Background CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), have markedly improved lung function in children with cystic fibrosis (cwCF). Their impact on fungal colonisation remains poorly investigated. Methods We conducted an ancillary prospective study within the real-world observational study MODUL-CF of cwCF naïve to CFTR modulators and initiating ETI. Clinical and microbiological data were collected up to 12 months before (baseline) and at 1, 3, 6, and 12 months post-ETI. Fungal colonisation, particularly Aspergillus, and its clinical impact were compared between Aspergillus-colonised and non-colonised children. Results A total of 238 cwCF from 26 centres were included. Fungal colonisation decreased from 59.2% to 47.0% (p<0.01), with a striking 61.0% reduction in Aspergillus fumigatus (p<0.001), whereas Candida albicans colonisation remained stable (32.4% vs. 31.5%). Furthermore, 83.1% of the 77 Aspergillus positive cwCF at baseline were Aspergillus-free by Year 2; 4 (5.2%) remained chronically and 7 (9.1%) transiently colonised. Conversely, 22 cwCF acquired Aspergillus colonisation during follow-up (n=13 in Year 1; n=9 in Year 2). At baseline, Aspergillus-colonised cwCF were older (13.6 vs. 11.7 years; p<0.001), had lower ppFEV₁ (79.5 vs. 86.3; p=0.017), and more pulmonary exacerbations (PEx) (2.79 vs. 1.81 /person/year; p<0.01) than non-Aspergillus colonised cwCF. Respiratory outcomes improved under ETI. Aspergillus colonisation was associated with a 57% higher PEx rate versus non-colonised cwCF in multivariate analyses (adjusted IRR 1.57, p<0.001). Conclusions ETI is associated with a sustained decline in A. fumigatus colonisation in cwCF. As early fungal colonisation may contribute to CF lung disease progression, its culture conversion under ETI contribute to improvement in PEx.

Pigeon paramyxovirus type 1 (PPMV-1) is a genotype of avian paramyxovirus type 1 that uses species of the family Columbidae as reservoir species. We report fatal PPMV-1 encephalitis in a human without immunosuppression or travel history outside metropolitan France. Postmortem analyses revealed PPMV-1 in tissues, underscoring that physicians should consider this potential diagnosis.

ABSTRACTBackgroundThe airways of patients with cystic fibrosis (pwCF) harbour complex fungal and bacterial microbiota involved in pulmonary exacerbations (PEx) and requiring antimicrobial treatment. Descriptive studies analysing bacterial and fungal microbiota concomitantly are scarce, especially using both culture and high‐throughput‐sequencing (HTS).ObjectivesWe analysed bacterial–fungal microbiota and inter‐kingdom correlations in two French CF centres according to clinical parameters and antimicrobial choices.MethodsForty‐eight pwCF with PEx from Creteil (n = 24) and Lille (n = 24) CF centres were included over 2 years. Sputa were collected for culture and targeted‐HTS (ITS2 and V3‐V4 targets). Sequencing and culture data, along with clinical, radiological and treatment data, were analysed. Two‐level stratified analysis was performed to study potential confounding factors (age, CF mutation, FEV1 and antibiotics) on the centre factor. Inter‐kingdom correlations were analysed.ResultsSignificant differences in the bacterial microbiota profile were found between centres (p‐value = 0.03). For mycobiota, the taxonomic distribution and diversity were comparable. HTS provided concordant but more detailed information than culture and increased detection of main CF fungi (> 25% more positive samples for Aspergillus or Scedosporium). FEV1 and systemic antibiotic before PEx influenced bacterial microbiota, but no clinical association was found with the mycobiota. No inter‐kingdom correlation between Pseudomonas and fungi was found.ConclusionsDescribing concomitant bacterial and fungal communities of pwCF at the beginning of PEx using culture and HTS shows greater diversity in HTS and better detection in case of low microbial load. Interesting inter‐kingdom correlations were observed, requiring further research on larger cohorts to understand the potential microbial interactions.

Escherichia coli pathotypes are enteric pathogens detected in gastrointestinal multiplex polymerase chain reaction (mPCR), with controversial clinical relevance. Our study aimed to describe clinical features and therapeutic decisions associated with E. coli detections in gastrointestinal mPCR. Children with positive mPCR for enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), Shiga toxin-producing E. coli (STEC), and enteroinvasive E. coli (EIEC)/Shigella identified in two pediatric hospitals over 18 months (2020-2021) were included. We described the frequency of E. coli detection and subsequent modifications in antibiotic strategies. Among the 2,471 mPCRs performed, 338 (14%) tested positive for at least one E. coli pathotype. The patient's mean age was 4.2 years, with 95% experiencing gastrointestinal symptoms. Clinical presentation was generally comparable between E. coli pathotypes. A recent travel abroad was reported in 68/338 (20%) cases and was mainly observed in EIEC/Shigella infections. An E. coli was detected alone in 177/338 (52%) cases and with another virus, bacteria, or parasite in 161 (48%) cases. Multiple enteric pathogens were mainly detected with ETEC (n = 24/26, 92%) and EAEC (n = 82/121, 68%) detections. Antibiotic therapy was prescribed in 136/338 (40%) cases, with initiation based on mPCR results in 69/338 (20%). No antibiotic therapy was discontinued following positive mPCR results. Among the 69 initiations, 31 were deemed inappropriate after retrospective chart review. E. coli detection with mPCR tests may lead to inappropriate antibiotic initiation. Caution is advised when interpreting results from gastrointestinal mPCRs in children, as clinicians may be unaware of their often unclear or irrelevant clinical significance.IMPORTANCEEscherichia coli pathotypes are increasingly detected through the widely used syndromic gastrointestinal multiplex PCR panels. However, their clinical significance and impact on antibiotic therapy in children remain uncertain. This study describes the clinical and microbiological characteristics associated with E. coli detections, as well as the subsequent modifications in antibiotic strategies. It highlights the frequent detection of E. coli pathotypes, often in association with other enteric pathogens, and reveals that nearly half of the antibiotics prescribed following these results were deemed inappropriate. These results underscore the need to enhance clinicians' interpretation of E. coli-positive results and reassess treatment strategies to optimize patient care.

Despite the well-described association of skin lesions with Staphylococcus aureus, the distinct ability of clinical isolates to influence the local and systemic inflammatory response in a patient-specific manner is insufficiently characterized. In this study, we analyzed clinical recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by wounds chronically colonized with S. aureus, to explore the relationship between inflammatory immune response and strain diversity. Children with RDEB (moderate phenotype, n = 5; severe phenotype, n = 10) and controls (n = 18) were enrolled in the study. Profiling of plasma proteins (n = 800), immune cells (n = 30 subsets and cytokine-producing cells), and cytokines (n = 38) identified a specific inflammatory signature in severe disease. Furthermore, patients with severe RDEB presented a high frequency of interleukin-17A+ (IL-17A+) cells among CD4+ and mucosal-associated invariant T (MAIT) lymphocytes. Positive S. aureus cultures from the skin of patients with RDEB allowed whole-genome sequencing of patient strains and assessment of primary keratinocyte immune response upon bacterial challenge. S. aureus secretome and conditioned medium from keratinocytes challenged with S. aureus strains from patients with severe but not from those with moderate RDEB promoted strong activation and a pro-IL-17 response in both CD4+ and MAIT cells. Our findings show that S. aureus strains isolated from patients with severe RDEB induce an IL-17-skewed immune response and pave the way for precision microbiology to explain and predict the highly variable virulence potential of bacterial clinical isolates.

Group A Streptococcus infections have increased in Europe since September 2022. The French Pediatric Intensive Care and French Pediatric Infectious Diseases expert groups conducted a retrospective and prospective study of children who had severe group A Streptococcus infections during September 1, 2022-April 1, 2024, across 34 hospitals in France. A total of 402 pediatric patients (median age 4 [interquartile range 2-7.5] years; 42% girls, 58% boys) were enrolled. Cases were characterized by a low proportion of severe skin and soft tissue infections (16%), predominance of severe upper and lower respiratory tract infections (55%), and a 3.5% case-fatality rate. In multivariate analysis, hydrocortisone, corticosteroid, and vasopressor therapies were significantly associated with major sequelae or death. Molecular analysis revealed emm1 (73.0%) and emm12 (10.8%) strains; the M1UK clone represented 50% of emm1 strains. Clinicians, researchers, and public health authorities must collaborate to mitigate the effects of GAS on child health.

OBJECTIVE:Intracranial empyemas (IEs) are rare but severe complications of ear, nose, and throat (ENT) infections, defined as purulent collections in the normally virtual meningeal spaces. IEs can be classified as sinogenic (S-IE) or otogenic (O-IE), according to the initial infection. These life-threatening complications can entail long-term neurological disabilities. Few studies have described their characteristics, and cohorts are usually small and heterogeneous. In the Greater Paris area, all cases of pediatric IE are referred to the authors' center. The aim of this study was to describe the characteristics of IE and their treatment and risk factors for repeated surgery and neurological disabilities. METHODS:This single-center, retrospective observational cohort study included all consecutive cases of IE admitted to the authors' institution between January 2016 and January 2025. RESULTS:A total of 248 patients with IE were included: 115 with S-IE and 133 with O-IE. The mean age was 6.9 ± 5.2 years. An increase in the incidence of IEs was observed over the final years of the study. Two clinical presentations were distinguished. O-IEs were observed in younger children (mean 40 ± 37 months vs 133 ± 44 months for S-IE). O-IEs were almost exclusively extradural (96%), whereas around half of S-IEs had subdural involvement (51%). S-IEs were associated with more neurological symptoms. All patients underwent surgery. Overall, 95% of patients with O-IEs and 85% of those with S-IEs underwent ENT surgery. Neurosurgery was necessary for 7% (9/133) of O-IEs and 60% (69/115) of S-IEs. Bacteriological samples were obtained, and identification was achieved in 86% (culture or polymerase chain reaction techniques). For O-IE, Fusobacterium necrophorum (47%) was the most frequent, whereas in S-IE cases, the Streptococcus milleri group (52%) was predominant. Cerebral venous thrombosis (CVT) was the most frequent complication, in 55% of O-IE cases and 21% of S-IE cases (p < 0.0001). There were no deaths in this cohort. Neurological disabilities were observed in 17% of patients, with a higher rate for those with S-IEs (27%) than those with O-IEs (8%) (p < 0.0001). Subdural empyema and parietal and interhemispheric locations were identified risk factors for neurological sequelae. Repeat surgery was necessary for 30% of patients with S-IEs and 11% of patients with O-IEs (p < 0.0001). The observed risk factors were residual IE at control MRI and the association of CVT. CONCLUSIONS:This study describes the largest pediatric IE cohort to date. An increase in incidence has been observed since 2021. The favorable results of this cohort suggest that the authors' multidisciplinary standardized treatment protocol provides successful treatment to most patients with IE.

BACKGROUND:An unexpected surge in severe Group A Streptococcus (GAS) infections occurred during 2022-2023. We assessed changes in the epidemiology and clinical characteristics of severe GAS infections during and after the COVID-19 pandemic. METHODS:We analyzed severe GAS infections in children admitted to a university hospital in Paris, France (2018-2023). Proven and probable invasive GAS (iGAS and piGAS) cases were included. Using time-series analysis, we modeled the incidence of severe GAS infections across 4 periods: prepandemic, early pandemic, late pandemic and postpandemic. Infection characteristics were also compared between periods. RESULTS:We included 269 children with severe GAS infections (mean age 4.0 ± 4.0 years), including 92 iGAS cases. Most cases were severe ear-nose-throat (ENT) infections (192/269, 71%), followed by bone and joint infections (10%) and pleural empyema (8%). In the early pandemic period, GAS infections decreased by 83% [incidence rate ratio (IRR) 0.17 (95% CI: 0.10-0.27)], but increased significantly in the late pandemic period [IRR 1.65 (95% CI: 1.22-2.24)]. Postpandemic incidence returned to prepandemic levels [IRR 0.97 (95% CI: 0.68-1.38)]. Compared to other periods, late pandemic cases were more severe, with longer hospital stays (9.4 vs. 6.4 days; P = 0.0007), more iGAS forms (47% vs. 28%; P = 0.001), increased proportions of pleural empyema (15% vs. 4%) and bone and joint infections (14% vs. 7%; P = 0.008), and more complicated ENT infections (22% vs. 7%; P = 0.003). CONCLUSIONS:The late COVID-19 pandemic period was marked by a rise in both the incidence and severity of GAS infections. These findings may improve preparedness in future pandemics.

OBJECTIVE:To analyze the changes over the last 2 decades in clinical presentation, initial management, bacterial etiology, and rates of complications of acute mastoiditis (AM) in children. STUDY DESIGN:We conducted a retrospective study including all children diagnosed with AM between 2021 and 2024 in a French tertiary care center. Age at diagnosis, first-line surgical and medical treatment modalities, complications and bacteriological findings were collected. These data were compared with those of a previously published cohort of AM between 2001 and 2008 from the same facility. RESULTS:During the 3-year study period, 223 cases of AM were included (42 cases in 2021-2022; 104 in 2022 -2023; and 77 in 2023-2024). Among the 223 cases, 211 (95%) had a subperiosteal abscess (95%), 65 (29%) an extradural empyema, and 55 (25%) a lateral sinus thrombosis. The main pathogens identified were Streptococcus pyogenes (37%), Streptococcus pneumoniae (23%), and Fusobacterium necrophorum (19%). In cases of AM with intracranial complications, S. pyogenes and F. necrophorum were causative in over 70% compared with 46% in noncomplicated cases (P < .001). Comparing the 2021-2024 cohort with 2001-2008 cohort, we observed an increase in the number of cases (74 cases/year vs 27 cases/year), a rise in rate of intracranial complications (39% vs 4%; P < .001), an increase in performance of mastoidectomy (54% vs 33%; P < .001), and a shift in etiologic agents, with an increase in the proportion of S. pyogenes (P < .001) and F. necrophorum (P = .02) and concomitant decline in S. pneumoniae (P < .001). CONCLUSIONS:This large, single-center study highlights clear changes in the clinical manifestations and bacterial etiology of AM over the past decades. Ongoing surveillance of the bacterial etiology of AM is essential to optimize its initial management.

Introduction: Current international guidelines strongly recommend catheter removal in case of S. aureus central line-associated bloodstream infection (CLASBI), but a catheter salvage strategy may be considered in children given age-related specificities. No data is available regarding the outcome of this strategy in children. This study aims to evaluate catheter salvage strategy in children with S. aureus CLABSI, and to determine treatment failure rates and associated risk factors. Methods: We retrospectively analyzed data for all children <18 years having S. aureus CLABSI on a long-term central venous catheter in a tertiary hospital from 2010 to 2014. We defined catheter salvage strategy as a central venous catheter left in place ≥3 days after initiation of empiric treatment for suspected bacteremia, and catheter salvage strategy failure as the persistence or relapse of bacteremia with a S. aureus strain harboring the same antibiotic susceptibility pattern, or the occurrence or the worsening of local or systemic infectious complication between 72 h and 28 days after the first positive blood culture. Results: During the study period, 49 cases of S. aureus CLABSI on long-term central venous catheters were observed in 41 children (including 59% with long-term parenteral nutrition) and 6 (15%) isolates were resistant to methicillin. A catheter salvage strategy was chosen in 37/49 (76%) cases and failed in 12/37 (32%) cases. Initial presence of bloodstream co-infection, serum concentration of vancomycin under the targeted value and inadequate empiric treatment were significantly associated with catheter salvage therapy failure. Conclusions: The catheter salvage strategy of S. aureus CLABSI on a long-term central venous catheter was frequent in the studied hospital and failed only in one third of cases.

OBJECTIVE:To describe and compare clinical and microbiological features, surgical and medical management, and outcomes of children with otogenic and sinogenic intracranial empyema (IE) in an institution with an established multidisciplinary protocol. To use the study findings to inform and update the institutional algorithm. METHODS:Retrospective analysis was carried out on the electronic healthcare records of all children with oto-sinogenic IE admitted in a 5-year period. RESULTS:A total of 76 patients were identified and treated according to an institutional protocol. Two distinct groups were identified: intracranial empyema related to otogenic infection (OI-IE, n = 36) or sinogenic infection (SI-IE, n = 40). SI-IE was seen in older children and had a significantly higher morbidity. Sub-dural IE was seen in a minority (n = 16) and only in SI-IE and required urgent collaborative ENT-neurosurgery. Extra-dural IE occurred more frequently and was seen in both SI-IE and OI-IE. No death and overall low morbidity were observed. Particularities found in SI-IE and OI-IE groups (as thrombosis, microbiology, antibiotic treatment, duration and outcome) permitted the delineation of these groups in our updated algorithm. CONCLUSION:The presence of a collaborative multidisciplinary protocol permits the step-wise co-ordination of care for these complex patients in our institution. All patients received prompt imaging, urgent surgical intervention, and antibiotic treatment. Microbiological identification was possible for each patient and antibiotic rationalization was permitted through use of Polymerase chain reaction (PCR) testing in cases of sterile cultures. Of note, intracranial empyema related to sinogenic infection is shown to have significantly more severe clinical presentation, a higher morbidity, and a longer duration of antibiotic therapy than that related to otogenic infection. Study findings allowed for the update and clarification of the institutional protocol, which now clearly demarcates the clinical presentation, biological evidence, radiology, surgical and medical treatments in children with oto-sinogenic IE.

Helicobacter cinaedi bacteremia caused recurring multifocal cellulitis in a patient in France who had chronic lymphocytic leukemia treated with ibrutinib. Diagnosis required extended blood culture incubation and sequencing of the entire 16S ribosomal RNA gene from single bacterial colonies. Clinicians should consider H. cinaedi infection in cases of recurrent cellulitis.

Polarized light microscopy (POM) remains the gold standard for crystalluria analysis. However, such method is time consuming and requires well-trained staff. Here, to address this issue, we tested the Sysmex UF-4000 analyzer coupled to a UD10 module as an automated flow cytometry-digital particle imaging workflow to assess (i) the ability of the system to detect and identify the crystals species and (ii) the quality of the images provided by the UD-10 module (n = 40) for each urine sample analyzed. First, systematic analysis of 76 samples by POM and the UF-4000/UD-10 analyzer showed that only attentive examination of the 40 photos was able to confidently detect crystalluria-positive samples with no misses and thus serve to discriminate positive-test crystalluria from negative-test crystalluria. These first results were confirmed by sensitivity analysis and the negative predictive value calculated on 200 samples for the results provided by the UF-4000 (39% and 46%) and after examination of the 40 UD-10 photos (100% for the both values). Digital images can therefore serve to screen crystalluria without missing crystals. A part of samples were treated by POM whereas it was not necessary (positive predictive value: 78%). Finally, we compared the crystal identification performances of the Sysmex UF4000/UD10 workflow and the ‘gold standard’ POM method on 131 urine samples containing crystals. Only calcium oxalate dihydrate crystals were identified by the Sysmex UF-4000. A close examination of the digital photographs enabled exact identification of crystals in 84.7% of the samples, suggesting however that POM is still require as soon as crystals are observed on the photographs. We conclude that a SYSMEX UF-4000 coupled with a UD-10 module can be used in practice with close examination of the photographs to discriminate positive crystalluria from negative crystalluria.

Differentiation between Whipple disease (WD) patients and patients carrying Tropheryma whipplei but suffering from disease other than WD (“carriers”) remains complex. We aimed to evaluate T. whipplei PCR among patients with WD and carriers in a large cohort at our referral clinical microbiology laboratory. This is an observational retrospective cohort study, including all patients between 2008 and 2020 with at least one positive result for T. whipplei using the real-time PCR RealCycler TRWH-UX kit. A total of 233 patients were included: 197 were considered carriers, and 36 had WD.

Using metagenomic next-generation sequencing and reverse-transcription polymerase chain reaction, we detected the Aichi virus genome in tissues of patients with primary immune deficiency and unexplained multiorgan inflammatory involvement. We showed evidence supporting the causality of Aichi virus in these cases. Background Metagenomic next-generation sequencing (mNGS) was used to assess patients with primary or secondary immune deficiencies (PIDs and SIDs) who presented with immunopathological conditions related to immunodysregulation. Methods Thirty patients with PIDs or SIDs who presented with symptoms related to immunodysregulation and 59 asymptomatic patients with similar PIDs or SIDs were enrolled. mNGS was performed on organ biopsy. Specific Aichi virus (AiV) reverse-transcription polymerase chain reaction (RT-PCR) was used to confirm AiV infection and screen the other patients. In situ hybridization (ISH) assay was done on AiV-infected organs to identify infected cells. Virus genotype was determined by phylogenetic analysis. Results AiV sequences were detected using mNGS in tissue samples of 5 patients and by RT-PCR in peripheral samples of another patient, all of whom presented with PID and long-lasting multiorgan involvement, including hepatitis, splenomegaly, and nephritis in 4 patients. CD8+ T-cell infiltration was a hallmark of the disease. RT-PCR detected intermittent low viral loads in urine and plasma from infected patients but not from uninfected patients. Viral detection stopped after immune reconstitution obtained by hematopoietic stem cell transplantation. ISH demonstrated the presence of AiV RNA in hepatocytes (n = 1) and spleen tissue (n = 2). AiV belonged to genotype A (n = 2) or B (n = 3). Conclusions The similarity of the clinical presentation, the detection of AiV in a subgroup of patients suffering from immunodysregulation, the absence of AiV in asymptomatic patients, the detection of viral genome in infected organs by ISH, and the reversibility of symptoms after treatment argue for AiV causality.