Publications by authors named "Slimane Allali"

32 Publications

Chronic organ injuries in children with sickle cell disease.

Haematologica 2021 Feb 25. Epub 2021 Feb 25.

Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris (AP-HP), Université de Paris, Paris; Laboratory of Excellence GR-Ex, Paris; Institut National de la Transfusion Sanguine (INTS), Université de Paris, Inserm U1134, Paris.

Median life expectancy of patients with sickle cell disease has increased to up to 55 years but there are still frequent cases of premature death, mostly in patients with pre-existing organ failure such as pulmonary hypertension, kidney injury, and cerebral vasculopathy. Most organ injuries remain asymptomatic for a long time and can only be detected through early systematic screening. Protocols combining assessment of velocities on transcranial Doppler and regular transfusions in patients with abnormal velocities have been demonstrated to dramatically reduce the risk of stroke. In contrast, no consensus has been reached on systematic screening or therapy for silent cerebral infarcts. The prognostic significance of increased tricuspid regurgitant jet velocity on echocardiography has not yet been identified in children, whereas increased albuminuria is a good predictor of kidney injury. Finally, screening for hip and eye disorder is recommended; however, different countries adopt different screening strategies. Hydroxyurea is probably of potential benefit in preventing chronic organ damage but this requires further study in order to be fully demonstrated. Efficacy and safety of the other new drugs available are also under investigation.
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http://dx.doi.org/10.3324/haematol.2020.271353DOI Listing
February 2021

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

JAMA 2021 03;325(9):855-864

Assistance Publique-Hôpitaux de Paris, Paediatric Emergency Department, Necker-Enfants Malades University Hospital, Université de Paris, Paris, France.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown.

Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C.

Design, Setting, And Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021.

Exposures: IVIG and methylprednisolone vs IVIG alone.

Main Outcomes And Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1.

Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]).

Conclusions And Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.
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http://dx.doi.org/10.1001/jama.2021.0694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851757PMC
March 2021

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

Front Med (Lausanne) 2020 14;7:560685. Epub 2021 Jan 14.

Department of General Pediatrics and Pediatric Infectious Diseases, AP-HP, Necker Hospital for Sick Children, Université de Paris, Paris, France.

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. 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. 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; 28.6%), 13.0% (10.8-15.4; 91.5%), and 86.6% (84.2-88.9; 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; 89.0%), 52.6% (41.8-63.3; 98.1%), and 41.8% (32.0-51.9; 99%), respectively. 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.
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http://dx.doi.org/10.3389/fmed.2020.560685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840596PMC
January 2021

Gastrointestinal Symptoms Followed by Shock in a Febrile 7-Year-Old Child during the COVID-19 Pandemic.

Clin Chem 2021 01;67(1):54-58

Department of General Pediatrics and Pediatric Infectious Diseases, Necker-Enfants-Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France.

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http://dx.doi.org/10.1093/clinchem/hvaa279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929030PMC
January 2021

Distinctive Features of Kawasaki Disease Following SARS-CoV-2 Infection: a Controlled Study in Paris, France.

J Clin Immunol 2021 04 4;41(3):526-535. Epub 2021 Jan 4.

Department of General Pediatrics and Pediatric Infectious Diseases, Necker-Enfants Malades University Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Université de Paris, 75015, Paris, France.

Background: An outbreak of multisystem inflammatory syndrome in children, including Kawasaki disease (KD), emerged during COVID-19 pandemic. We explored whether Kawasaki-like disease (KD), when associated with confirmed SARS-CoV-2 infection, has specific characteristics.

Methods: We included children and adolescents with KD criteria admitted in the department of general pediatrics of a university hospital in Paris, France, between January 1, 2018, and May 26, 2020. The incidence of KD was compared between the outbreak and a pre-outbreak control period (January 1, 2018, to April 25). Characteristics of patients with positive SARS-CoV-2 testing (KD-SARS-CoV-2) were compared to those of the pre-outbreak period (classic KD).

Results: A total of 30 and 59 children with KD were admitted during the outbreak and pre-outbreak periods, respectively (incidence ratio 13.2 [8.3-21.0]). During the outbreak, 23/30 (77%) children were diagnosed as KD-SARS-CoV-2. When compared with patients with classic KD, those with KD-SARS-CoV-2 were more frequently of sub-Saharan African ancestry (OR 4.4 [1.6-12.6]) and older (median 8.2 vs. 4.0 years, p < 0.001), had more often initial gastrointestinal (OR 84 [4.9-1456]) and neurological (OR 7.3 [1.9-27.7] manifestations, and shock syndrome (OR 13.7 [4.2-45.1]). They had significantly higher CRP and ferritin levels. Noticeably, they had more frequently myocarditis (OR 387 [38-3933]).

Conclusions: Children and adolescents with KD-SARS-CoV-2 have specific features when compared with those with classic KD. These findings should raise awareness and facilitate the study of their pathogenesis.
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http://dx.doi.org/10.1007/s10875-020-00941-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780601PMC
April 2021

Association between SARS-CoV-2 infection and Kawasaki-like multisystem inflammatory syndrome: a retrospective matched case-control study, Paris, France, April to May 2020.

Euro Surveill 2020 12;25(48)

Université de Paris, Centre of Research in Epidemiology and Statistics - CRESS, INSERM, F-75004 Paris, France.

We assessed the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and Kawasaki disease (KD)-like multisystem inflammatory syndrome in a retrospective case-control study in France. RT-PCR and serological tests revealed SARS-CoV-2 infection in 17/23 cases vs 11/102 controls (matched odds ratio: 26.4; 95% confidence interval: 6.0-116.9), indicating strong association between SARS-CoV-2 infection and KD-like illness. Clinicians should keep a high level of suspicion for KD-like illness during the COVID-19 pandemic.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.48.2001813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716402PMC
December 2020

Appropriate thresholds for accurate screening for β-thalassemias in the newborn period: results from a French center for newborn screening.

Clin Chem Lab Med 2020 Aug 19;59(1):209-216. Epub 2020 Aug 19.

AP-HP, Robert-Debré, Molecular Genetics Department, Paris, France.

Objectives: Newborn screening (NBS) for β-thalassemia is based on measuring the expression of the hemoglobin A (HbA) fraction. An absence or very low level of HbA at birth may indicate β-thalassemia. The difficulty is that the HbA fraction at birth is correlated with gestational age (GA) and highly variable between individuals. We used HbA expressed in multiples of the normal (MoM) to evaluate relevant thresholds for NBS of β-thalassemia.

Methods: The chosen threshold (HbA≤0.25 MoM) was prospectively applied for 32 months in our regional NBS program for sickle cell disease, for all tests performed, to identify patients at risk of β-thalassemia. Reliability of this threshold was evaluated at the end of the study.

Results: In all, 343,036 newborns were tested, and 84 suspected cases of β-thalassemia were detected by applying the threshold of HbA≤0.25 MoM. Among the n=64 cases with confirmatory tests, 14 were confirmed using molecular analysis as β-thalassemia diseases, 37 were confirmed as β-thalassemia trait and 13 were false-positive. Determination of the optimum threshold for β-thalassemia screening showed that HbA≤0.16 MoM had a sensitivity of 100% and a specificity of 95.3%, whatever the GA.

Conclusions: NBS for β-thalassemia diseases is effective, regardless of the birth term, using the single robust threshold of HbA≤0.16 MoM. A higher threshold would also allow screening for carriers, which could be interesting when β-thalassemia constitutes a public health problem.
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http://dx.doi.org/10.1515/cclm-2020-0803DOI Listing
August 2020

The Liver in Sickle Cell Disease.

J Pediatr Gastroenterol Nutr 2021 01;72(1):5-10

Department of Pediatric Gastroenterology-Hepatology-Nutrition, Reference Centre for Biliary Atresia and Genetic Cholestasis and Department of General Pediatrics and Pediatric Infectious Diseases, Reference Centre for Sickle Cell Disease; Hôpital Universitaire Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.

Abstract: Liver involvement is found in nearly 40% of children with sickle cell disease. The most frequent complication is cholelithiasis. The most severe complication is acute hepatic crisis, with symptoms ranging from increasing jaundice to multiple organ failure and death. The emergency and mostly efficient treatment is exchange transfusion. Chronic cholangiopathy is increasingly recognized, with autoimmune features in most cases, worsened by chronic ischemia. Transfusion-related iron overload is not yet a concern in children, and hepatotoxicity of iron chelators is rare. We propose recommendations to prevent, explore, and treat these complications. We emphasize the close collaboration required between hepatologists and specialists of sickle cell disease.
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http://dx.doi.org/10.1097/MPG.0000000000002886DOI Listing
January 2021

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study.

BMJ 2020 06 3;369:m2094. Epub 2020 Jun 3.

Department of General Paediatrics and Paediatric Infectious Diseases, Necker-Enfants Malades University Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Université de Paris, 149 rue de Sèvres, 75015 Paris, France.

Objectives: To describe the characteristics of children and adolescents affected by an outbreak of Kawasaki-like multisystem inflammatory syndrome and to evaluate a potential temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Design: Prospective observational study.

Setting: General paediatric department of a university hospital in Paris, France.

Participants: 21 children and adolescents (aged ≤18 years) with features of Kawasaki disease who were admitted to hospital between 27 April and 11 May 2020 and followed up until discharge by 15 May 2020.

Main Outcome Measures: The primary outcomes were clinical and biological data, imaging and echocardiographic findings, treatment, and outcomes. Nasopharyngeal swabs were prospectively tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) and blood samples were tested for IgG antibodies to the virus.

Results: 21 children and adolescents (median age 7.9 (range 3.7-16.6) years) were admitted with features of Kawasaki disease over a 15 day period, with 12 (57%) of African ancestry. 12 (57%) presented with Kawasaki disease shock syndrome and 16 (76%) with myocarditis. 17 (81%) required intensive care support. All 21 patients had noticeable gastrointestinal symptoms during the early stage of illness and high levels of inflammatory markers. 19 (90%) had evidence of recent SARS-CoV-2 infection (positive RT-PCR result in 8/21, positive IgG antibody detection in 19/21). All 21 patients received intravenous immunoglobulin and 10 (48%) also received corticosteroids. The clinical outcome was favourable in all patients. Moderate coronary artery dilations were detected in 5 (24%) of the patients during hospital stay. By 15 May 2020, after 8 (5-17) days of hospital stay, all patients were discharged home.

Conclusions: The ongoing outbreak of Kawasaki-like multisystem inflammatory syndrome among children and adolescents in the Paris area might be related to SARS-CoV-2. In this study an unusually high proportion of the affected children and adolescents had gastrointestinal symptoms, Kawasaki disease shock syndrome, and were of African ancestry.
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http://dx.doi.org/10.1136/bmj.m2094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500538PMC
June 2020

Innate immune cells, major protagonists of sickle cell disease pathophysiology.

Haematologica 2020 31;105(2):273-283. Epub 2020 Jan 31.

Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris Descartes University, Paris

Sickle cell disease (SCD), considered the most common monogenic disease worldwide, is a severe hemoglobin disorder. Although the genetic and molecular bases have long been characterized, the pathophysiology remains incompletely elucidated and therapeutic options are limited. It has been increasingly suggested that innate immune cells, including monocytes, neutrophils, invariant natural killer T cells, platelets and mast cells, have a role in promoting inflammation, adhesion and pain in SCD. Here we provide a thorough review of the involvement of these novel, major protagonists in SCD pathophysiology, highlighting recent evidence for innovative therapeutic perspectives.
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http://dx.doi.org/10.3324/haematol.2019.229989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012475PMC
January 2020

Sickle cell disease: a comprehensive program of care from birth.

Hematology Am Soc Hematol Educ Program 2019 12;2019(1):490-495

Reference Center for Sickle Cell Disease, Hôpital Necker-Enfants malades, AP-HP, Université Paris Descartes, Labex GR-Ex, Paris, France; and.

As more children are appropriately being diagnosed, the burden of sickle cell disease is increasing greatly in Africa and in high-resource countries such as the United States and Europe. Early management is mandatory, but newborn screening is not implemented everywhere. Point-of-care testing devices are increasingly being used in low-resource countries, showing good sensitivity and specificity. Because the diagnosis is often traumatic for the families, the announcement should be made by an experienced person. The development of care networks is urgently required to facilitate daily life by defining the respective functions of nearby and highly specialized health care professionals, who should work in close collaboration. Comprehensive programs targeting the prevention of pneumococcal infections, malaria in infested zones, and stroke may substantially improve patient care. Hydroxyurea is increasingly being used, but whether it should be systematically prescribed in all children is debated, and its access is still limited in many African countries. Yearly checkups should be organized early in life in order to screen and then treat any organ impairment. Enhancing parents' and patients' knowledge and skills is mandatory.
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http://dx.doi.org/10.1182/hematology.2019000053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913505PMC
December 2019

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

J Clin Med 2019 Sep 18;8(9). Epub 2019 Sep 18.

Department of Pediatric Gastroenterology-Hepatology-Nutrition, Hepatology Unit, Necker-Enfants malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, 75005 Paris, France.

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.
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http://dx.doi.org/10.3390/jcm8091481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780325PMC
September 2019

Innate-like T cells in children with sickle cell disease.

PLoS One 2019 28;14(6):e0219047. Epub 2019 Jun 28.

Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants malades, Centre National de la Recherche Scientifique (CNRS) UMR 8253, Inserm UMR 1151, Paris Descartes - Sorbonne Paris Cité University, Paris, France.

Background: The implication of lymphocytes in sickle cell disease pathogenesis is supported by a number of recent reports. These studies provided evidence for the activation of invariant natural killer T (iNKT) cells in adult patients, but did not investigate the involvement of other innate-like T cell subsets so far.

Methods: Here we present a monocentric prospective observational study evaluating the number and functional properties of both circulating conventional and innate-like T cells, namely iNKT, Mucosal-Associated Invariant T (MAIT) and gammadelta (γδ) T cells in a cohort of 39 children with sickle cell disease.

Results: Relative to age-matched healthy controls, we found that patients had a higher frequency of IL-13- and IL-17-producing CD4+ T cells, as well as higher MAIT cell counts with an increased frequency of IL-17-producing MAIT cells. Patients also presented increased Vδ2 γδ T cell counts, especially during vaso-occlusive crisis, and a lower frequency of IFNγ-producing Vδ2 γδ T cells, except during crisis. iNKT cell counts and the frequency of IFNγ-producing iNKT cells were unchanged compared to controls. Our study revealed positive correlations between 1) the frequency of IFNγ-producing CD4+, CD8+ and Vδ2 γδ T cells and the number of hospitalizations for vaso-occlusive crisis in the previous year; 2) the frequency of IFNγ-producing iNKT cells and patients' age and 3) the frequency of IL-17-producing Vδ2 γδ T cells and hemoglobin S level.

Conclusion: These results strongly suggest a role of innate-like T cells in sickle cell disease pathophysiology, especially that of IL-17-producing MAIT and γδ T cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219047PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599217PMC
February 2020

Plasma histamine elevation in a large cohort of sickle cell disease patients.

Br J Haematol 2019 07 28;186(1):125-129. Epub 2019 Mar 28.

Department of Internal Medicine, Tenon Hospital, AP-HP, Paris VI University, Paris, France.

The role of mast cells has been questioned in sickle cell disease (SCD). We performed a prospective study evaluating plasma histamine and tryptase levels in a cohort of paediatric and adult patients, in steady state (n = 132) and during vaso-occlusive crisis (VOC) (n = 121). Histamine level was elevated in 18% of patients in steady state and in 61% during VOC. Median histamine level was significantly higher during VOC than in steady state (24·1 [7·0-45·0] vs 9·6 [6·2-14·4] nmol/l, P < 0·0001). Tryptase level was slightly increased during VOC without reaching pathological values. These results suggest a role of mast cell activation in SCD pathophysiology.
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http://dx.doi.org/10.1111/bjh.15900DOI Listing
July 2019

Conjugate Haemophilus influenzae type b vaccines for sickle cell disease.

Cochrane Database Syst Rev 2018 08 20;8:CD011199. Epub 2018 Aug 20.

Department of General Pediatrics, Necker Hospital for Sick Children, 149 rue de Sevres, Paris, France, 75015.

Background: People affected with sickle cell disease (SCD) are at high risk of infection from Haemophilus influenzae type b (Hib). 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, Hib remains one of the most common causes of bacteraemias in children with SCD. The increased uptake of this conjugate vaccination may substantially improve the survival of children with SCD. This is an update of a previously published Cochrane Review.

Objectives: The primary objective was to determine whether Hib conjugate vaccines reduce mortality and morbidity in children and adults with SCD.The secondary objectives were to assess the following in children and adults with SCD: the immunogenicity of Hib 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's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched trial registries (04 July 2018) and contacted relevant pharmaceutical companies to identify unpublished trials.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinoapthies Trials Register: 18 December 2017.

Selection Criteria: All randomised controlled trials (RCTs) and quasi-RCTs comparing Hib conjugate vaccines with placebo or no treatment, or comparing different types of Hib conjugate vaccines in people with SCD.

Data Collection And Analysis: No trials of Hib conjugate vaccines in people with SCD were found.

Main Results: There is an absence of evidence from RCTs relating to the subject of this review.

Authors' Conclusions: There has been a dramatic decrease in the incidence of invasive Hib infections observed in the post-vaccination era in people with SCD living in high-income countries. Therefore, despite the absence of evidence from RCTs, it is expected that Hib conjugate vaccines may be useful in children affected with SCD, especially in African countries where there is a high prevalence of the disease. The implementation of childhood immunisation schedules, including universal Hib conjugate vaccination, may substantially improve the survival of children with SCD living in low-income countries. We currently lack data to evaluate the potential effect of Hib vaccination among unvaccinated adults with SCD. Further research should assess the optimal Hib immunisation schedule in children and adults with SCD.
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http://dx.doi.org/10.1002/14651858.CD011199.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513445PMC
August 2018

Early Noninvasive Ventilation and Nonroutine Transfusion for Acute Chest Syndrome in Sickle Cell Disease in Children: A Descriptive Study.

Pediatr Crit Care Med 2018 05;19(5):e235-e241

Pediatric Intensive Care Unit, AP-HP, Hôpital Necker Enfants Malades, Paris, France.

Objectives: To describe the need for transfusion and short- and long-term evolutions of pediatric sickle cell disease patients with acute chest syndrome for whom early continuous noninvasive ventilation represented first-line treatment.

Design: Single-center retrospective chart study in PICU.

Setting: A tertiary and quaternary referral PICU.

Patients: All sickle cell disease patients 5-20 years old admitted with confirmed acute chest syndrome and not transfused in the previous month were included.

Interventions: None.

Measurements And Main Results: Demographic data, laboratory and radiologic findings, transfusions, invasive ventilation, oxygen and noninvasive ventilation settings, duration of opioid treatment, length of hospital stay, and severe sickle cell disease complications in the ensuing 2 years were extracted from medical charts. Sixty-six acute chest syndrome in 48 patients were included. Continuous early noninvasive ventilation was well tolerated in 65 episodes, with positive expiratory pressure 4 cm H2O and pressure support 10 cm H2O (median) administered continuously, then discontinued during 7 days (median). No patient necessitated invasive ventilation or died. Twenty-three acute chest syndrome (35%) received transfusions; none received blood exchange. Transfused patients had more frequent upper lobe radiologic involvement, more severe anemia, higher reticulocyte counts, and higher C-reactive protein than nontransfused patients. Their evolution was more severe in terms of length of opioid requirement, length of noninvasive ventilation treatment, overall time on noninvasive ventilation, and length of stay. At 2-year follow-up after the acute chest syndrome episode, no difference was observed between the two groups.

Conclusions: Early noninvasive ventilation combined with nonroutine transfusion is well tolerated in acute chest syndrome in children and may spare transfusion in some patients. Early recognition of patients still requiring transfusion is essential and warrants further studies.
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http://dx.doi.org/10.1097/PCC.0000000000001468DOI Listing
May 2018

Anemia in children: prevalence, causes, diagnostic work-up, and long-term consequences.

Expert Rev Hematol 2017 11 12;10(11):1023-1028. Epub 2017 Oct 12.

a Department of General Pediatrics and Pediatric Infectious Diseases , Hôpital Necker-Enfants malades , Paris , France.

Introduction: Anemia in children is a major public health problem throughout the world. It is often multifactorial, iron deficiency being the most frequent etiology. Consequences are diverse and largely under evaluated. Areas covered: This paper briefly reviews the main causes and focus on the potential consequences of acute and chronic anemia in children. Expert commentary: Anemia in children should never be trivialized. Even if iron deficiency is frequently involved, other potentially life-threatening causes are possible and should be looked for. The exact contribution of anemia to child mortality and morbidity is difficult to assess because of overlapping comorbidities. Chronic anemia may impair growth, cardiac function and cognitive development in infants but other consequences are rather poorly described and should be explored more thoroughly.
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http://dx.doi.org/10.1080/17474086.2017.1354696DOI Listing
November 2017

Prevalence and risk factors for red blood cell alloimmunization in 175 children with sickle cell disease in a French university hospital reference centre.

Br J Haematol 2017 05 12;177(4):641-647. Epub 2017 Apr 12.

Department of Paediatrics, Necker Hospital for Sick Children, Paris Descartes University, Paris, France.

Patients with sickle cell disease (SCD) show a high prevalence of red blood cell (RBC) alloimmunization, but few studies have focused on children. We aimed to study the prevalence and risk factors of RBC alloimmunization in SCD children. We retrospectively analysed the medical and transfusion files for 245 SCD children hospitalized in our centre in 2014 and included 175 patients who had received at least one RBC unit in their lifetime. The main clinical and immuno-haematological characteristics of alloimmunized and non-alloimmunized patients were compared. The prevalence of alloimmunization was 13·7% [95% confidence interval (CI) (8·6-18·6)], and 7·4% [95% CI (3·5-11·3)] after excluding the probable irregular natural antibodies (anti-M, anti-Le , anti-Le , anti-Le ). Main risk factors for alloimmunization were increased number of RBC units received (median of 65 vs. 10 units per patient; P = 0·01) and the presence of one or more red cell autoantibodies (46·2% vs. 4·7%; P < 0·0001). The alloimmunization rate was higher for episodically transfused than chronically transfused patients (1·43 vs. 0·24/100 units received; P < 0·001). The presence of red cell autoantibodies appears to be a major risk factor for alloimmunization in SCD children and could justify specific transfusion guidelines.
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http://dx.doi.org/10.1111/bjh.14609DOI Listing
May 2017

Childhood immune thrombocytopenia: A nationwide cohort study on condition management and outcomes.

Pediatr Blood Cancer 2017 Jul 1;64(7). Epub 2016 Dec 1.

French Reference Center for Rare Diseases and Autoimmune Cytopenias of Childhood (CEREVANCE), Pellegrin Hospital, Bordeaux, France.

Objectives: Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in routine clinical practice and (ii) the predictors of chronicity at 12 months.

Procedure: Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months-18 years and diagnosed with primary ITP over a 5-year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI).

Results: One hundred thirty-seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0-4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1-6.0), and platelet counts ≥10 × 10 /l (OR = 3.2; 95% CI = 1.5-6.9).

Conclusions: In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.
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http://dx.doi.org/10.1002/pbc.26389DOI Listing
July 2017

Conjugate Haemophilus influenzae type b vaccines for sickle cell disease.

Cochrane Database Syst Rev 2016 Feb 16;2:CD011199. Epub 2016 Feb 16.

Department of General Pediatrics, Necker Hospital for Sick Children, 149 rue de Sevres, Paris, France, 75015.

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's 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' 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.
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http://dx.doi.org/10.1002/14651858.CD011199.pub2DOI Listing
February 2016

Efficacy of colchicine in a child with relapsing bullous Henoch-Schönlein purpura.

Eur J Pediatr 2016 Jan 21;175(1):147-9. Epub 2015 Jul 21.

Department of General Pediatrics, Hôpital Necker-Enfants Malades, APHP, Paris Descartes University, 149 rue de Sèvres, 75015, Paris, France.

Unlabelled: Colchicine is not usually considered a treatment option for cutaneous lesions of Henoch-Schönlein purpura (HSP) in children. We report a case of pediatric HSP with severe chronic and relapsing cutaneous manifestations that were resistant to corticosteroids. Colchicine had remarkable therapeutic efficacy, with positive dechallenge and rechallenge, without any adverse effects.

Conclusion: Colchicine should be considered for chronic, severe cutaneous lesions of pediatric HSP.

What Is Known: Colchicine is not usually considered a treatment option for cutaneous lesions of Henoch-Schönlein purpura (HSP) in children. What is New: We report a case of pediatric HSP with severe cutaneous manifestations that responded well to colchicine. Colchicine should be considered for chronic cutaneous lesions of HSP in children.
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http://dx.doi.org/10.1007/s00431-015-2594-5DOI Listing
January 2016

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

PLoS One 2014 30;9(5):e97462. Epub 2014 May 30.

Paris Descartes University, Paris, France; Pediatrics Department and Sickle Cell Clinic, Hospital Necker, AP-HP, Paris, France.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097462PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039516PMC
January 2015

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

PLoS One 2013 30;8(7):e70931. Epub 2013 Jul 30.

Université Paris Descartes and Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728106PMC
April 2014

Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46, XY disorders of sex development (DSD) including hypospadias.

PLoS One 2011 20;6(10):e24117. Epub 2011 Oct 20.

Université Paris Descartes, Faculté de médecine and AP-HP, Hôpital Bicêtre, Unité d'Endocrinologie, Pédiatrique, Le Kremlin Bicêtre, France.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024117PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197579PMC
February 2012

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

PLoS One 2011 10;6(8):e23292. Epub 2011 Aug 10.

Université Paris Descartes and AP-HP, Hôpital Bicêtre, Unité d'Endocrinologie Pédiatrique, Le Kremlin Bicêtre, France.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023292PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154292PMC
December 2011

Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias.

Am J Hum Genet 2011 Jul 16;89(1):7-14. Epub 2011 Jun 16.

Department of Genetics, Université Paris Descartes, Unité Institut National de la Santé et de la Recherche Médicale, Hôpital Necker Enfants Malades, Paris, France.

Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
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http://dx.doi.org/10.1016/j.ajhg.2011.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135800PMC
July 2011