Journal of the Pediatric Infectious Diseases Society

Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng/mL of both IFN-2 and IFN-{omega} (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.

Background: Infections of the central nervous system (CNS) in children remain a major cause of mortality and long-term disability globally, particularly in low- and middle-income countries (LMICs), where a high proportion of cases lack an identified pathogen. Sporadically, human parvovirus 4 (PARV4) has been detected in a small number of cerebrospinal fluid (CSF) from children with CNS infections, but its pathogenic role is unclear. We investigated the prevalence, clinical impact, and genomic characteristics of PARV4 in children with suspected meningitis. Methods: We retrospectively analyzed CSF samples collected from children with WHO-defined suspected meningitis at the largest pediatric hospital in Bangladesh between 2015-2022. All samples underwent routine diagnostics, including bacterial culture and serological testing. Additional testing for PARV4 and parvovirus B19 was performed using qPCR of samples with >9 white blood cell (WBC)/ul followed by metagenomic sequencing of a subset. Clinical and laboratory data were extracted from patient records. Associations between PARV4 detection and mortality were assessed using logistic regression, adjusting for age, WBC count, and co-infections. Genomic and phylogenetic analyses were conducted on PARV4-positive samples. Findings: Among 2,793 CSF samples with >9 WBC/ul, 526 (18.8%) were PARV4-positive. The median age of PARV4-positive cases was lower than that of PARV4-negative cases (4 vs 7 months, p<0.001). Co-infections were more common among PARV4-positive cases (49.6%) than PARV4-negative cases (16.4%). PARV4 positivity was independently associated with increased in-hospital mortality (adjusted odds ratio 2.09, 95%CI:1.46-2.96; p<0.001). Phylogenetic analysis indicated most strains belonged to genotype 2, with two sequences forming a distinct clade. Interpretation: PARV4 is frequently detected in the CSF of children with suspected meningitis and is associated with increased in-hospital mortality. Its high prevalence, detection early in life, and frequent co-infection with other pathogens highlight the need to investigate PARV4 as an emerging CNS pathogen in LMICs. Funding: Gates Foundation

Background: Several large multisite studies have been conducted to describe etiology-specific burden of diarrhea among children in low-resource settings. Here, we combined data across studies to describe geographic and temporal trends in incidence and attributable fractions (AFs) of etiology-specific moderate-to-severe diarrhea (MSD), and to evaluate etiology-specific case fatality ratios (CFRs). Methods: We harmonized case definitions and analytic methods across the Global Enteric Multicenter Study (GEMS), Malnutrition and Enteric Disease (MAL-ED), Vaccine Impact on Diarrhea in Africa (VIDA), AntiBiotics for Children with severe Diarrhea (ABCD), and Enterics for Global Health (EFGH) studies. Cases were 6-35-month-olds with acute MSD. Incidence estimates for GEMS, VIDA, and EFGH were adjusted for enrollment, healthcare seeking, and diagnostic testing. AFs were calculated as the proportion of MSD cases attributed to each etiology, and CFRs were estimated within 14 and 90 days of an MSD episode. Findings: Pre-rotavirus vaccine introduction, rotavirus had the highest incidence and was the leading etiology among 6-11-month-olds, accounting for approximately 22-28% of MSD; the proportion of diarrhea due to rotavirus declined following vaccine introduction, with average AF 10-11% in Africa and Asia. Shigella incidence was highest among 12-23-month-olds and was the dominant etiology among 12-23 and 24-35-month-olds, causing approximately one-third to one-half of MSD. Overall, 90-day mortality declined substantially over time, from 2.21% in GEMS to 0.30% in EFGH. Bacterial (2.52%) and protozoal pathogens (3.55%) had higher average CFRs than viral pathogens (1.42%). Conclusion: Harmonized analysis of five multisite studies reveals consistent evidence that rotavirus and Shigella are the dominant causes of MSD in children under three years in low-resource settings, with burden shifting toward Shigella following rotavirus vaccine introduction.

BackgroundMultiple countries reported unprecedented increases in invasive group A streptococcal (iGAS) disease following widespread SARS-CoV-2 circulation. Whether this surge reflects reduced pathogen exposure during non-pharmaceutical interventions ("immunity debt") or effects of SARS-CoV-2 infection on host immunity remains unresolved. MethodsWe conducted a population-based time-series analysis of weekly iGAS incidence in central Ontario, Canada (population {approx}11 million) from March 2011 through March 2024 (676 weeks). Using negative binomial panel regression, we modeled acute (2-week lagged) and cumulative SARS-CoV-2 exposure while adjusting for seasonality, secular trends, age, and sex. Population attributable fractions (PAFs) were estimated by counterfactual prediction. Specificity was assessed through negative control analyses (influenza, RSV). The immunity debt hypothesis was evaluated using cumulative streptococcal exposure as a predictor of iGAS. ResultsAmong 2,906 iGAS episodes, 34.3% during the pandemic period were associated with acute SARS-CoV-2 effects (range by age group: 16.5-39.1%). Models incorporating cumulative SARS-CoV-2 burden showed markedly better fit ({Delta}AIC=-157.5); cumulative exposure was strongly associated with iGAS (IRR 1.193, 95% CI 1.151-1.235), increasing the estimated PAF to 66.7%. Cumulative effects were strongest in children (IRR 1.309). SARS-CoV-2 was comparably associated with non-invasive streptococcal disease, with no increase in invasion propensity. Cumulative streptococcal exposure was not protective (overall IRR 1.000, p=0.730); where significant, the association was positive, opposite to immunity debt predictions. ConclusionsCumulative SARS-CoV-2 burden was strongly associated with pandemic-era iGAS incidence. Cumulative streptococcal exposure did not support the immunity debt hypothesis. These ecological findings are consistent with SARS-CoV-2-associated immune dysregulation and warrant individual-level confirmation.

Background: Human metapneumovirus (hMPV) is commonly associated with respiratory tract infections (RTIs) in young children. Methods: We estimated the annual hospital incidence of hMPV RTIs in children under 5 years in Scotland from 2017 to 2023 using national hospital and laboratory data. Incidence outside Lothian, where testing practices were uncertain, was extrapolated from Lothian laboratory data, where hMPV testing was advised for all RTI admissions. We also examined the severity and mortality of laboratory-confirmed hMPV cases. We developed similar estimates for RSV and Influenza A for comparison. Results: This analysis included 1,462 laboratory-confirmed hMPV hospitalisations in children aged under 5 years. The extrapolated hMPV hospital incidence ranged from 19 per 100,000 to 537 per 100,000 in children aged under 5 years. The extrapolated incidence was two to three times higher than that based on laboratory-confirmed data. Hospital incidence was higher in infants than in toddlers. hMPV incidence dropped substantially during the 2020/21 season, followed by a rebound during the 2021/22 season. About 10% of hMPV RTI hospital admissions required hospital stay [&ge;]5 days, but <1% required intensive care unit admissions or resulted in in-hospital death. RSV hospital incidence appeared substantially higher than the hMPV hospital incidence in this population. Conclusions: hMPV RTIs contribute to a substantial hospital burden in young children in Scotland. However, the RSV RTI burden is likely to be higher in the population unvaccinated against both viruses. Improved surveillance and diagnosis strategies are required to develop robust hospital burden estimates.

BackgroundNeonatal disorders such as post-infectious hydrocephalus exhibit a higher incidence in Africa, where the intricate relationships between genetic ancestry, environmental exposures, and other risk factors likely contribute to the increased incidence. MethodsTo start to characterize the common genetic architecture of Ugandan infants, we analyzed genome sequencing data from 1,030 Ugandan infants recruited from studies targeting neonatal sepsis and hydrocephalus. We employed genetic admixture analysis and integrated geospatial data to examine the relationships between genetic backgrounds and disease prevalence within this cohort. ResultsOur results identified four distinct genetic admixture groups, each correlating strongly with specific geographic distributions across Uganda. Notably, a predominance of one admixture group, most common in northern Uganda, was overrepresented in the participants with post-infectious hydrocephalus. ConclusionThis study underscores the importance of genetic factors in disease manifestation at the population level, and a role for such precision public health approaches in complex neonatal disorders in African populations.

Klebsiella pneumoniae (KP) isolates belonging to multi-locus sequence type 258 (ST258) are a frequent cause of hospital-associated outbreaks and display extensive multidrug resistance. The KP ST258 lineage consists of two genetically distinct clades, called Clade 1 and Clade 2. These two clades are genetically related to one another, but are historically distinguished by having different capsular polysaccharide types. While bacteria belonging to both clades are isolated from clinical infections, Clade 2 is isolated more frequently compared to Clade 1. To investigate drivers of this difference in clade prevalence, we collected 172 clinical KP ST258 isolates from patients at a single medical center. Clinical review showed that patients infected with Clade 2 isolates were more acutely ill than Clade 1-infected patients, despite having fewer comorbidities. We also found that Clade 2 isolates were more resistant to killing by human serum, despite binding more complement protein C3 than Clade 1 isolates. Additionally, mice infected with a Clade 2 isolate had increased bacterial dissemination from the lungs to the liver and spleen than mice infected with a Clade 1 isolate, and this dissemination required an intact capsule locus. Increased dissemination in mice was not due to differential serum killing, as mouse serum was unable to kill isolates of either clade, but dissemination was associated with decreased macrophage uptake of the Clade 2 isolate. Taken together, these data suggest that KP ST258 Clade 2 is more virulent than Clade 1, though the specific mechanisms at play appear to differ between mice and humans.

Abstract Introduction: Streptococcus is the second genus involved in bone and joint infections (BJIs) after Staphylococcus. Streptococcus agalactiae is the predominant Streptococcus species implicated in BJIs. However, unlike Staphylococcus-related BJIs, data on S. agalactiae infections remain scarce. Methods: We conducted a retrospective cohort study from the West Region cohort of the CRIOAc registry among six university hospitals including all microbiologically confirmed streptococcal BJI in adults between 2014 and 2023. Results: 1454 patients were included, with a median age of 67 years and 65% male. S. agalactiae was the predominant streptococcal species involved 423/1454(29%). The most prevalent comorbidities identified were obesity (378/1454;26%) and diabetes mellitus (343/1454;24%). Prosthetic joint infections (PJIs) were the most common (653/1454;45%), although diabetic foot osteitis was less prevalent overall, it was significantly more associated with S. agalactiae infections (48/423;11% versus 70/1031;7%, p=0.05). S. agalactiae BJIs were more frequently lower-limb infections and chronic infections (240/423;57% versus 502/1031;49%, p=0.04). Half of the cohort had a polymicrobial infection and were slightly more frequent with S. agalactiae BJIs (235/423;56% versus 498/1031;48%, p=0.1). These results were consistent with a sensitivity analysis excluding diabetic foot related osteitis. Logistic regression analysis identified arteriopathy (OR: 4.16; IC95:1.64-11.24, p=0.003), and obesity (OR: 2.57; IC95: 1.41-4.78, p=0.002) as specific risk factors for S. agalactiae BJIs. Conclusion: S. agalactiae emerges as a prominent and distinct pathogen in complex streptococcal BJIs, with specific risk factors such as arteriopathy, obesity and diabetes mellitus, and more chronic infections.

Co-designed research in paediatric HSCT is limited. We sought to determine research priorities which represent the shared priorities of patients, parents, carers, and healthcare professionals (HCP) within Australia, New Zealand, the Netherlands and United Kingdom. An international, multiphase priority-setting methodology was implemented in partnership with the James Lind Alliance and delivered over an 18-month period. Part 1: an international scoping survey asked respondents to submit their research uncertainties related to paediatric HSCT. Part 2: summarising and evidence-checking the submitted uncertainties. Part 3: interim prioritisation survey. Part 4: consensus workshop. In the first international scoping survey, 667 topic ideas were suggested (45% by consumers, 55% by HCP), which were categorized into 80 summary questions. After systematic literature review, 35 summary questions were judged to be true uncertainties (i.e. not answered by existing evidence). These 35 uncertainties were included in a second interim prioritisation survey, completed by 224 participants. From those, a shortlist of 19 questions was drawn. After a multistakeholder workshop, consensus was reached on the top 10 priorities. The PSP identified important research gaps in the management of paediatric HSCT. Priority areas included: implementing personalised medicine approaches, improving immune recovery and adjunct interventions such as exercise, nutrition and microbiome-directed strategies.

Objectives: Group B Streptococcus (GBS) is a leading cause of neonatal mortality worldwide. However, the global burden of early-onset GBS disease (EOD-GBS) has not been fully elucidated. We aimed to describe the geographical distribution and epidemiological characteristics of the EOD-GBS burden, and analyze its association with socio-economic development and universal health coverage. Methods: We used data from the Global Burden of Disease Study 2021 and the Universal Health Coverage Service Coverage Index (UHC-SCI) to calculate estimated annual percentage changes (EAPCs) of EOD-GBS mortality. Sex differences were analyzed using the conservative overlap assessment. The geographical distribution of EOD-GBS clinical presentations and mortality was mapped. Health inequality analysis was conducted to evaluate the relationship between the sociodemographic index (SDI), UHC-SCI, and EOD-GBS burden. Results: Global EOD-GBS mortality decreased by nearly 50% from 1990 (693.41 per 100,000) to 2021 (348.80 per 100,000). However, the decline was not uniform: the most significant decrease occurred in high-middle SDI regions (EAPC: -7.17%), and the slowest in low SDI regions (EAPC: -2.23%). Male neonates accounted for the most EOD-GBS deaths, particularly in high SDI regions. Lower respiratory infections were common in Asia and Oceania; meningitis was more prominent in Europe. Inequality analysis revealed a phenomenon of "absolute convergence but relative differentiation": as social development and universal health coverage improves, the absolute mortality gap between countries narrowed, but relative burden concentrated increasingly among the poorest populations. Conclusions: The global burden of EOD-GBS has decreased substantially, but there are marked differences among countries. Continued socioeconomic development and expanded universal health coverage are critical to further reduce neonatal mortality.

Neonatal sepsis caused by Klebsiella pneumoniae is a major cause of under-five mortality in sub-Saharan Africa, and the rapid increase of infections caused by bacteria resistant to most or all available antimicrobials severely limits treatment options. An effective, maternally-administered vaccine could make a substantial reduction in neonatal sepsis and associated negative outcomes, as well as reduce the overall need for antimicrobials, a key driver of antimicrobial resistance. This study explored the potential for a maternally administered protein-based vaccine to provide neonatal protection via antibodies transferred transplacentally and through breastfeeding. A case-control study of mother and baby dyads was designed with 20 neonates developing K. pneumoniae sepsis and 80 uninfected control neonates to analyse breastmilk IgA, cord blood IgG and maternal serum IgA and IgG antibodies on a protein microarray with 161 selected K. pneumoniae proteins representing 152 unique genes. This analysis identified a set of proteins eliciting antibody responses, some associated with lack of K. pneumoniae sepsis, that indicate the presence of potentially protective antibodies. This is an essential first step in exploring surface protein accessibility, despite the large capsule. We highlight fimbrial structures, conjugative pili, and small lipoproteins associated with large outer membrane complexes as potential protein vaccine targets.

BackgroundAfter the global deployment of pneumococcal conjugate vaccines (PCVs), serotype 12F has become the predominant serotype responsible for invasive pneumococcal disease (IPD) worldwide. As PCVs that include serotype 12F are gradually introduced, we aim to characterise the global population structure and genetic diversity of the 12F capsule locus using whole-genome sequencing. Capsule variants with vaccine evasion potential were further investigated by functional experiments. MethodsA global collection of pneumococcal serotype 12F genomes (n=806) from 37 countries across six continents were included in this study. To characterise the serotype 12F population, Global Pneumococcal Sequence Cluster (GPSC), in silico serotype, and antimicrobial resistance profile were inferred from whole-genome data for each isolate. The capsule biosynthesis (cps) locus was analysed for gene content variations that could alter polysaccharide capsule production or structure, thereby influencing recognition by vaccine-induced antibodies. These isolates were further investigated by assessing their capsule production using immunofluorescence assays and its susceptibility to vaccine-elicited antibody killing by opsonophagocytosis assays. FindingsThe global increase in serotype 12F was driven by both distinct pneumococcal lineages across different continents, and a globally-disseminated and multidrug-resistant lineage GPSC26. We identified six capsule variants in nine isolates that had disruptive mutations in cps genes including wze, wcil, wciJ and fnlA. Most (6/9) of the disruptive mutations were a result of strand-slippage mutations. A convergent strand-slippage mutation disrupting the glycosyltransferase gene wciJ was identified in four isolates from distinct lineages and countries. Despite the truncation, three of four isolates with available Quellung typing results still identified them as 12F, indicating the production of the capsule. We then created a genetically engineered lab strain with wciJ knockout and complemented with wciJ containing the strand-slipppage mutation. The knockout strain did not produce any capsule. In contrast, the lab strain with wciJ containing the strand-slippage mutation produced a mixed population of encapsulated and non-encapsulated pneumococci, even within the same chain of pneumococcal cells. This observation indicated encapsulated subpopulation possesses a functional WciJ and rapidly reversible strand-slippage mutation during replication. Opsonophagocytosis assays indicated that the clinical 12F strain with strand-slippage mutation in wciJ exhibited reduced susceptibility to vaccine-elicited serum killing, compared to a genetically closely related 12F clinical strain with an intact wciJ. However, substantial inter-individual antisera variation limits definitive interpretation. InterpretationOur work revealed the global rise of serotype 12F pneumococci has been driven by both regional-specific lineages, and a globally-disseminated and multidrug-resistant lineage GPSC26. We demonstrated that strand-slippage mutation is one of the major drivers of serotype 12F capsule variants and represents a novel mechanism enabling reversible on-off switching of capsule production. The ability to switch off capsule expression in a subpopulation may enable evasion of antibody-mediated killing but increase susceptibility to innate immune clearance. FundingBill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control and Prevention.

Enteroviruses initiate infection at the intestinal epithelium but can spread systemically to cause severe disease. Although both MDA5 and TLR3 have been implicated in enterovirus sensing, the mechanisms by which the intestinal epithelium detects these viruses remain poorly defined. To address this, we infected human intestinal organoids (enteroids) with echovirus 11 (E11) and compared responses in models differentiated to mimic either crypt-like or villus-like epithelium. Villus-like enteroids produced significantly more type III interferons (IFN-{lambda}s) following E11 infection or treatment with the dsRNA mimetic poly I:C, and exhibited heightened responsiveness to IFN-{lambda} signaling. Single-cell RNA sequencing (scRNA-seq) of infected enteroids revealed that E11 broadly infected epithelial cell types, but IFN-{lambda} expression was largely restricted to mature enterocytes. Notably, enterocyte differentiation was also associated with upregulation of innate immune genes. Using CRISPR-Cas9 knockout enteroids, we found that TLR3 signaling was essential for intestinal IFN-{lambda} responses to E11 infection, whereas loss of MAVS, the adaptor for MDA5, had no effect. Together, these data support a model in which mature enterocytes serve as key sensors of enterovirus infection via TLR3, triggering a localized IFN-{lambda} response that may help restrict viral spread. ImportanceEnteroviruses are commonly circulating viruses that can cause a broad spectrum of disease, particularly in pediatric populations. Innate immune sensing in the intestinal epithelium likely plays a critical role in determining the outcome of enterovirus infections. Deficiencies in TLR3 signaling, IFN-{lambda} responses, or crypt-villus architecture may contribute to severe disease presentations. Our findings highlight the importance of TLR3-mediated sensing in mature enterocytes, which may also have broader implications for other intestinal viruses, as well as for inflammatory conditions like inflammatory bowel disease. A deeper understanding of how TLR3 sensing and IFN-{lambda} production are regulated in the intestine could inform new therapeutic strategies aimed at modulating mucosal sensitivity to viral nucleic acids and enhancing antiviral defense.

Objective To examine ethnic differences in the incidence and age-related trajectories of childhood health conditions from birth to adolescence within a UK birth cohort. Design Longitudinal population-based birth cohort with linkage to primary care electronic health records. Setting Born in Bradford (BiB), a multi-ethnic birth cohort in Bradford, UK. Participants 13,282 children (36% White British, 44% Pakistani British, 20% other ethnicity) born 2007 to 2011 with linked primary care records and over 1 year follow-up. Main outcome measures Incident diagnoses of atopic conditions (asthma, eczema, allergic rhinoconjunctivitis), overweight/obesity, common mental health disorders (anxiety, depression), and neurodevelopmental disorders (including ADHD and autism). Incidence rates, Kaplan-Meier cumulative incidence, and Cox regression hazards ratios (HRs) were estimated. Results Atopic conditions emerged early (median onset 5 to 6 years) and were more common among Pakistani British children, with higher hazards of eczema (HR 2.29, 95% CI 2.01 to 2.61), allergic rhinoconjunctivitis (HR 2.27, 2.00 to 2.58), and asthma (HR 1.35, 1.22 to 1.50). Overweight/ obesity developed later (median 9 to 10 years) and were also more frequent in Pakistani British children (HR 1.25, 1.16 to 1.35). In contrast, common mental health disorders emerged predominantly in early adolescence (median around 13 years), and both mental health and neurodevelopmental diagnoses were more frequently recorded among White British children; Pakistani British children had lower hazards of neurodevelopmental diagnoses (HR 0.28, 0.23 to 0.35) and mental health disorders (HR 0.53, 0.41 to 0.70). Conclusions Ethnic differences in childhood health are condition-specific and vary by age of onset, emerging at distinct stages. These findings inform the timing of prevention, service planning, and research into underlying mechanism.

Objectives: Acute gastroenteritis is a leading cause of pediatric emergency department (ED) visits. While ondansetron reduces vomiting, intravenous rehydration, and hospital admissions, its efficacy when initiated at triage remains unclear. We aimed to evaluate whether triage nurse-initiated administration of ondansetron in children with suspected gastroenteritis reduces the proportion of patients requiring observation following initial physician assessment. Methods: We conducted a randomized, double-blind, placebo-controlled trial in a tertiary pediatric ED in Canada. Children aged 6 months to 17 years presenting with morae than 3 episodes of vomiting in the preceding 24 hours (including 1 within 2 hours of arrival), were eligible. At triage, we randomized participants to receive liquid ondansetron or a color- and taste-matched placebo. The primary outcome was the proportion of patients requiring observation after the first physician evaluation. Secondary outcomes included post-intervention vomiting, ED length of stay, patient comfort, and 48-hour return visits. The trial was registered at ClinicalTrials.gov (NCT03052361). Results: Recruitment was stopped prematurely due to the COVID-19 pandemic. Ninety-one participants were randomized to ondansetron (n= 44) or placebo (n= 47). Overall, 40 patients (45%) were discharged immediately after the initial physician assessment, with no difference between the ondansetron and placebo groups (44% vs. 45%; absolute difference -1%, 95% CI: -20% to 19%). No significant differences were observed in all secondary outcomes. Conclusion: In this trial, triage nurse-initiated ondansetron administration did not reduce the need for ED observation in children with presumed gastroenteritis. While being underpowered, this study could inform researchers planning larger clinical trials.

BackgroundNeurological Long COVID (n-LC) includes persistent cognitive and autonomic symptoms after SARS-CoV-2 infection. Prior studies of post-COVID conditions have described diverse humoral autoreactivity, but findings are heterogeneous, and it remains unclear whether n-LC is associated with a consistent CNS-directed humoral signature. MethodsWe performed a cross-cohort case-control analysis to detect autoantibodies in cerebrospinal fluid (CSF) and serum from n-LC participants. In the Yale COVID Mind Study cohort, CSF from n-LC participants and from pre-pandemic and post-COVID asymptomatic controls was assessed by mouse brain immunofluorescence and proteome-wide phage immunoprecipitation sequencing (PhIP-Seq), with candidate reactivities evaluated by orthogonal assays and supervised modeling. In the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (IDCRP EPICC) cohort, post-COVID sera collected prior to iPhone- or iPad-based cognitive screening were profiled by PhIP-Seq and compared between participants with and without cognitive impairment. ResultsCSF immunoreactivity on mouse brain tissue was observed in both n-LC and controls, with similar overall frequencies, although n-LC participants more often showed nuclear-predominant staining patterns. PhIP-Seq identified sparse, largely patient-specific peptide reactivities to nuclear and neuronal proteins in CSF and serum. Supervised models provided limited discrimination between cases and controls. Candidate autoantigens had limited disease specificity on orthogonal testing. EPICC serum autoantibody profiling similarly failed to distinguish individuals with and without cognitive impairment. ConclusionsAcross cohorts and compartments, n-LC did not exhibit a shared autoantibody signature. These findings support the absence of a dominant, common CNS autoantibody-mediated mechanism in n-LC. FundingGrants HU00012020067, HU00012120103, HU00011920111, R01NS125693, R01MH125737, R01AI157488 from Defense health program and NIH.

Acinetobacter baumannii is a major cause of severe hospital-acquired infections, with a steadily increasing global prevalence driven by a few clinically adapted lineages. Animals and natural environments also harbor A. baumannii populations, but assessing their connections to clinical lineages is limited by sparse genomic data and a lack of integrated sampling. We conducted a local One Health genomic epidemiology study, sampling, isolating, sequencing, and characterizing several hundred A. baumannii isolates from clinical, animal, and environmental contexts. Within a geographically restricted area, we recovered several globally distributed clinical lineages (international clones, ICs), as well as livestock- and environment-associated lineages shared across Europe, highlighting widespread dissemination beyond clinical settings. Isolates closely related to the emerging clinical lineage IC11 were found in livestock, but no other clinically associated lineages were detected outside clinical contexts. Among these, the epidemic superlineage IC2 was identified in both human and veterinary clinical settings, indicating that similar practices in human and animal medicine select for closely related opportunistic pathogens. We found that hospitals host distinct, antibiotic-sensitive endemic populations capable of causing infection. These populations belong to a diversifying clade spanning clinical and environmental contexts and carry a high load of insertion sequences. Strong plasmid conservation further suggests frequent horizontal gene transfer across ecological compartments. Overall, A. baumannii comprises diverse, context-adapted lineages with a high potential for global spread. Although intercontext transmission appears limited, plasmids may overcome these ecological barriers. Our findings underscore the need for integrated One Health surveillance to better understand transmission pathways and limit the emergence of clinically adapted strains.

Corynebacterium ulcerans is a zoonotic pathogen causing infections in humans that are clinically indistinguishable from those of Corynebacterium diphtheriae. In many developed countries, companion animals such as dogs and cats, are the predominant sources of infection by C. ulcerans, as is the case in Japan. To date, we have collected 106 Japanese clinical and domestic animal isolates of C. ulcerans and a recently branched species, C. ramonii, most of which were isolated from humans and cats. In the present study, we performed a comparative analysis of whole-genome sequences from Japanese isolates and 597 published isolates from Japan and outside Japan. The Japanese isolates were divided into two distinct lineages: C. ulcerans and C. ramonii. The MLST types of C. ulcerans Japanese isolates exhibited a unique distribution pattern, with one major type (ST337) accounting for 69.0%, which is very rare in Europe. In addition to Japan, distinct MLST pattern compositions were observed across geographically distinct regions. The sequence types were associated with lysogenized prophage types that encode the diphtheria toxin (tox) gene and were partially associated with toxin production under certain conditions. Through SNV analysis, transmission from animals to humans has been suggested in some clinical cases. Significance StatementBy analyzing more than 700 genomes, we demonstrate striking geographic differences in multilocus sequence types and toxigenic prophage compositions between Japanese and European isolates. Notably, we identify the predominance of sequence type ST337 in Japan, a lineage that is rare in Europe, and show that prophage types encoding the diphtheria toxin are closely associated with specific sequence types and toxin production phenotypes. Our single-nucleotide variant analyses further provide genomic evidence supporting zoonotic transmission between companion animals and humans in several clinical cases.

Carbapenem-resistant (CR) Klebsiella pneumoniae (Kp) are designated by the WHO as a top-priority pathogen due to their antibiotic resistance profiles, capacity to disseminate resistance, and associated mortality. The prototypical CRKp clade, CG258, is associated with acute respiratory infections; however, urinary tract infections (UTIs) caused by CRKp are increasing, and frequently linked to the emergent clade CG307. Notably, CG307 isolates have extensive accessory genomes that may drive adaptation to the urinary tract, including a novel capsule gene cluster and high-affinity urea transporter. In this study, we show that UTIs caused by Kp are increasing across the Southern US and that in addition to CG307s circulating within Houston, TX hospital systems, the lineage was also detected in healthcare systems in the broader Gulf Coast region. Characterization of CG307 isolates demonstrate that while these strains exhibit similar mucoviscosity compared to the reference UTI strain TOP52, the lineage displays significantly higher i) growth in artificial urine, ii) urease activity, and iii) UTI in a mouse model. These results suggest that CG307 is spreading across the Southern US and encodes distinct pathogenic features that promote urinary tract tropism, underscoring a need for targeted surveillance and future studies that mechanistically examine the factors that promote UTI.

Syphilis is a sexually transmitted and bloodborne infection caused by Treponema pallidum spp. pallidum. Given the paucity of data on syphilis in Kenyan sex workers and gay, bisexual, and other men who have sex with men (GBMSM), we conducted a retrospective study of syphilis seropositivity in female sex workers (FSW) and GBMSM in Nairobi, Kenya. Seropositivity testing of cryopreserved plasma samples showed that 11.1% (72/647) were positive. Syphilis seropositivity was associated with HIV status, and FSWs were disproportionately represented in the seropositive group (66/72, 92%). Here, we report a higher seropositive rate than in previous studies in Kenya, and ongoing community and surveillance supports are important for addressing the ongoing public health impacts of syphilis.