Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants - identification of 11 novel mutations in CYBB.

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910 , X91- or X91+ ), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910 -CGD and two X91- -CGD). One X910 -CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91- -CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91- -CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91- -CGD patients correlates with mild clinical forms of CGD, whereas X910 -CGD and X91+ -CGD cases remain the most clinically severe forms.

Impact of intermittent versus continuous infusions on central line-associated bloodstream infection risk in haemato-oncology patients: a quasi-experimental study.

BACKGROUND: Continuous fluid infusions delivered between therapies by piggy-back systems avoid disconnection and reconnection of central venous catheters (CVCs), thereby reducing opportunities for line contamination. However, the impact of continuous versus intermittent infusions on central line-associated bloodstream infections (CLABSIs) is unknown. AIM: To investigate the effect of temporary infusion interruption and line disconnection, with or without use of a 70% isopropyl alcohol cap (IPA-C) on CLABSI rates in haematology patients. METHODS: Quasi-experimental study in two haemato-oncology units. At baseline (P1, September 2020 to August 2021), continuous intravenous piggy-back infusions were mandatory. In a first intervention phase (P2, September 2021 to August 2022), infusion disconnections were implemented with use of a 70% isopropyl alcohol cap (IPA-C) for passive decontamination. In a second intervention phase (P3, September 2022 to August 2023), infusion disconnections continued without the use of IPA-C. Rates of CLABSI were compared across the three intervention periods using segmented Poisson regression. FINDINGS: A total of 11,039 catheter-days across 764 CVCs and 16,226 patient-days were included. Twenty-one CLABSIs were recorded across all intervention periods. Compared with P1, incidence rate ratios (IRRs) for CLABSI did not significantly change in P2 (IRR 0.76 (95% CI 0.27-2.15)) and P3 (IRR 0.79 (95% CI 0.28-2.22)). No CVCs were removed due to occlusion during the study period. Five of 21 CLABSIs were polymicrobial, and coagulase-negative staphylococci were isolated in 19/21 cases (90%). CONCLUSION: Interruption of continuous infusions in haemato-oncology patients with a CVC was not associated with a substantial change in CLABSI rates, whether or not an IPA-C was used.

Risk of catheter-associated bloodstream infection by catheter type in a neonatal intensive care unit: a large cohort study of more than 1100 intravascular catheters.

BACKGROUND: The aim of this study was to evaluate the risk of catheter-associated bloodstream infection (CABSI) among different catheter types using a large prospective database in the neonatal intensive care unit (NICU) of a tertiary care centre in Switzerland. METHODS: We included all neonates admitted to the NICU with at least one central intravascular catheter inserted between January 2017 and December 2020. We used marginal Cox model to determine the risk of CABSI among different catheter types. RESULTS: A total of 574 neonates and 1103 intravascular catheters were included in the study: 581 venous umbilical catheters, 198 arterial umbilical catheters and 324 peripherally inserted central catheters (PICCs). We identified 17, four and four CABSIs in neonates with venous umbilical catheters, arterial umbilical catheters and PICCs, respectively. The risk of CABSI increased after two days of umbilical catheter maintenance. Using univariable Cox models, and adjusting for sex and gestational age, we observed a similar CABSI risk between venous and arterial umbilical catheters (HR 0.57; 95% CI 0.16e2.08). Birth weight was associated with CABSI, with higher weight being protective (HR 0.37, 95% CI 0.16e0.81). CONCLUSIONS: Strategies aimed at reducing umbilical catheter dwell time, particularly in low and very low birth weight neonates, may be effective in decreasing the incidence of CABSI in this population.

Training of pediatricians in infectious diseases in France: survey among pediatricians enrolled in the French infectious diseases training program: Training of pediatricians in infectious diseases in France.

The French infectious diseases (ID) program was accessible to all medical trainees enrolled in postgraduate training for other specialties until 2017, when it became an independent specialty. Therefore, the national ID training is no longer accessible to pediatricians, and a specific program for pediatric ID (PID) is under development. We conducted a survey among French pediatric trainees enrolled in the former ID training to assess their satisfaction and describe the barriers they may have faced during the training. A questionnaire was sent in October 2018 to all pediatricians enrolled in this curriculum. Among the 17 trainees who replied, almost half (8/17) described the ID training as being hardly accessible to pediatricians, and six reported difficulties in finding a mandatory one-year position in an ID department to complete their training. Future training in PID should address these issues.

Use of stewardship smartphone applications by physicians and prescribing of antimicrobials in hospitals: A systematic review.

BACKGROUND: Antimicrobial stewardship (AMS) programs promote appropriate use of antimicrobials and reduce antimicrobial resistance. Technological developments have resulted in smartphone applications (apps) facilitating AMS. Yet, their impact is unclear. OBJECTIVES: Systematically review AMS apps and their impact on prescribing by physicians treating in-hospital patients. DATA SOURCES: EMBASE, MEDLINE (Ovid), Cochrane Central, Web of Science and Google Scholar. STUDY ELIGIBILITY CRITERIA: Studies focusing on smartphone or tablet apps and antimicrobial therapy published from January 2008 until February 28th 2019 were included. PARTICIPANTS: Physicians treating in-hospital patients. INTERVENTIONS: AMS apps. METHODS: Systematic review. RESULTS: Thirteen studies met the eligibility criteria. None was a randomized controlled trial. Methodological study quality was considered low to moderate in all but three qualitative studies. The primary outcomes were process indicators, adherence to guidelines and user experience. Guidelines were more frequently accessed by app (53.0% - 89.6%) than by desktop in three studies. Adherence to guidelines increased (6.5% - 74.0%) significantly for several indications after app implementation in four studies. Most users considered app use easy (77.4%->90.0%) and useful (71.0%->90%) in three studies and preferred it over guideline access by web viewer or booklet in two studies. However, some physicians regarded app use adjacent to colleagues or patients unprofessional in three qualitative studies. Susceptibility to several antimicrobials changed significantly post-intervention (from 5% decrease to 10% - 14% increase) in one study. CONCLUSIONS: Use of AMS apps seems to promote access to and knowledge of antimicrobial prescribing policy, and increase adherence to guidelines in hospitals. However, this has been assessed in a limited number of studies and for specific indications. Good quality studies are necessary to properly assess the impact of AMS apps on antimicrobial prescribing. To improve adherence to antimicrobial guidelines, use of AMS apps could be considered.

[Disseminated actinomycosis treated with clindamycin]. / Actinomycose disséminée traitée par clindamycine.

Actinomycosis is a rare bacterial disease caused by Actinomyces spp., an anaerobic bacteria from the oropharynx, digestive, and female genital tracts. Initial clinical presentation often mimics malignancy, which can lead to a delay in diagnosis. Cervico-facial, genitourinary, digestive, and respiratory features are the most frequent. Few cases are reported in children and risk factors are not well known in this population. We report on the case of an 8-year-old boy with disseminated actinomycosis with cervico-facial, pulmonary, and bone involvement caused by Actinomyces israelii. The infiltrative appearance initially suggested malignancy and the patient was started on chemotherapy for presumed histiocytosis. Evaluation of subsequent tissue samples demonstrated the presence of filamentous structures consistent with fungal or filamentous bacterial infection. Prolonged culture yielded the correct diagnosis. The patient had a severe allergic reaction to piperacillin/tazobactam and was therefore transitioned to clindamycin to complete a 9-month course. This treatment, which has not been reported in children, led to a favorable clinical, biological, and radiological response, with a good clinical tolerance.

[Children exposed to multidrug-resistant tuberculosis: How should we manage? Analysis of 46 child contacts and review of the literature]. / Enfants au contact d'individus atteints d'une tuberculose multi-résistante : quelles stratégies adopter ? Analyse de 46 enfants contacts et revue de la littérature.

INTRODUCTION: Tuberculosis-related morbidity and mortality remain important. Emergence and diffusion of multidrug-resistance tuberculosis (MDR-TB) is a global public health concern. Cases of MDR-TB in children are a sentinel event indicating the spread of a mycobacterial strain within a community. Latent TB precedes MDR-TB and screening and follow-up of contact individuals are key points of TB infection control. METHODS: We performed the case-investigation of 20 adult cases of MDR-TB managed in our institution. RESULTS: Forty-six pediatric contact individuals were identified. A high proportion of these children were lost to follow-up (80% at 12 months), showing that monitoring this reservoir population with migrant history is challenging. Five (11%) children presented a secondary infection: one child was diagnosed with active TB infection (positive tuberculin skin test associated with abnormalities on chest computer tomography [CT] scan). Four children were diagnosed with latent TB infection (isolated positive tuberculin skin test with normal CT scan). Two of these children received a treatment adjusted to the strain of the index case. DISCUSSION: In the setting of emerging MDR-TB, tuberculin skin test may be likely replaced by specific interferon-gamma release assays (IGRA), independent of prior BCG vaccination. In addition, chest CT scan is preferred to chest X-ray to detect TB lesions. The management of latent TB infection is controversial: immediate treatment with second-line anti-TB drugs adapted to the index case strain or, consistently with WHO guidelines, a simple follow-up with subsequent treatment in case of active TB.

Management of emerging multidrug-resistant tuberculosis in a low-prevalence setting.

Multidrug-resistant (MDR) tuberculosis (TB) is an emerging concern in communities with a low TB prevalence and a high standard of public health. Twenty-three consecutive adult MDR TB patients who were treated at our institution between 2007 and 2013 were reviewed for demographic characteristics and anti-TB treatment management, which included surgical procedures and long-term patient follow-up. This report of our experience emphasizes the need for an individualized approach as MDR TB brings mycobacterial disease management to a higher level of expertise, and for a balance to be found between international current guidelines and patient-tailored treatment strategies.

[Intrafamilial transmission of Staphylococcus aureus Panton-Valentine leukocidin responsible for two cases of neonatal necrotizing pneumonia]. / Transmission intrafamiliale de Staphylococcus aureus sécréteur de toxine leucocidine Panton-Valentine responsable de deux cas de pneumopathies nécrosantes néonatales.

Necrotizing Staphylococcus aureus Panton-Valentine leukocidin (SA-PLV+) accounts for less than 1% of community-acquired lung diseases in children and young adults. Neonatal cases are exceptional. We report the observations of two newborn female twins, who were not breastfed, presenting a necrotizing lung disease due to the same strain of SA-PVL+ despite nasal decolonization measures taken. These two cases are informative and bring to light (1) the possibility of severe SA-PVL+ lung infections in young infants and (2) their strictly intrafamilial mode of transmission for which eradication measures were ineffective.