Tularemia in Pediatric Patients: A Case Series and Review of the Literature.

BACKGROUND: Unfamiliar to pediatricians, tularemia can lead to delays in diagnosis and hinder appropriate treatment, as its clinical presentation often shares similarities with other more prevalent causes of lymphadenopathy diseases in children. We conducted a comprehensive literature review to offer contemporary insights into the clinical manifestations and treatment strategies for tularemia infection in children. METHODS: Three cases of glandular tularemia were diagnosed in the Pediatric Robert Debré Hospital (Paris) between October 2020 and February 2022. In addition, we conducted a literature search using PubMed in December 2023 of cases of tularemia in children published in English. RESULTS: The 94 cases of the literature review highlight the large age range (from 6 weeks to 17 years) and multiple sources of infection, including diverse zoonotic transmission (86.7%) and contact with contaminated water (13.3%). Fever was a consistent symptom. Ulceroglandular (46.7%), glandular (17%) and oropharyngeal forms (18.1%) predominated. The most frequently used diagnostic method was serology (60.6%). The median time to diagnosis for tularemia was 23.5 days. Hospitalization was required in 63.2% of cases, with a median duration of 4 days. Targeted treatment was based on aminoglycosides (37.6%), fluoroquinolones (30.6%) or tetracyclines (12.9%), in accordance with WHO recommendations, with a mainly favorable outcome, although several cases of meningitis were observed. CONCLUSION: Pediatricians should be aware of the etiology of this febrile lymphadenopathy, notably when experiencing beta-lactam treatment failure, even in young infants, which could help reduce the extra costs associated with inappropriate antibiotic use and hospitalization.

Common Seasonal Pathogens and Epidemiology of Henoch-Schönlein Purpura Among Children.

Importance: Henoch-Schönlein purpura (HSP) is the most common type of vasculitis in children. The factors that trigger the disease are poorly understood. Although several viruses and seasonal bacterial infections have been associated with HSP, differentiating the specific associations of these pathogens with the onset of HSP remains a challenge due to their overlapping seasonal patterns. Objective: To analyze the role of seasonal pathogens in the epidemiology of HSP. Design, Setting, and Participants: This cohort study comprised an interrupted time-series analysis of patient records from a comprehensive national hospital-based surveillance system. Children younger than 18 years hospitalized for HSP in France between January 1, 2015, and March 31, 2023, were included. Exposure: Implementation and relaxation of nonpharmaceutical interventions (NPIs) for the COVID-19 pandemic, such as social distancing and mask wearing. Main Outcomes and Measures: The main outcomes were the monthly incidence of HSP per 100 000 children, analyzed via a quasi-Poisson regression model, and the estimated percentage of HSP incidence potentially associated with 14 selected common seasonal pathogens over the same period. Results: The study included 9790 children with HSP (median age, 5 years [IQR, 4-8 years]; 5538 boys [56.4%]) and 757 110 children with the infectious diseases included in the study (median age, 0.7 years [IQR, 0.2-2 years]; 393 697 boys [52.0%]). The incidence of HSP decreased significantly after implementation of NPIs in March 2020 (-53.6%; 95% CI, -66.6% to -40.6%; P < .001) and increased significantly after the relaxation of NPIs in April 2021 (37.2%; 95% CI, 28.0%-46.3%; P < .001). The percentage of HSP incidence potentially associated with Streptococcus pneumoniae was 37.3% (95% CI, 22.3%-52.3%; P < .001), the percentage of cases associated with Streptococcus pyogenes was 25.6% (95% CI, 16.7%-34.4%; P < .001), and the percentage of cases associated with human rhino enterovirus was 17.1% (95% CI, 3.8%-30.4%; P = .01). Three sensitivity analyses found similar results. Conclusions and Relevance: This study found that significant changes in the incidence of HSP simultaneously with major shifts in circulating pathogens after NPIs for the COVID-19 pandemic indicated that approximately 60% of HSP incidence was potentially associated with pneumococcus and group A streptococcus. This finding suggests that preventive measures against these pathogens could reduce the incidence of pediatric HSP.

Early-Onset Infection Caused by Escherichia coli Sequence Type 1193 in Late Preterm and Full-Term Neonates.

Using whole-genome sequencing, we characterized Escherichia coli strains causing early-onset sepsis (EOS) in 32 neonatal cases from a 2019-2021 prospective multicenter study in France and compared them to E. coli strains collected from vaginal swab specimens from women in third-trimester gestation. We observed no major differences in phylogenetic groups or virulence profiles between the 2 collections. However, sequence type (ST) analysis showed the presence of 6/32 (19%) ST1193 strains causing EOS, the same frequency as in the highly virulent clonal group ST95. Three ST1193 strains caused meningitis, and 3 harbored extended-spectrum ß-lactamase. No ST1193 strains were isolated from vaginal swab specimens. Emerging ST1193 appears to be highly prevalent, virulent, and antimicrobial resistant in neonates. However, the physiopathology of EOS caused by ST1193 has not yet been elucidated. Clinicians should be aware of the possible presence of E. coli ST1193 in prenatal and neonatal contexts and provide appropriate monitoring and treatment.

Fatal Meningitis from Shiga Toxin-Producing Escherichia coli in 2 Full-Term Neonates, France.

We report fatal meningitis in 2 neonates in France caused by Shiga toxin 1-producing Escherichia coli. Virulence factors capsular K1 antigen and salmochelin were present in both strains, potentially representing a new hybrid pathotype. Clinicians should remain aware of emerging pathotypes and design therapeutic strategies for neonatal E. coli infections.

Diagnostic accuracy of a rapid nucleic acid test for group A streptococcal pharyngitis using saliva samples: protocol for a prospective multicenter study in primary care.

BACKGROUND: Group A streptococcus is found in 20-40% of cases of childhood pharyngitis; the remaining cases are viral. Streptococcal pharyngitis ("strep throat") is usually treated with antibiotics, while these are not indicated in viral cases. Most guidelines recommend relying on a diagnostic test confirming the presence of group A streptococcus before prescribing antibiotics. Conventional first-line tests are rapid antigen detection tests based on throat swabs. Recently, rapid nucleic acid tests were developed; they allow the detection of elements of the genome of group A streptococcus. We hypothesize that these rapid nucleic acid tests are sensitive enough to be performed on saliva samples instead of throat swabs, which could be more convenient in practice. METHODS: This is a multicenter, prospective diagnostic accuracy study evaluating the performance of a rapid nucleic acid test for group A streptococcus (Abbott ID NOW STREP A2) in saliva, compared with a conventional pharyngeal rapid antigen detection test (EXACTO PRO STREPTATEST, lateral flow assay, comparator test), with a composite reference standard of throat culture and group A streptococcus PCR in children with pharyngitis in primary care (i.e., 27 primary care pediatricians or general practitioners). To ensure group A streptococcus is not missed, the salivary rapid nucleic acid test requires a minimally acceptable value of sensitivity (primary outcome) set at 80%. Assuming 35% of participants will have group A streptococcus, we will recruit 800 consecutive children with pharyngitis. Secondary outcomes will include difference in sensitivity between the pharyngeal rapid antigen detection test and the salivary rapid nucleic acid test; variability in sensitivity and specificity of the salivary rapid nucleic acid test with the level of McIsaac score; time to obtain the result of the salivary rapid nucleic acid test; patient, physician, and parents satisfaction; and barriers and facilitators to using rapid tests for group A streptococcus in primary care. ETHICS AND DISSEMINATION: Approved by the Institutional Review Board "Comité de protection des personnes Ile de France I" (no. 2022-A00085-38). Results will be presented at international meetings and disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05521568.

Diagnostic Accuracy of Group A Streptococcus Rapid Antigen Detection Test on Middle Ear Fluid in Children With Acute Otitis Media With Spontaneous Perforation: A Prospective Multicenter Evaluation.

Group A Streptococcus is one of the leading causes of otorrhea. The performance of rapid antigen tests in 256 children with otorrhea showed excellent sensitivity, 97.3% (95% confidence interval: 90.7%-99.7%), and specificity, 100% (95% confidence interval: 98.0%-100%). In a period of increasing invasive and noninvasive group A Streptococcus infections, an early diagnosis could be useful.

Otorrhea bacterial profile, epidemiology before widespread use of the third-generation pneumococcal conjugate vaccine in French children, a prospective study from 2015 to 2023.

OBJECTIVES: The aim of this study was to describe the bacterial profile of middle ear fluid from spontaneous perforation of the tympanic membrane (SPTM) prior to widespread utilization of third- generation pneumococcal conjugate vaccines (PCVs). PATIENTS AND METHODS: From October 2015 to January 2023, children with SPTM were prospectively enrolled by pediatricians. RESULTS: Among the 852 children with SPTM, 73.2% were less than 3 years old; more frequently than older children, they were and suffering from complex acute otitis media (AOM) (27.9%) and conjunctivitis (13.1%). In children under 3 years of age, NT Haemophilus influenzae (49.7%) was the main otopathogen isolated, particularly in those with complex AOM (57.1%). In children over 3 years of age, Group A Streptococcus accounted for 57%. In pneumococcal cases (25.1%), serotype 3 was the main serotype isolated (16.2%), followed by 23B (15.2%). CONCLUSION: Our data from 2015 to 2023 represent a robust baseline preceding the widespread utilization of next-generation PCVs.

Unexpected Increase in Invasive Group A Streptococcal Infections in Children After Respiratory Viruses Outbreak in France: A 15-Year Time-Series Analysis.

In a 15-year pediatric time-series analysis, we showed a rise of invasive Group A streptococcal (iGAS) infections since October 2022, mainly involving pleural empyema, simultaneously to a respiratory virus outbreak. Physicians should be aware of this increased risk of pediatric iGAS infections, especially in settings with intense respiratory viruses' circulation.

Optimizing COVID-19 Vaccination Strategy in Pediatric Kidney Transplant Recipients: Humoral and Cellular Response to SARS-CoV-2 mRNA Vaccination.

In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865 BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.

Comparative genomic analysis of ESBL-producing Escherichia coli from faecal carriage and febrile urinary tract infection in children: a prospective multicentre study.

Background: The reliability of ESBL-producing Escherichia coli (ESBL-Ec) faecal carriage monitoring to guide probabilistic treatment of febrile urinary tract infection (FUTI) in children remains unclear. Objectives: To compare the genomic characteristics of ESBL-Ec isolates from faecal carriage and FUTI to assess their correlation and identify a FUTI-associated virulence profile. Methods: We conducted a prospective multicentre hospital and ambulatory-based study. We analysed the genotypes and virulence factors of both faecal and FUTI ESBL-Ec by whole genome sequencing. Correlations were assessed by non-parametric Spearman coefficient and virulence factors were assessed by chi-squared tests with Bonferroni correction. Results: We included 218 ESBL-Ec causing FUTI and 154 ESBL-Ec faecal carriage isolates. The most frequent ST was ST131 (44%) in both collections. We found high correlation between carriage and ESBL-Ec FUTI regarding genes/alleles (rho = 0.88, P < 0.0001) and combinations of virulence genes, MLST and serotypes (rho = 0.90, P < 0.0001, rho = 0.99, P = 0.0003, rho = 0.97, P = 0.005 respectively). Beside this strong correlation, we found five genes that were significantly associated with FUTI (papC, papGII, hlyC, hek and traJ). The strongest association with FUTI was found with adhesin gene allele papGII (54% in FUTI versus 16% in carriage) and for papGII and gene traJ alone or in combination (63% versus 24%). Conclusions: The genomic profile of ESBL-Ec causing FUTI in children strongly correlates with faecal carriage isolates except for a few genes. The presence of papGII and/or traJ in a previously identified carriage strain could be used as a marker of uropathogenicity and may guide the empirical antimicrobial choice in subsequent FUTI.

Kingella kingae and Viral Infections.

Kingella kingae (K. kingae) is an oropharyngeal commensal agent of toddlers and the primary cause of osteoarticular infections in 6-23-month-old children. Knowing that the oropharynx of young children is the reservoir and the portal of entry of K. kingae, these results suggested that a viral infection may promote K. kingae infection. In this narrative review, we report the current knowledge of the concomitance between K. kingae and viral infections. This hypothesis was first suggested because some authors described that symptoms of viral infections were frequently concomitant with K. kingae infection. Second, specific viral syndromes, such as hand, foot and mouth disease or stomatitis, have been described in children experiencing a K. kingae infection. Moreover, some clusters of K. kingae infection occurring in daycare centers were preceded by viral outbreaks. Third, the major viruses identified in patients during K. kingae infection were human rhinovirus or coxsackievirus, which both belong to the Picornaviridae family and are known to facilitate bacterial infections. Finally, a temporal association was observed between human rhinovirus circulation and K. kingae infection. Although highly probable, the role of viral infection in the K. kingae pathophysiology remains unclear and is based on case description or temporal association. Molecular studies are needed.

Clinical impact of a gastrointestinal PCR panel in children with infectious diarrhoea.

OBJECTIVES: Multiplex gastrointestinal PCR (GI-PCR) allows fast and simultaneous detection of 22 enteric pathogens (including Campylobacter, Salmonella, Shigella/enteroinvasive Escherichia coli (EIEC), among other bacteria, parasites and viruses). However, its impact on the management of children with infectious diarrhoea remains unknown. PATIENTS/DESIGN: All children eligible for stool culture from May to October 2018 were prospectively included in a monocentric study at Robert-Debré University-Hospital. INTERVENTION: A GI-PCR (BioFire FilmArray) was performed on each stool sample. MAIN MEASURES: Data on the children's healthcare management before and after GI-PCR results were collected. Stool culture results were also reported. RESULTS: 172 children were included. The main criteria for performing stool analysis were mucous/bloody diarrhoea and/or traveller's diarrhoea (n=130). GI-PCR's were positive for 120 patients (70%). The main pathogens were enteroaggregative E. coli (n=39; 23%), enteropathogenic E. coli (n=34; 20%), Shigella/EIEC (n=27; 16%) and Campylobacter (n=21; 12%). Compared with stool cultures, GI-PCR enabled the detection of 21 vs 19 Campylobacter, 12 vs 10 Salmonella, 27 Shigella/EIEC vs 13 Shigella, 2 vs 2 Yersinia enterocolitica, 1 vs 1 Plesiomonas shigelloides, respectively. Considering the GI-PCR results and before stool culture results, the medical management was revised for 40 patients (23%): 28 initiations, 2 changes and 1 discontinuation of antibiotics, 1 hospitalisation, 2 specific room isolations related to Clostridioides difficile infections, 4 additional test prescriptions and 2 test cancellations. CONCLUSION: The GI-PCR's results impacted the medical management of gastroenteritis for almostone-fourth of the children, and especially the prescription of appropriate antibiotic treatment before stool culture results.

Azithromycin Resistance in Shiga Toxin-Producing Escherichia coli in France between 2004 and 2020 and Detection of mef(C)-mph(G) Genes.

We described and characterized Shiga-toxin-producing Escherichia coli (STEC) strains with high levels of resistance to azithromycin isolated in France between 2004 and 2020. Nine of 1,715 (0.52%) STEC strains were resistant to azithromycin, with an increase since 2017. One isolate carried a plasmid-borne mef(C)-mph(G) gene combination, described here for the first time for E. coli. Azithromycin resistance, although rare, needs consideration, as this treatment may be useful in cases of STEC infection.

Emergence of New ST301 Shiga Toxin-Producing Escherichia coli Clones Harboring Extra-Intestinal Virulence Traits in Europe.

O80:H2 enterohemorrhagic Escherichia coli (EHEC) of sequence type ST301 is one of the main serotypes causing European hemolytic and uremic syndrome, but also invasive infections, due to extra-intestinal virulence factors (VFs). Here, we determined whether other such heteropathotypes exist among ST301. EnteroBase was screened for ST301 strains that were included in a general SNP-phylogeny. French strains belonging to a new heteropathotype clone were sequenced. ST, hierarchical clusters (HC), serotype, resistome, and virulome were determined using EnteroBase, the CGE website, and local BLAST. The ST301 general phylogeny shows two groups. Group A (n = 25) is mainly composed of enteropathogenic E. coli, whereas group B (n = 55) includes mostly EHEC. Three serotypes, O186:H2, O45:H2 and O55:H9, share the same virulome as one of the O80:H2 sub-clones from which they derive subsequent O-antigen switches. The O55:H9 clone, mainly present in France (n = 29), as well as in the UK (n = 5) and Germany (n = 1), has a low background of genetic diversity (four HC20), although it has three Stx subtypes, an H-antigen switch, and genes encoding the major extra-intestinal VF yersiniabactin, and extended-spectrum beta-lactamases. Diverse heteropathotype clones genetically close to the O80:H2 clone are present among the ST301, requiring close European monitoring, especially the virulent O55:H9 clone.

Clavulanate combinations with mecillinam, cefixime or cefpodoxime against ESBL-producing Enterobacterales frequently associated with blaOXA-1 in a paediatric population with febrile urinary tract infections.

OBJECTIVES: Oral treatment of febrile urinary tract infections (FUTIs) can be impaired by MDR Enterobacterales often combining ESBL and inhibitor-resistant genes. We studied the impact of ß-lactamases and Enterobacterales' genotypes on the cefixime, cefpodoxime and mecillinam ± amoxicillin/clavulanate MICs. MATERIALS AND METHODS: In this multicentric study, we included 251 previously whole-genome-sequenced ESBL-producing Enterobacterales, isolated in French children with FUTIs. The MICs of cefixime, cefpodoxime, mecillinam alone and combined with amoxicillin/clavulanate were determined and analysed with respect to genomic data. We focused especially on the isolates' ST and their type of ß-lactamases. Clinical outcomes of patients who received cefixime + amoxicillin/clavulanate were also analysed. RESULTS: All isolates were cefixime and cefpodoxime resistant. Disparities depending on blaCTX-M variants were observed for cefixime. The addition of amoxicillin/clavulanate restored susceptibility for cefixime and cefpodoxime in 97.2% (MIC50/90 of 0.38/0.75 mg/L) and 55.4% (MIC50/90 of 1/2 mg/L) of isolates, respectively, whatever the ST, the blaCTX-M variants or the association with inhibitor-resistant ß-lactamases (34.2%). All isolates were susceptible to mecillinam + amoxicillin/clavulanate with MIC50/90 of 0.19/0.25 mg/L, respectively. Neither therapeutic failure nor any subsequent positive control urine culture were reported for patients who received cefixime + amoxicillin/clavulanate as an oral relay therapy (n = 54). CONCLUSIONS: Despite the frequent association of ESBL genes with inhibitor-resistant ß-lactamases, the cefixime + amoxicillin/clavulanate MICs remain low. The in vivo efficacy of this combination was satisfying even when first-line treatment was ineffective. Considering the MIC distributions and pharmacokinetic parameters, mecillinam + amoxicillin/clavulanate should also be an alternative to consider when treating FUTIs in children.

Diagnostic accuracy of rapid nucleic acid tests for group A streptococcal pharyngitis: systematic review and meta-analysis.

BACKGROUND: Acute pharyngitis is one of the most common conditions in outpatient settings and an important source of inappropriate antibiotic prescribing. Rapid antigen detection tests (RADTs) offer diagnosis of group A streptococcus at the point of care but have limited sensitivity. Rapid nucleic acid tests (RNATs) are now available; a systematic review of their accuracy is lacking. OBJECTIVES: To evaluate the accuracy of RNATs in patients with pharyngitis; to explore test-level and study-level factors that could explain variability in accuracy; and to compare the accuracy of RNATs with that of RADTs. DATA SOURCES: MEDLINE, Embase, Web of Science (1990-2020). STUDY ELIGIBILITY CRITERIA: Cross-sectional studies and randomized trials. PARTICIPANTS: Patients with pharyngitis. INDEX TEST/S AND REFERENCE STANDARDS: RNAT commercial kits compared with throat culture. METHODS: We assessed risk of bias and applicability using QUADAS-2. We performed meta-analysis of sensitivity and specificity using the bivariate random-effects model. Variability was explored by subgroup analyses and meta-regression. RESULTS: We included 38 studies (46 test evaluations; 17 411 test results). RNATs were most often performed in a laboratory. The overall methodological quality of primary studies was uncertain because of incomplete reporting. RNATs had a summary sensitivity of 97.5% (95% CI 96.2%-98.3%) and a summary specificity of 95.1% (95% CI 93.6%-96.3%). There was low variability in estimates across studies. Variability in sensitivity and specificity was partially explained by test type (p < 0.05 for both). Sensitivity analyses limited to studies with low risk of bias showed robust accuracy estimates. RNATs were more sensitive than RADTs (13 studies; 96.8% versus 82.3%, p 0.004); there was no difference in specificity (p 0.92). CONCLUSIONS: The high diagnostic accuracy of RNATs may allow their use as stand-alone tests to diagnose group A streptococcus pharyngitis. Based on direct comparisons, RNATs have greater sensitivity than RADTs and equal specificity. Further studies should evaluate RNATs in point-of-care settings.

Diagnostic challenge of gastrointestinal infection due to lactose-fermenting Salmonella enterica subsp. enterica serovar 4,5:I:.

Here, we describe a case of a nontyphoidal Salmonella disease caused by a Salmonella enterica serovar 4,5:i:- (monophasic Salmonella typhimurium) which acquired a Lac operon. This lactose-fermenting bacterium presents a major challenge for phenotypical detection of Salmonella. Only specific agar plates or molecular techniques allow reliable detection.