in first cousins (n = 2). The sequences of all the genes studied were normal. CONCLUSION: Undetectable plasma concentrations of AMH and inhibin B and an elevated plasma FSH, together with 46,XY complement are sufficient for diagnosis of anorchia. The hCG test is unnecessary. NR5A1 and other genes implicated in gonadal development and testicle descent were not mutated, which suggests that other genes involved in these developments contribute to the phenotypes

Predicting the adult height of girls with central precocious puberty

International audiencePrediction of differences between adult and target heights and time between puberty onset and first menstruation in 122 girls with precocious puberty after a positive revie

Factors predicting the adult height and age at first menstruation in 138 girls with idiopathic central precocious puberty

International audienceMultiple linear regression models are built to predict either the adult height or the age at first menstruation, for girls with an idiopathic central precocious puberty

Severe nocturnal and postexercise hypoxia in children and adolescents with sickle cell disease.

Hypoxia is a common feature in children with sickle cell disease (SCD) that is inconsistently associated with painful crises and acute chest syndrome. To assess the prevalence and risk factors of hypoxia, we recorded daytime, nocturnal, and postexercise pulse oximetry (SpO2) values in 39 SCD patients with a median age of 10.8 years. Median daytime SpO2 was 97% (range, 89%-100%), and 36% of patients had daytime hypoxia defined as SpO2<96%. Median nocturnal SpO2 was 94.7% (range, 87.7%-99.5%), 50% of patients had nocturnal hypoxia defined as SpO2≤93%, and 11(37%) patients spent more than 10% of their total sleep time with SpO2<90%. Median postexercise SpO2 was 94% (range, 72%-100%) and 44.7% of patients had postexercise hypoxia defined as an SpO2 decrease ≥3% after a 6-minute walk test. Among patients with normal daytime SpO2, 35% had nocturnal and 42% postexercise hypoxia. Compared to 9 patients without daytime, nocturnal, or postexercise hypoxia, 25 patients with hypoxia under at least one of these three conditions had greater anemia severity (P = 0.01), lower HbF levels (P = 0.04), and higher aspartate aminotransferase levels (P = 0.03). Males predominated among patients with postexercise hypoxia (P = 0.004). Hypoxia correlated neither with painful crises nor with acute chest syndrome. Of 32 evaluable patients, 6 (18.8%) had a tricuspid regurgitation velocity ≥2.6 m/s, and this feature was associated with anemia (P = 0.044). Median percentage of the predicted distance covered during a 6-minute walk test was 86% [46-120]; the distance was negatively associated with LDH (P = 0.044) and with a past history of acute chest syndrome (P = 0.009). In conclusion, severe episodes of nocturnal and postexercise hypoxia are common in children with SCD, even those with normal daytime SpO2

COVID-19–Related Fatalities and Intensive-Care-Unit Admissions by Age Groups in Europe: A Meta-Analysis

Objectives: Precise international estimates of the age breakdown of COVID-19–related deaths and intensive-care-unit (ICU) admissions are lacking. We evaluated the distribution of COVID-19–related fatalities and ICU admissions by age groups in Europe. Materials and methods: On April 6, 2020, we systematically reviewed official COVID-19–related data from 32 European countries. We included countries that provided data regarding more than 10 COVID-19–related deaths stratified by age according to pre-specified age groups (i.e., <40, 40–69, ≥70 years). We used random-effects meta-analysis to summarize the data. Results: Thirteen European countries were included in the review, for a total of 31,864 COVID-19–related deaths (range: 27–14,381 per country). In the main meta-analysis (including data from Germany, Hungary, Italy, The Netherlands, Portugal, Spain, Switzerland; 21,522 COVID-19–related fatalities), the summary proportions of individuals <40, 40–69, and ≥70 years old among all COVID-19–related deaths were 0.1% (0.0–0.2; I 2 28.6%), 13.0% (10.8–15.4; I 2 91.5%), and 86.6% (84.2–88.9; I 2 91.5%), respectively. ICU data were available for four countries (France, Greece, Spain, Sweden). The summary proportions of individuals around <40–50, around 40–69, and around ≥60–70 years old among all COVID-19–related ICU admissions were 5.4% (3.4–7.8; I 2 89.0%), 52.6% (41.8–63.3; I 2 98.1%), and 41.8% (32.0–51.9; I 2 99%), respectively. Conclusions: People under 40 years old represent a small fraction of most severe COVID-19 cases in Europe. These results may help health authorities respond to public concerns and guide future physical distancing and mitigation strategies. Specific measures to protect older people should be considered