Antiphospholipid syndrome and other autoimmune diseases associated with chronic intervillositis.

OBJECTIVES: Chronic intervillositis of unknown etiology (CIUE) is characterized by an intervillous infiltrate of mononuclear cells and a high recurrence rate of adverse obstetrical outcomes. The aim was to describe obstetrical history in patients with at least one event characterized by CIUE, and the possible impact of systematic investigation of an underlying autoimmune disease on the obstetrical outcome of subsequent pregnancies. METHODS: We retrospectively reviewed all pregnancies in patients having experienced at least one adverse obstetric outcome associated with chronic intervillositis of unknown etiology diagnosed by placental histological analysis between 2004 and 2011 in our university hospital. For each patient, data pertaining to obstetrical history, treatments during pregnancies, the results of systematic investigation of an underlying autoimmune disease, and treatments as well as obstetrical outcome in subsequent pregnancies, were collected. RESULTS: Twelve patients with 38 pregnancies were included [median age 30 (22; 40 years)]. Autoimmune disease or autoimmune antibodies (AID group) were found in 7/12 patients: primary antiphospholipid syndrome (APS) (n = 4), Sjögren's syndrome (n = 1), pernicious anemia (n = 1) and celiac disease (n = 1). When comparing pregnancies of patients with and without AID, there was no difference with regard to the type of obstetrical events or live-born babies, in spite of appropriate treatment. Corticosteroids (prednisone 10 mg/day) were used in only 2 cases with AID (Sjögren's syndrome and APS; n = 1 each), and these 2 pregnancies resulted in live-born babies. CONCLUSION: This study shows that the immunological assessment in patients with CIUE raises the possibility of a specific severity when AID or obstetrical APS is associated with CIUE, since conventional treatment did not improve obstetrical outcome in these patients as compared to those without autoimmune diseases. The benefit of immunosuppressant agents in this subset of patients needs further evaluation.

European registry of babies born to mothers with antiphospholipid syndrome.

OBJECTIVES: This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the child's immunological profile with their mothers. METHODS: A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening. Children were examined at 3, 9, 24 months and 5 years. RESULTS: 134 children were analysed (female sex in 65 cases, birth weight 3000±500 g, height 48±3 cm). Sixteen per cent had a preterm birth (<37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Four children displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotony with psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-ß(2) glycoprotein-I (anti-ß2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-ß2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-ß2GPI IgG were correlated with the same mother's antibodies before 6 months of age (p<0.05). CONCLUSION: Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.

Evaluation of nevirapine dosing recommendations in HIV-infected children.

AIMS: Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations. METHODS: Concentrations were measured on a routine basis in 94 children aged from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected, and a population pharmacokinetic model was developed with Monolix 4.0. RESULTS: Nevirapine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. After standardization to a 70 kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Estimates of apparent clearance and volume of distribution were 3.9 l h(-1) (70 kg)(-1) and 140 l (70 kg)(-1) , respectively. Based on simulations of European Medicines Agency (EMA) and World Health Organization (WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3 mg l(-1) is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3-6 and 6-10 kg weight ranges following the WHO recommendations. CONCLUSIONS: It is suggested to increase doses to 75 and 100 mg twice daily for the 3-6 and 6-10 kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3 mg l(-1) .

Performance of HIV-1 DNA or HIV-1 RNA tests for early diagnosis of perinatal HIV-1 infection during anti-retroviral prophylaxis.

OBJECTIVE: To compare performance of testing for human immunodeficiency virus (HIV)-1 DNA and HIV-1 RNA for diagnosis of HIV-1 infection in infants receiving preventive antiretroviral therapy. STUDY DESIGN: This substudy of the French multicenter prospective cohort of neonates born to HIV-infected mothers, included 1567 infants tested for HIV with polymerase chain reaction (PCR) in a single laboratory, receiving post-natal prophylaxis, not breastfed, and having simultaneous HIV-1 DNA and RNA results before 45 days. The performance of PCR was assessed in reference to the 6-month HIV-1 RNA result. RESULTS: Specificity of both HIV-1 RNA and HIV-1 DNA PCR was 100% at all ages (except 99.8% for DNA at birth); sensitivity was 58% (RNA) and 55% (DNA) at birth, and 89% at 1 month, 100% at 3 months for both, and 100% at 6 months (DNA). Concordance between HIV-1 DNA and RNA results was 0.78 and 0.81 (Kappa) at birth and 1 month and 100% at 3 and 6 months. Type of maternal and neonatal prophylaxis had no effect on sensitivity, but influenced viral load. CONCLUSION: The performances of testing for HIV-1 DNA and RNA were similar with 100% sensitivity at 3 months. At 1 month during prophylaxis, 11% of infected children had negative PCR results.

Germline gain-of-function mutations of ALK disrupt central nervous system development.

Neuroblastoma (NB) is a frequent embryonal tumor of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harboring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.

Isolated congenital asplenia: a French nationwide retrospective survey of 20 cases.

OBJECTIVE: To better describe the natural history, mode of inheritance, and the epidemiological and clinical features of isolated congenital asplenia, a rare and poorly understood primary immunodeficiency. STUDY DESIGN: A French national retrospective survey was conducted in hospital pediatric departments. A definitive diagnosis of ICA was based on the presence of Howell-Jolly bodies, a lack of detectable spleen, and no detectable cardiovascular malformation. RESULTS: The study included 20 patients (12 males and 8 females) from 10 kindreds neither related to each other nor consanguineous. The diagnosis of ICA was certain in 13 cases (65%) and probable in 7 cases (35%). Ten index cases led to diagnosis of 10 additional cases in relatives. Five cases were sporadic and 15 were familial, suggesting autosomal dominant inheritance. Median age was 12 months at first infection (range, 2-516 months), 11 months at diagnosis of asplenia (range, 0-510 months), and 9.9 years at last follow-up (range, 0.7-52 years). Fifteen patients sustained 18 episodes of invasive bacterial infection, caused mainly by Streptococcus pneumoniae (61%). Outcomes were poor, with 9 patients (45%) dying from fulminant infection. CONCLUSIONS: ICA is more common than was previously thought, with an autosomal dominant inheritance in at least some kindreds. Relatives of cases of ICA should be evaluated for ICA, as should children and young adults with invasive infection.

SARS-CoV-2 transmission among children and staff in daycare centres during a nationwide lockdown in France: a cross-sectional, multicentre, seroprevalence study.

BACKGROUND: The extent to which very young children contribute to the transmission of SARS-CoV-2 is unclear. We aimed to estimate the seroprevalence of antibodies against SARS-CoV-2 in daycare centres that remained open for key workers' children during a nationwide lockdown in France. METHODS: Children and staff who attended one of 22 daycare centres during a nationwide lockdown in France (between March 15 and May 9, 2020) were included in this cross-sectional, multicentre, seroprevalence study. Hospital staff not occupationally exposed to patients with COVID-19, or to children, were enrolled in a comparator group. The primary outcome was SARS-CoV-2 seroprevalence in children, daycare centre staff, and the comparator group. The presence of antibodies against SARS-CoV-2 in capillary whole blood was measured with a rapid chromatographic immunoassay. We computed raw prevalence as the percentage of individuals with a positive IgG or IgM test, and used Bayesian smoothing to account for imperfect sensitivity and specificity of the assay. This study is registered with ClinicalTrials.gov, NCT04413968. FINDINGS: Between June 4 and July 3, 2020, we enrolled 327 children (mean age 1·9 [SD 0·9] years; range 5 months to 4·4 years), 197 daycare centre staff (mean age 40 [12] years), and 164 adults in the comparator group (42 [12] years). Positive serological tests were observed for 14 children (raw seroprevalence 4·3%; 95% CI 2·6-7·1) and 14 daycare centre staff (7·7%; 4·2-11·6). After accounting for imperfect sensitivity and specificity of the assay, we estimated that 3·7% (95% credible interval [95% CrI] 1·3-6·8) of the children and 6·8% (3·2-11·5) of daycare centre staff had SARS-CoV-2 infection. The comparator group fared similarly to the daycare centre staff; nine participants had a positive serological test (raw seroprevalence 5·5%; 95% CI 2·9-10·1), leading to a seroprevalence of 5·0% (95% CrI 1·6-9·8) after accounting for assay characteristics. An exploratory analysis suggested that seropositive children were more likely than seronegative children to have been exposed to an adult household member with laboratory-confirmed COVID-19 (six [43%] of 14 vs 19 [6%] of 307; relative risk 7·1 [95% CI 2·2-22·4]). INTERPRETATION: According to serological test results, the proportion of young children in our sample with SARS-CoV-2 infection was low. Intrafamily transmission seemed more plausible than transmission within daycare centres. Further epidemiological studies are needed to confirm this exploratory hypothesis. FUNDING: Assistance Publique-Hôpitaux de Paris; Mairie de Paris, Conseil Départemental de Seine Saint Denis. TRANSLATIONS: For the French translation of the abstract see Supplementary Materials section.

Tuberculosis in adolescents: A French retrospective study of 52 cases.

BACKGROUND: The only available data about tuberculosis (TB) among adolescents date back to the 1980s, although the incidence of tuberculosis has been increasing in this age group. METHODS: Medical records were reviewed for all adolescents aged 12 to 18 years hospitalized with the diagnosis of TB in Avicenne/Jean Verdier Teaching hospital (Seine-Saint-Denis, suburb of Paris) between September 2000 and December 2004. RESULTS: Of the 52 patients identified, 52% were female. Median age at diagnosis was 15 years (range, 12-18 years). The proportion of adolescents known to be born abroad was 90%. Diagnoses resulted from the examination of a sick child in 79% of cases, a case contact investigation of an adult suspected of having TB in 19% and routine tuberculin skin test in 2%. Twenty-seven of 52 patients (52%) had isolated pulmonary disease. Sixteen patients (31%) had pulmonary and extrapulmonary TB and 8 cases (17%) had exclusively extrapulmonary disease. The site of extrapulmonary TB included pleural (n = 8), meningitis (n = 4), lymph node (n = 4), peritoneal (n = 5), osteoarticular (n = 3) and genitourinary (n = 1). TB was confirmed by the isolation of Mycobacterium tuberculosis from sputum (n = 21), gastric aspirate (n = 8), bone (n = 1) or cerebrospinal fluid (n = 2). No case had a relapse or recurrence of disease in median 3.2 years of follow up. CONCLUSIONS: Our results indicate that demographic and clinical characteristics of adolescents with TB differed from adults and children. A specific approach to the prevention and treatment of TB in adolescents is absolutely necessary.

Early versus deferred antiretroviral multidrug therapy in infants infected with HIV type 1.

BACKGROUND: The clinical impact of early antiretroviral multidrug therapy on the risk of early-onset severe human immunodeficiency virus (HIV) disease has not been evaluated on a large scale. METHODS: We evaluated the risk of early-onset events associated with acquired immunodeficiency syndrome (AIDS), particularly the risk of encephalopathy, among infants in the French Perinatal Cohort, according to whether antiretroviral multidrug therapy was initiated before or after the age of 6 months. RESULTS: Of 83 HIV-infected infants born in 1996 (when HAART became available) or later, 40 received early treatment on or before the age of 6 months, and 43 received deferred multidrug therapy after the age of 6 months. In the group that received early multidrug therapy, no child developed an opportunistic infection or an encephalopathy during the first 24 months of life. In the deferred multidrug therapy group, 6 infants presented with a total of 7 AIDS-associated events (P=.01), 3 of which were encephalopathies (P=.08). The small number of events prevented the identification of clinical and biological markers that accurately predict progression of early-onset severe HIV disease. CONCLUSION: In this observational study, infants who received multidrug therapy before 6 months of age did not have the early-onset severe form of childhood HIV disease. Further studies are needed to find accurate early markers of disease progression in this age group.

Autism spectrum disorders in babies born to mothers with antiphospholipid syndrome.

OBJECTIVES: To evaluate the outcomes of babies born to mothers with primary antiphospholipid syndrome and to compare to the outcomes of babies of mothers with systemic lupus erythematosus. METHODS: A retrospective study from 2003 to 2010 assessing the clinical characteristics and psychomotor development, as well as the immunological data, of children born to mothers with antiphospholipid syndrome (APS) (group 1) and systemic lupus erythematosus (group 2). RESULTS: Group 1 consisted of 36 children born to mothers (n = 26) with a primary APS. Autism spectrum disorders occurred in 3 children from group 1 and all of them had persistent anti-ß2GP1 IgG antibodies. Group 2 consisted of 12 children born to mothers (n = 9) with lupus erythematosus. Three children experienced cutaneous neonatal lupus, but there were no neurodevelopmental disorders. Comparing children of groups 1 and 2, no significant difference was found with regard to the parameters at birth or during follow-up. The children in group 2 had antinuclear antibodies more frequently (p < 0.05). CONCLUSION: Autism spectrum disorders could be observed in babies born to mothers with antiphospholipid syndrome, but there is no risk of thrombosis. KEY MESSAGES: Neonatal lupus is well-known complication in children born to mothers with systemic lupus erythematosus, but there is no risk of thrombosis in APS-exposed children. In children of APS mothers the rate of prematurity and small-for-gestational age weight remain high even in treated pregnancy. The presence of several cases of autism spectrum disorders in APS-exposed children could be related to mother's antibodies exposition, but need to be confirmed.

Outcomes and treatment of obstetrical antiphospholipid syndrome in women with low antiphospholipid antibody levels.

Our objective was to determine whether there is a relationship between low antiphospholipid (aPL) antibody levels and the obstetrical complications of antiphospholipid syndrome (APS) and to analyze the impact of conventional APS treatment in patients with low aPL levels. To this end, we retrospectively reviewed the files of all patients referred to our unit (2003-2010) for unexplained pregnancy morbidity, with an aPL test result. We compared patients with APS confirmed by Sapporo criteria (Group 1) with patients with APS-like obstetrical complications with an aPL titer below the intermediate titer (Group 2). Overall, 57 patients were included (25 in Group 1; 32 in Group 2). Obstetrical events were recurrent spontaneous abortion <10th week of gestation (n=9 patients in Group 1; n=13 patients in Group 2), fetal death (n=11 and 16, respectively), preeclampsia (n=5 in Group 1; n=6 in Group 2). The total number of obstetrical events per patient was very similar before APS treatment (3 [1-8] in Group 1; 3 [1-6] in Group 2) and decreased significantly after APS treatment to 0 [0-2] and 0 [0-2], respectively (p<0.05). The incidence of premature births and the characteristics of neonates were similar in the two groups. In this study, treatment of patients with low aPL levels and APS-like obstetrical events was associated with outcomes similar to those found in otherwise normal women with recurrent miscarriage or other adverse events. However, properly designed treatment trials would be required to prove the benefit of such treatments.

Late postnatal HIV infection in children born to HIV-1-infected mothers in a high-income country.

OBJECTIVE: To evaluate the risk of late postnatal HIV-1 infection in nonbreastfed children enrolled in the French ANRS Cohort CO01 (EPF). METHODS: The EPF cohort has prospectively enrolled HIV-infected mother/child pairs with a low proportion of known breastfeeding (<0.2%). Children were followed until they were 24 months old, with HIV-1 DNA/RNA PCR tests performed at birth, M1, M3 and M6 and a late serology at 18-24 months. This substudy included 4539 children who were uninfected at the age of 6 months in 1984-2005. RESULTS: Five children were late diagnosed with HIV-1 infection despite negative PCR tests until 6 months. In three cases, the infection was diagnosed between 14 and 18 months. The other infections were diagnosed at 10 and 12 years of age because of AIDS-defining symptoms; their last (negative) serologies were performed at 19 and 9 months, respectively. A phylogenetic study performed in the latest case revealed a strong homology between the mother and child strains. No known mode of viral transmission (including breastfeeding or use of premasticated food) could be found. However, we observed previously reported risk factors for intrafamilial HIV-1 transmission: poor socioeconomic backgrounds and sustained HIV-1 viremia in the mothers during the follow-up of their children. CONCLUSION: Late postnatal HIV-1 infection can rarely be diagnosed in the absence of known breastfeeding in high-income countries. Our results highlight the need for a maintained close follow-up of the noninfected children even after 6 months, especially when there are risk factors for intrafamilial viral transmission.

Uncomplicated outcome after an accidental overdose of nevirapine in a newborn.

We report the first case of a massive accidental overdose of nevirapine in a 1-week newborn, due to confusion between nevirapine (Viramune) and nelfinavir (Viracept). The drug was eliminated spontaneously and quickly. We only observed mild neutropenia and hyperlactatemia, which regressed on its own without any clinical complication. Despite the good evolution of this massive overdose, physicians should be aware of confusion risks between some antiretroviral drugs.