Abstract
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.
Since the beginning of the COVID-19 pandemic, other respiratory illnesses decreased worldwide. This study described the consequences of public health measures on respiratory syncytial virus (RSV) ...severe infections in France, where an interseasonal resurgence of RSV occurred recently. All patients admitted to Necker Hospital (Paris) between August 2018 and April 2021 with a diagnosis of RSV-associated acute lung respiratory infection (ALRI) were enrolled. Characteristics of subjects with RSV-associated ALRI in 2020/2021 were compared to those infected during the two previous outbreaks. Overall, 664 inpatients were diagnosed with RSV-associated ALRI: 229, 183, and 252 during the 2018/2019, 2019/2020, and 2020/2021 outbreaks, respectively. During autumn 2020, a national lockdown began in France but schools remained open. A 3-month delayed RSV epidemic occurred at the end of this lockdown. Compared to previous outbreaks, the 2020/2021 epidemics involved more children aged 6 to 11 months (25.8% versus 13.1%,
p
< 0.0001), but less infants aged < 6 months (41.3% versus 56.6%,
p
< 0.0001) and less adults (0.0 versus 2.7%,
p
< 0.0001). Shorter length of stay at hospital, less frequent requirement of admission to intensive care unit, use of non-invasive ventilation, and/or high-flow nasal oxygen were observed in 2020/2021 than during previous epidemics (
p
< 0.0001). Delayed RSV outbreak was associated with more hospitalizations for ALRI, higher age of pediatric inpatients, but milder median clinical phenotype. Reinforced public health measures (even while keeping nurseries and schools open with mandatory face masks since six years of age) could impact, at least transiently, the burden of RSV-related hospitalizations.
Effectiveness of anti-HIV in the prevention of perinatal transmission has been established. Assessing the tolerance of drug exposure during pregnancy is of the utmost importance given the number of ...children exposed. HIV integrase and the recombinase-activating gene enzyme involved in the establishment of the T-lymphocyte repertoire show structural similarity. The inhibition of recombinase-activating (RAG) gene by anti-integrases is observed in vitro, in a variable way according to the molecules. Here, we show that in utero exposure to raltegravir did not alter the T-lymphocyte repertoire of 12 newborns. These reassuring data merit verification for other anti-integrases. ( ClinicalTrial.org NCT04024150).
•In the post-ART era, HIV infections still leads to a variety of infections.•Some PIDs share the same pathogens and mechanisms with HIV-infected individuals.•Specific pathways and T cell subsets are ...responsible for these infections.
Following infection with almost any given microorganism other than an emerging pathogen, only a minority of individuals develop life-threatening clinical disease, implying that these individuals have some form of immunodeficiency. A growing number of inherited and acquired immunodeficiencies have been deciphered over the last 50 years. HIV infection is probably the best-known acquired immunodeficiency. It emerged about 40 years ago and precipitates various severe infections, the occurrence of which is associated with a fall in circulating CD4+ T cells. However, despite the strength of this correlation, infection rates differ between patients with similar levels and durations of CD4+ T lymphopenia in the presence or absence of antiretroviral treatment. Moreover, a few infections seem to be less dependent on total CD4+ T-cell levels. The fine detail of the mechanisms underlying these infections is unknown. We discuss here how studies of the human genetics and immunology of some of these infections in patients with primary immunodeficiencies (PIDs) have provided unique insights into their molecular and cellular basis. Defects of specific CD4+ Th-cell subsets account for some of these infections, as best exemplified by Th1* for mycobacteriosis and Th17 for candidiasis. PIDs are individually rare, but collectively much more common than initially thought, with new disorders being discovered at an ever-increasing pace and a global prevalence worldwide approaching that of HIV infection. Studies of known and new PIDs should make it possible to dissect the pathogenesis of most human infections at an unprecedented level of molecular and cellular precision. The predictive, preventive, and therapeutic implications of studies of immunity to infection in PIDs may extend to HIV-infected patients and patients with infectious diseases in other settings.
Background Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying ...molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia. Objective On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect. Methods We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers. Conclusions Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
PARN, poly(A)‐specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with ...Høyeraal–Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down‐regulation. Whether PARN deficiency was affecting the expression of telomere‐related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock‐out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down‐regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down‐regulation of dyskerin‐encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN‐deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.
Synopsis
PARN deficiency impairs telomerase activity and causes telomere shortening and instability, together with defective ribosomal RNA biogenesis. The many functional consequences of PARN deficiency likely explain the clinical severity of Høyeraal‐Hreidarsson patients carrying biallelic PARN mutations.
Steady‐state mRNA levels of several telomere‐related genes are reduced in PARN‐deficient cells.
Telomere instability is induced by PARN deficiency.
Down‐regulation of DKC1 mRNA in PARN‐deficient cells is due to p53 up‐regulation.
Ribosomal RNA biogenesis is impaired in PARN‐deficient cells.
Parn knock‐out mice are embryonic lethal and are not reverted by p53 knock‐out.
PARN deficiency impairs telomerase activity and causes telomere shortening and instability, together with defective ribosomal RNA biogenesis. The many functional consequences of PARN deficiency likely explain the clinical severity of Høyeraal‐Hreidarsson patients carrying biallelic PARN mutations.
Background Expression of the pre–B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre–B-cell receptor result in early ...B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre–B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients with BLNK gene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified. Methods B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiency in vitro and in vivo. Results Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation in BLNK , which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre–BI- to pre–BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with the BLNK gene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes.
Antimicrobial stewardship programs aim at reducing the overuse of broad-spectrum antibiotics such as carbapenems, but their impact remains unclear. We compared the use of carbapenems between ...paediatric and adult subjects admitted to a French tertiary hospital and described the intervention of an antibiotic stewardship team (AST). As part of AST routine activity, all adult and paediatric patients receiving carbapenems are identified in real time using a computer-generated alert system and reviewed by the AST. Data associated with carbapenem prescriptions were extracted for 2 years (2014–2015) and were compared between paediatric and adult wards. Prescription appropriateness (i.e. no clinically suitable narrower spectrum alternative to carbapenem for de-escalation) and AST intervention were analysed. In total, 775 carbapenem prescriptions for 291 children and 262 adults were included. Most patients (95%) had a comordity and 52% had known recent carriage of extended-spectrum beta-lactamase producing
Enterobacteriaceae
(ESBLE). Most carbapenem prescriptions came from intensive care units (
n
= 269, 35%) and were initiated for urinary tract (
n
= 200, 27%), sepsis (
n
= 181, 25%), and lung (
n
= 153, 21%) infections. Carbapenems were initiated empirically in 537 (70%) cases, and an organism was isolated in 523 (67%) cases. Among the isolated organisms, 47% (
n
= 246) were ESBLE and 90% (
n
= 468) were susceptible to carbapenems, but an alternative existed in 61% (
n
= 320) of cases according to antibiotic susceptibility testing. Among prescriptions reviewed by the AST, 39% (
n
= 255) were considered non-appropriate and led to either antibiotic discontinuation (
n
= 47, 7%) or de-escalation (
n
= 208, 32%). Non-appropriate prescriptions were more frequent in paediatric wards (
p
= 0.01) and in microbiologically documented infections (
p
= 0.013), and less observed in immunocompromised patients (
p
= 0.009) or with a known ESBLE carriage (
p
< 0.001). Tailored stewardship programs are essential to better control carbapenem use and subsequent antimicrobial resistance.
Durable HIV-1 remission after interruption of combined antiretroviral therapy (ART) has been reported in some adults who started treatment during primary infection; however, whether long-term ...remission in vertically infected children is possible was unknown. We report a case of a young adult perinatally infected with HIV-1 with viral remission despite long-term treatment interruption.
The patient was identified in the ANRS EPF-CO10 paediatric cohort among 100 children infected with HIV perinatally who started ART before 6 months of age. HIV RNA viral load and CD4 cell counts were monitored from birth. Ultrasensitive HIV RNA, peripheral blood mononuclear cell (PBMC)-associated HIV DNA, HIV-specific T-cell responses (ie, production of cytokines and capacity to suppress HIV infection), reactivation of the CD4 cell reservoir (measured by p24 ELISA and HIV RNA in supernatants upon phytohaemagglutinin activation of purified CD4 cells), and plasma concentrations of antiretroviral drugs were assessed after 10 years of documented control off therapy.
The infant was born in 1996 to a woman with uncontrolled HIV-1 viraemia and received zidovudine-based prophylaxis for 6 weeks. HIV RNA and DNA were not detected 3 days and 14 days after birth. HIV DNA was detected at 4 weeks of age. HIV RNA reached 2·17× 10(6) copies per mL at 3 months of age and ART was started. HIV RNA was undetectable 1 month later. ART was discontinued by the family at some point between 5·8 and 6·8 years of age. HIV RNA was undetectable at 6·8 years of age and ART was not resumed. HIV RNA has remained below 50 copies per mL and CD4 cell counts stable through to 18·6 years of age. After 11·5 years of control off treatment, HIV RNA was below 4 copies per mL and HIV DNA was 2·2 log10 copies per 10(6) PBMCs. The HLA genotype showed homozygosity at several loci (A*2301-, B*1503/4101, C*0210/0802, DRB1*1101-, and DQB1*0602-). HIV-specific CD8 T-cell responses and T-cell activation were weak.
Findings from this case suggest that long-term HIV-1 remission is possible in perinatally infected children who receive treatment early, with characteristics similar to those reported in adult HIV post-treatment controllers. Further studies are needed to understand the mechanisms associated with HIV remission and whether early treatment of infected children might favour the conditions needed to achieve HIV control after treatment discontinuation.
Agence de recherche ANRS (France Recherche Nord & Sud Sida-HIV Hépatites).
Inherited deficiency of major histocompatibility complex (MHC) class II molecules impairs antigen presentation to CD4+ T cells and results in combined immunodeficiency (CID). Autosomal-recessive ...mutations in the RFXANK gene account for two-thirds of all cases of MHC class II deficiency. We describe here the genetic, clinical, and immunologic features of 35 patients from 30 unrelated kindreds from North Africa sharing the same RFXANK founder mutation, a 26-bp deletion called I5E6-25_I5E6 + 1), and date the founder event responsible for this mutation in this population to approximately 2250 years ago (95% confidence interval CI: 1750-3025 years). Ten of the 23 patients who underwent hematopoietic stem cell transplantation (HSCT) were cured, with the recovery of almost normal immune functions. Five of the patients from this cohort who did not undergo HSCT had a poor prognosis and eventually died (at ages of 1-17 years). However, 7 patients who did not undergo HSCT (at ages of 6-32 years) are still alive on Ig treatment and antibiotic prophylaxis. RFXANK deficiency is a severe, often fatal CID for which HSCT is the only curative treatment. However, some patients may survive for relatively long periods if multiple prophylactic measures are implemented.
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