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Objectives: Lung disease progression in people with cystic fibrosis (pwCF) varies from one individual to another. Different immunological characteristics have been suggested to explain this variation, and we hypothesised that lung capacity may be associated with the innate immune response in pwCF. In an exploratory study, we aimed to investigate potential links between the innate immune response and lung function in pwCF using the standardised immune function assay TruCulture. Methods: In a single-centre study with combined cross-sectional and longitudinal data before and after intravenous antibiotics, blood was sampled from Pseudomonas aeruginosa-infected pwCF. Whole blood was analysed by TruCulture to reveal the unstimulated and stimulated cytokine release. Tobit regressions and Spearman's correlations were used to estimate the associations between lung function and cytokine release. Results: We included 52 pwCF in the cross-sectional study and 24 in the longitudinal study. In the cross-sectional study, we found that compared to a healthy population, the release of toll-like receptor (TLR)3, TLR4- and TLR7/8-stimulated interferon-γ, and interleukin (IL)-12p40 was reduced. Although TLR3-stimulated IL-1ß and IL-6 release increased with lung function, overall, cytokine release did not correlate well with lung function. In the longitudinal study, the cytokine release was modified by antibiotic treatment, but the cytokine release before antibiotic treatment did not associate with changes in lung function after treatment. Conclusion: The stimulated cytokine release could not predict lung function levels or changes in pwCF, but our data indicate that pwCF experience exhaustion in the innate immune response after years of chronic bacterial infection.
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Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real-world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed-effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI-treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively-48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes.
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INTRODUCTION: Greenlandic patients may be referred to Denmark for specialised diagnostics and treatment. The main collaborator for these activities is the National University Hospital, Rigshospitalet, Copenhagen. We aimed to investigate the referral pattern of Greenlandic paediatric patients to Rigshospitalet. METHODS: This was an observational quality assurance project comprising all Greenlandic patients below 18 years who received healthcare services at Rigshospitalet in the 2017-2021 period. This period was chosen to obtain the most updated, available and coherent data possible. Unique patients and disease courses were stratified by paediatric subspecialities and procedures. RESULTS: During the five-year period, a total of 310 unique patients were referred to Rigshospitalet, resulting in a total of 676 disease courses and yielding an average 62 annual referrals of paediatric Greenlandic patients. This represents around 0.5% of all Greenlandic children. Age groups were distributed as 28% aged 0-1 years, 23% 2-4 years, 13% 5-9 years, 21% 10-14 years and 16% 15-17 years. During the study period, the number of disease courses increased by 89% with most patients being managed as outpatients. The subspecialities with most referrals were ophthalmology (17%), oto-rhino-laryngology (16%) and cardiovascular diseases (10%). CONCLUSIONS: Approximately 0.5% of Greenlandic children were referred annually to Rigshospitalet with a marked increase being observed during the five-year study period. We observed a shift towards an increasing proportion of outpatient treatments at Rigshospitalet. FUNDING: None. TRIAL REGISTRATION: Not relevant.
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Hospitales Universitarios , Derivación y Consulta , Humanos , Groenlandia , Niño , Dinamarca , Adolescente , Derivación y Consulta/estadística & datos numéricos , Preescolar , Lactante , Masculino , Femenino , Hospitales Universitarios/estadística & datos numéricos , Recién Nacido , Garantía de la Calidad de Atención de Salud , Pediatría/estadística & datos numéricosRESUMEN
BACKGROUND: Improved growth in children with CF may have resulted from advances in treatment for cystic fibrosis (CF) over the past two decades, including the implementation of newborn screening in Denmark in 2016. This observational cohort study focuses on changes in early growth in Danish children with CF born between 2000 and January 2022. METHODS: Age, length/height, and weight data of children 0-5 years old were obtained from the Danish CF Cohort. Data were stratified to four birth cohorts born between 2000 and 2022. Weight-for-age (WAZ), length-for-age (LAZ), height-for-age (HAZ) and body-mass-index (BMZ) z-scores were computed using WHO growth curves. Cubic spline mixed effects models were used to evaluate growth over 5 years between birth cohorts. RESULTS: We included 255 children in the analyses. Cubic spline mixed effects models show that catch-up growth improved in birth cohorts over time, with the 2016-2022 birth cohort achieving growth reference curve values in WAZ, LAZ/HAZ and BMZ the earliest. The proportion of underweight and stunting observations among children born 2000-2004 decreased by the 2016-2022 birth cohort, while the proportion of overweight, low BMZ and high BMZ observations increased. CONCLUSION: Advances in care for young children with CF have led to improvements in growth - with the 2016-2022 birth cohort approaching potential for overweight. Nonetheless, low BMZ remains. Immediate, individualized nutrition care throughout early childhood remain crucial in mitigating malnutrition.
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Estatura , Fibrosis Quística , Humanos , Fibrosis Quística/epidemiología , Fibrosis Quística/fisiopatología , Fibrosis Quística/terapia , Dinamarca/epidemiología , Masculino , Femenino , Preescolar , Lactante , Recién Nacido , Peso Corporal , Desarrollo Infantil/fisiología , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/diagnóstico , Estudios de Cohortes , Tamizaje Neonatal/métodos , Índice de Masa CorporalRESUMEN
The vast majority of people with cystic fibrosis (pwCF) have untreated secondary chronic rhinosinusitis (CRS). Whereas the introduction of the cystic fibrosis transmembrane conductance regulator modulator (CFTRm) treatment regime has improved the lung function of pwCF, few studies have been published examining the effect on sinonasal symptoms in children. Our aim was to explore the effect of double CFTRm treatment on CRS and olfaction in children with CF. pwCF were included in this non-randomized cross-sectional study, where an otolaryngologist performed a complete ENT examination before initiating treatment with elaxacaftor/tezacaftor/ivacaftor (ETI). Twenty-three pwCF aged 6-12 years were included. Eighteen of 23 patients were on a double CFTRm treatment, and 5 patients were CFTRm naive, respectively. Altogether, 19 had normal olfaction, 20 had none or mild CRS symptoms according to SNOT-22, and 14 had a normal endoscopy. None of the patients had symptoms of chronic rhinosinusitis lasting for more than 12 weeks, thus none of the patients fulfilled the criteria for CRS. Children with CF treated with double CFTRm have few to no symptoms of CRS and normal olfaction, which is an improvement compared with children following treatment modalities prior to CFTRm.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Rinosinusitis , Niño , Femenino , Humanos , Masculino , Aminofenoles/uso terapéutico , Enfermedad Crónica , Estudios Transversales , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/complicaciones , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Combinación de Medicamentos , Quinolonas/uso terapéutico , Rinosinusitis/tratamiento farmacológico , Rinosinusitis/etiologíaRESUMEN
BACKGROUND: Excessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated. METHODS: Peripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group. Systemic immune cell subsets and surface markers were quantified using multiparameter flow cytometry. Lung microbiome composition was reconstructed using metatranscriptomics on sputum samples, and microbial taxa were correlated to circulating immune cells and surface markers expression. RESULTS: In pwCF, we found a specific systemic immune profile characterized by widespread hyperactivation and altered frequencies of several subsets. These included substantial changes in B-cell subsets, enrichment of CD35+/CD49d+ neutrophils, and reduction in dendritic cells. Activation markers and checkpoint molecule expression levels differed from healthy subjects. CTLA-4 expression was increased in Tregs and, together with impaired B-cell subsets, correlated with patients' lung function. Concentrations and frequencies of key immune cells and marker expression correlated with the relative abundance of commensal and pathogenic bacteria in the lungs. CONCLUSION: The CF-specific immune signature, involving hyperactivation, immune dysregulation with alteration in Treg homeostasis, and impaired B-cell function, is a potential source of lung function heterogeneity. The activity of specific microbes contributes to disrupting the balance of the immune response. Our data provide a unique foundation for identifying novel markers and immunomodulatory targets to develop the future of cystic fibrosis treatment and management.
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BACKGROUND: Cystic Fibrosis (CF) is an inherited multiorgan disease that causes lung damage and early death. People with CF (pwCF) experience diminished exercise capacity compared to the general population. This is due to an accelerated decline in lung function resulting from recurrent lung infections, declining lung function and nutritional challenges. Since 2020 the CFTR-modulator Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been approved for pwCF aged 12 and above in Denmark. Initial experiences with the medication have shown promising results, including improved lung function and disease stability. To date a limited number of studies have evaluated the impact of CFTR-modulators on exercise capacity in pwCF. OBJECTIVE: The study aims to assess the impact of one year of ETI treatment, without any further intervention, on exercise capacity measured through cardiopulmonary exercise test (CPET) in pwCF aged 12 years and above. METHODS: A Danish prospective registry cohort study including pwCF from CF-Center Copenhagen, Copenhagen University Hospital and CF-Center Aarhus, Aarhus University Hospital. Participants underwent CPET before initiating ETI and at follow up one year later. Primary outcomes were VO2 peak (ml/kg/min), secondary outcomes were VO2 peak (ml/min), VO2 peak (% pred), watt-max, HR-max and saturation at max. The difference between baseline and follow-up was assessed using a paired-sample t-test and regression analyses were applied to relevant outcomes. RESULTS: We included 229 pwCF in the analyses. An increase in oxygen uptake, VO2 peak (ml/kg/min) from baseline to follow-up was observed; 0.6, 95% CI [0.06; 1.09] p = 0.03. Moreover, significant increase was noted for all other CPET outcomes. Regression analysis showed that changes in FEV1% pred and BMI could explain some of the differences, 0.05 ml/kg/min, 95% CI [0.01, 0.1] p = 0.02 and -0.5 ml/kg/min, 95% CI [-0.8, -0.2] p = 0.002 respectively. CONCLUSION: Among Danish pwCF we found a significant, but not clinically relevant, increase in oxygen uptake, after one year of ETI treatment.
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BACKGROUND: Past and ongoing advancements in cystic fibrosis (CF) care warrant long-term analysis of the societal impact of the condition. This study aims to evaluate changes in key socioeconomic factors across three decades among people living with CF (pwCF), compared with both the general population and an early-onset chronic disease population. METHODS: This nationwide, registry-based, matched cohort study included all pwCF ≥ 18 years in Denmark in the years 1990, 2000, 2010, and 2018. Each person living with CF was matched to five individuals in the general population and five individuals living with type 1 diabetes or juvenile arthritis based on age, sex, and municipality. RESULTS: The Danish adult CF population increased nearly fourfold from 88 in 1990 to 331 in 2018, and mean age increased by ten years. The educational level of pwCF was similar to the two comparator cohorts, while pwCF were less often in employment and more often permanently outside the labor force. Personal and household income levels of the CF cohort were higher than those of the comparator cohorts. CONCLUSIONS: The disadvantage in employment for pwCF remained, but, over time, the societal profiles of the one-year CF cohorts increasingly converged with those of the comparator cohorts, indicative of improved clinical management, extended life expectancy, and the supportive role of the Danish welfare system in reducing health inequalities. Further research should be done to evaluate the effects of the newly introduced modulator therapies on employment, considering the broader societal impact and impact on quality of life.
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Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.
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Antiinfecciosos , Fibrosis Quística , Humanos , Fibrosis Quística/complicaciones , Europa (Continente) , Antiinfecciosos/uso terapéutico , DinamarcaRESUMEN
BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. CLINICALTRIALS: GOV: NCT03219164.
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Fibrosis Quística , Infecciones por Pseudomonas , Adolescente , Humanos , Niño , Aztreonam/efectos adversos , Pseudomonas aeruginosa , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Administración por Inhalación , Antibacterianos/uso terapéutico , Infecciones por Pseudomonas/diagnóstico , Infecciones por Pseudomonas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved the clinical status of individuals with cystic fibrosis (CF), however, whether ETI impacts glucose tolerance remains unknown. We aimed to study the change in glycated hemoglobin (HbA1c) and CF related diabetes (CFRD) status after initiation of ETI. METHODS: We included individuals ≥12 years treated with ETI in Denmark in a longitudinal observational study. HbA1c was measured at baseline, 3, 6, 9 and 12 months after treatment initiation. Change in HbA1c was assessed in mixed models adjusted for age, sex, glucose tolerance and prior CFTR modulator treatment. In a sub-population with CFRD, we assessed the change in insulin usage, hypoglycemic events and the 30-day continuous glucose monitoring (CGM) parameters (i.e., average blood glucose, time below (≤3.9 mM) and above (>10.0 mM) normal range, and the variation in glucose) after 12 months of treatment. RESULTS: Among 321 individuals with CF, HbA1c declined by 2.1 mmol/mol [95 % confidence interval (CI): -2.6; -1.5 mmol/mol] after 3 months and by 2.3 mmol/mol [95 %CI: -2.8; -1.9 mmol/mol] after 12 months of ETI treatment. The decline was independent of glucose tolerance status at baseline. In 26 individuals with CFRD at baseline, the mean decline in HbA1c was 3.6 mmol/mol [95 %CI: -6.9; -0.4 mmol/mol] after 12 months, but we did not observe any change in insulin usage, weekly number of hypoglycemic events or CGM parameters. CONCLUSION: In the Danish CF cohort, HbA1c declined over 12 months of ETI treatment, however, among a subset with CFRD, we observed no change in insulin usage and CGM glucose levels.
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Glucemia , Fibrosis Quística , Indoles , Pirazoles , Piridinas , Pirrolidinas , Quinolonas , Humanos , Automonitorización de la Glucosa Sanguínea , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/epidemiología , Hemoglobina Glucada , Insulina , Hipoglucemiantes/uso terapéutico , Glucosa , Dinamarca/epidemiología , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Benzodioxoles , Mutación , Aminofenoles/uso terapéuticoRESUMEN
Background: Cystic fibrosis (CF) lung disease starts in infancy and can be assessed for structural lung abnormalities using computed tomography or magnetic resonance scans, or for lung function impairment using multiple breath washout (MBW). However, in infancy these two methods are not well correlated. Trajectories of CF lung disease assessed by MBW in infants and toddlers remain poorly described, which is why we aimed to 1) describe the trajectory of lung function, 2) explore risk factors for progression and 3) explore the real-life effect of lumacaftor/ivacaftor. Methods: This was a nationwide observational cohort study (2018-2021) using data collected as part of the routine clinical surveillance programme (including MBW and monthly endo-laryngeal suction sampling for bacterial pathogens) in children born after implementation of newborn screening for CF (May 2016). Lumacaftor/ivacaftor commenced from age 2â years in children homozygous for F508del. Ventilation distribution efficiency (VDE), recently described to have advantages over lung clearance index (LCI), was reported as the primary MBW outcome after z-score calculations based on published reference data. Mixed effect linear regression models were the main statistical analyses performed in this study. Results: 59 children, aged 2-45â months, contributed with 211 MBW occasions (median (interquartile range (IQR)) 3 (2-5) MBW occasions per child) with a median (IQR) follow-up time of 10.8 (5.2-22.3)â months. An overall mean annual deterioration rate of -0.50 (95% CI -0.78- -0.22) z-VDE was observed, starting from an estimated mean z-VDE of -1.68 (95% CI -2.15- -1.22) at age 0.0â years (intercept). Pseudomonas aeruginosa "ever" (n=14, MBWs 50) had a significantly worse z-VDE trajectory versus P. aeruginosa "never" (mean difference 0.53 (95% CI 0.16-0.89)â per year; p=0.0047) and lumacaftor/ivacaftor treatment (n=22, MBWs 46) significantly improved the trajectory of z-VDE (mean difference 1.72 (95% CI 0.79-2.66)â per year; p=0.0004), leading to a stable mean z-VDE trajectory after start of treatment. Conclusions: Infants and toddlers with CF demonstrated progressive deterioration in z-VDE over the first years of life. P. aeruginosa isolation "ever" was associated with an accelerated deterioration in lung function, while lumacaftor/ivacaftor therapy significantly improved and stabilised the trajectory.
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We describe 10 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant BA.2.86 detected in Denmark, including molecular characteristics and results from wastewater surveillance that indicate that the variant is circulating in the country at a low level. This new variant with many spike gene mutations was classified as a variant under monitoring by the World Health Organization on 17 August 2023. Further global monitoring of COVID-19, BA.2.86 and other SARS-CoV-2 variants is highly warranted.
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COVID-19 , Humanos , SARS-CoV-2/genética , Aguas Residuales , Monitoreo Epidemiológico Basado en Aguas Residuales , Dinamarca/epidemiologíaRESUMEN
Introduction. The emergence of vancomycin-resistant Enterococcus faecium (VREfm) has left the vancomycin-sensitive E. faecium (VSEfm) strains almost unnoticed.Hypothesis. Molecular characteristics, hospital transmission patterns and clinical impact of VSEfm have changed, and VSEfm is a predictor of VREfm introduction.Aim. We wanted to do a molecular characterization of VSEfm to identify hospital transmissions and links between VSEfm and VREfm, and to investigate the demographics, treatment and impact on mortality of VSEfm bacteraemia.Methodology. VSEfm and VREfm blood culture isolates from Odense University Hospital, Denmark, from 2015 to 2019 were characterized using whole-genome sequencing and core-genome multilocus sequence typing (cgMLST). Clonal shifts and diversity of the VREfm isolates were compared to the VSEfm isolates. Hospital records were used for clinical data and transmission investigation of VSEfm cases.Results. Six-hundred and thirty VSEfm isolates from 599 patients belonged to 42 sequence types (STs) and 131 complex types (CTs) in several clusters. Multiple types were involved in putative transmission, occurring over the entire period. Twenty-seven VREfm bacteraemia cases were included. No correlation between the VSEfm and VREfm clones was identified. The 30 day mortality was 40â%, but only in 6.3â% of the cases, VSEfm bacteraemia was the likely cause of death.Conclusion. The molecular types of VSEfm bacteraemia isolates are changing and diverse. No direct correlation between VSEfm and the introduction of VREfm was found, but widespread hospital transmission indicates a presence of risk factors that could facilitate transmission of other micro-organisms as well. VSEfm bacteraemia is rarely the cause of death, indicating that 30 day mortality does not reflect the cause of death.
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Bacteriemia , Infección Hospitalaria , Enterococcus faecium , Infecciones por Bacterias Grampositivas , Enterococos Resistentes a la Vancomicina , Humanos , Vancomicina/farmacología , Vancomicina/uso terapéutico , Enterococcus faecium/genética , Proteínas Bacterianas/genética , Hospitales Universitarios , Enterococos Resistentes a la Vancomicina/genética , Tipificación de Secuencias Multilocus , Dinamarca/epidemiologíaRESUMEN
Bacteroides fragilis is among the most abundant and pathogenic bacterial species in the gut microbiota and is associated with diarrheal disease in children, inflammatory bowel disease, and the development of colorectal cancer. It is increasingly resistant to potent antimicrobial agents such as carbapenems and metronidazole, making it among the most resistant anaerobic bacteria. These factors combined call for increased monitoring of B. fragilis and its population structure on a worldwide scale. Here, we present a possible solution through the development of a multilocus sequence typing scheme (MLST). The scheme is based on seven core gene fragments: groL (hsp60), rpoB, recA, dnaJ, rprX, prfA, and fusA. These gene fragments possess high discriminatory power while retaining concordance with whole core genome-based phylogenetic analysis. The scheme proved capable of differentiating B. fragilis isolates at the strain level. It offers a standardized method for molecular typing and can be applied to isolates from various sampling backgrounds, such as patient isolates, environmental samples, and strains obtained from food and animal sources. In total, 567 B. fragilis genomes were sequence typed and their isolate data collected. The MLST scheme clearly divided the B. fragilis population into two divisions based on the presence of the cfiA and cepA resistance genes. However, no other specific subpopulations within the analyzed genomes were found to be associated with any specific diseases or geographical location. With this MLST scheme, we hope to provide a powerful tool for the study and monitoring of B. fragilis on an international scale. IMPORTANCE Here, we present the first MLST scheme for Bacteroides fragilis, one of the most abundant pathogenic bacteria in the human gut microbiota. The scheme enables standard classification and monitoring of B. fragilis on a worldwide scale and groups the majority of current isolate data in one place. A more unified approach to the collection and analysis of B. fragilis data could provide crucial insights into how the pathogen operates and develops as a species. Close monitoring of B. fragilis is especially relevant, as it is increasingly resistant to potent antimicrobial agents and engages in horizontal gene transfer with other bacteria. Hopefully, this approach will guide new discoveries into how B. fragilis evolves and interacts with its human host. Additionally, the scheme could potentially be applied to other species of the genus Bacteroides.
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Molecular methods for diagnosing Lyme neuroborreliosis (LNB) have shown suboptimal diagnostic sensitivities. The objective of this study was to improve the clinical sensitivity of PCR detection of Borrelia burgdorferi sensu lato spirochetes by inoculating cerebrospinal fluid (CSF) from patients suspected of LNB directly into culture medium at the time of lumbar puncture, with this pursuing enrichment of Borrelia spirochetes before PCR analysis. Adult patients with symptoms suggestive of LNB were prospectively enrolled at two hospitals in the Region of Southern Denmark. The CSF-culture samples were incubated for at least eight weeks. During this period, culture sample aliquots were analysed for the presence of Borrelia DNA by separate PCR protocols in two independent clinical laboratories. The included patients were diagnosed with definite (n=12) or possible (n=2) LNB, and non-LNB (n=171) based on clinical and paraclinical findings. Patients in the LNB and the non-LNB group had a median duration from symptom onset to lumbar puncture of 40 days (IQR [23-90] days) and 120 days (IQR [32-365] days), respectively. Pre-enrichment growth of Borrelia spirochetes was accomplished from three patients (21 %) in the LNB group. The positive culture samples were confirmed by both the digital droplet PCR and the real-time PCR methods employed. All CSF samples were PCR negative in the non-LNB group. The results of this study do not support the use of Borrelia-specific PCR as a general routine diagnostic tool in adults. Still, they suggest it may prove of additional value in selected patients with a limited time from symptom onset to sample collection.
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Grupo Borrelia Burgdorferi , Borrelia , Neuroborreliosis de Lyme , Adulto , Humanos , Grupo Borrelia Burgdorferi/genética , Neuroborreliosis de Lyme/diagnóstico , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Borrelia/genética , ADN , Reacción en Cadena en Tiempo Real de la Polimerasa , Líquido CefalorraquídeoRESUMEN
During routine surveillance at the National Influenza Center, Denmark, we detected a zoonotic swine influenza A virus in a patient who became severely ill. We describe the clinical picture and the genetic characterization of this variant virus, which is distinct from another variant found previously in Denmark.
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Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Humana , Animales , Humanos , Porcinos , Subtipo H1N1 del Virus de la Influenza A/genética , Virus de la Influenza A/genética , Zoonosis/epidemiología , Gripe Humana/diagnóstico , Gripe Humana/epidemiología , Dinamarca/epidemiologíaRESUMEN
Delftia acidovorans (D. acidovorans) is a Gram-negative bacteria and an uncommon cause of human infections. This retrospective cohort study investigated clinical and microbiological characteristics and outcomes of patients with D. acidovorans infections. We included patients with culture-confirmed D. acidovorans infections attending Rigshospitalet, during 2002-2020. Fifty-nine patients with a median interquartile ranges (IQR) age of 47 (15-67) years were included. Thirty-five (59%) were males, and 57 (97%) had at least one comorbidity, including 25 (42%) with solid or hematologic malignancies. Eight (14%) were admitted to ICU, and 15 (25%) died within 365 days after infection. Persistent infection was found in 4 (6.8%) patients, and 41 (70%) had polymicrobial cultures, mainly with Pseudomonas spp. and Stenotrophomonas maltophilia. More than 85% of the D. acidovorans isolates were susceptible to meropenem or ceftazidime. Although, 88% and 62% of the isolates were resistant to gentamicin and colistin, respectively. D. acidovorans infections mainly affect patients with preexisting comorbidities, including malignancies. In the first year, all-cause mortality is considerable, polymicrobial cultures are common, and meropenem or cephalosporins with antipseudomonal activity could be the antibiotics of choice. IMPORTANCE Delftia acidovorans (D. acidovorans) is a Gram-negative bacteria that can cause infection in immunocompetent and immunocompromised individuals. The current knowledge comes mainly from case reports and case series. In this retrospective cohort study, we found that D. acidovorans infections mainly affect male patients with preexisting comorbidities, including malignancies. Persistent infections were not common, and most of the patients had polymicrobial cultures, mainly with Pseudomonas spp. and Stenotrophomonas maltophilia. More than 85% of the D. acidovorans isolates were susceptible to meropenem or ceftazidime. In contrast, 88% and 62% of the isolates were resistant to gentamicin and colistin, respectively.
Asunto(s)
Delftia acidovorans , Infecciones por Bacterias Gramnegativas , Stenotrophomonas maltophilia , Adolescente , Adulto , Anciano , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Ceftazidima , Colistina , Femenino , Gentamicinas , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/epidemiología , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Masculino , Meropenem , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Free fatty acids (FFAs) are known to exhibit antimicrobial and anti-virulent properties against bacterial pathogens. Specific FFAs, such as lauric acid (LA; C12:0), exert both effects against the foodborne pathogen Listeria monocytogenes: at low levels, LA acts to inhibit the activity of the virulence regulator PrfA, whereas at higher levels, LA inhibits bacterial growth. Deletion of prfA is known to promote tolerance toward antimicrobial FFAs, suggesting that the response of L. monocytogenes to anti-virulent and antimicrobial FFAs could be linked. In this study, we explored the response of L. monocytogenes toward antimicrobial FFAs holding an anti-virulence activity by isolating strains that can grow at high concentrations of LA. We found that LA-tolerant isolates carry mutations in the gene encoding the global regulator CcpA. Importantly, we discovered that mutation or deletion of ccpA protect L. monocytogenes against the antimicrobial activity of FFAs, whereas the ccpA mutants remain sensitive toward FFA's PrfA inhibitory effect. A regulatory link involving CcpA, connecting the response toward the antimicrobial and anti-virulence activities of FFAs, is therefore unlikely. To further study how deletion of ccpA promotes FFA tolerance, we performed a transcriptomic analysis of the response to LA. Our data indicated that the FFA-tolerant phenotype of the ∆ccpA strain is not induced upon LA exposure but appears to be an inherent phenotypic trait of the ccpA deletion mutation. Interestingly, we found that the bacterial surface of L. monocytogenes becomes more hydrophilic upon deletion of ccpA, and we demonstrate that CcpA plays a role in the response of L. monocytogenes to other stress conditions, including low pH and antibiotics. Altogether, our study revealed that regulatory activities of CcpA lead to an increased hydrophobicity of the bacterial surface, which may confer sensitivity of L. monocytogenes against the antimicrobial activity of FFAs. Notably, CcpA is not involved in responding to the PrfA inhibitory effect of FFAs, showing that FFA-tolerant strains can still be targeted by the anti-virulent activity of FFAs.