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Assessment of vancomycin-resistant Enterococcus faecium (VREfm) prevalence upon hospital admission and analysis of risk factors for colonization.From 2014 to 2018, patients were recruited within 72 hours of admission to seven participating German university hospitals, screened for VREfm and questioned for potential risk factors (prior multidrug-resistant organism detection, current/prior antibiotic consumption, prior hospital, rehabilitation or long-term care facility stay, international travel, animal contact and proton pump inhibitor [PPI]/antacid therapy). Genotype analysis was done using cgMLST typing. Multivariable analysis was performed.In 5 years, 265 of 17,349 included patients were colonized with VREfm (a prevalence of 1.5%). Risk factors for VREfm colonization were age (adjusted OR [aOR], 1.02; 95% CI, 1.01-1.03), previous (aOR, 2.71; 95% CI, 1.87-3.92) or current (aOR, 2.91; 95% CI, 2.60-3.24) antibiotic treatment, prior multidrug-resistant organism detection (aOR, 2.83; 95% CI, 2.21-3.63), prior stay in a long-term care facility (aOR, 2.19; 95% CI, 1.62-2.97), prior stay in a hospital (aOR, 2.91; 95% CI, 2.05-4.13) and prior consumption of PPI/antacids (aOR, 1.29; 95% CI, 1.18-1.41). Overall, the VREfm admission prevalence increased by 33% each year and 2% each year of life. 250 of 265 isolates were genotyped and 141 (53.2%) of the VREfm were the emerging ST117. Multivariable analysis showed that ST117 and non-ST117 VREfm colonized patients differed with respect to admission year and prior multidrug-resistant organism detection.Age, healthcare contacts and antibiotic and PPI/antacid consumption increase the individual risk of VREfm colonization. The VREfm admission prevalence increase in Germany is mainly driven by the emergence of ST117.

To investigate the response of the immune system (and its influencing factors) to vaccination with BNT162b2 or mRNA-1273.531 vaccinees, recruited from healthcare professionals, donated samples before, in between, and after the administration of the two doses of the vaccine. T- and B-cell responses were examined via interferon-γ (IFN-γ) release assay, and antibodies against different epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (S1 and NCP) were detected via ELISA and surrogate neutralization assay. Results were correlated with influencing factors such as age, sex, prior infection, vaccine received (BNT162b2 or mRNA-1273), and immunosuppression. Furthermore, antinuclear antibodies (ANAs) were measured to screen for autoimmune responses following vaccination with an mRNA vaccine.No markers of immunity against SARS-CoV-2 were found before the first vaccination. Two weeks after it, specific responses against SARS-CoV-2 were already measurable (median ± median absolute deviation (MAD): anti-S1 IgG 195.5 ± 172.7 BAU/mL; IgA 6.7 ± 4.9 OD; surrogate neutralization 39 ± 23.7%), and were significantly increased two weeks after the second dose (anti-S1 IgG 3744 ± 2571.4 BAU/mL; IgA 12 ± 0 OD; surrogate neutralization 100 ± 0%, IFN-γ 1897.2 ± 886.7 mIU/mL). Responses were stronger for younger participants (this difference decreasing after the second dose). Further influences were previous infection with SARS-CoV-2 (causing significantly stronger responses after the first dose compared to unexposed individuals (p ≤ 0.0001)) and the vaccine received (significantly stronger reactions for recipients of mRNA-1273 after both doses, p 0.05-0.0001). Some forms of immunosuppression significantly impeded the immune response to the vaccination (with no observable immune response in three immunosuppressed participants). There was no significant induction of ANAs by the vaccination (no change in qualitative ANA results (p 0.2592) nor ANA titres (p 0.08) from pre-to post-vaccination.Both vaccines elicit strong and specific immune responses against SARS-CoV-2 which become detectable one week (T-cell response) or two weeks (B-cell response) after the first dose.

Background Although blood cultures (BCs) are the "gold standard" for detecting bacteremia, the utility of BCs in patients with community-acquired pneumonia (CAP) is controversial. This study describes the proportion of patients with CAP and afebrile bacteremia and identifies the clinical characteristics predicting the necessity for BCs in patients who are afebrile. Methods Bacteremia rates were determined in 4,349 patients with CAP enrolled in the multinational cohort study The Competence Network of Community-Acquired Pneumonia (CAPNETZ) and stratified by presence of fever at first patient contact. Independent predictors of bacteremia in patients who were afebrile were determined using logistic regression analysis. Results Bacteremic pneumonia was present in 190 of 2,116 patients who were febrile (8.9%), 101 of 2,149 patients who were afebrile (4.7%), and one of 23 patients with hypothermia (4.3%). Bacteremia rates increased with the CURB-65 score from 3.5% in patients with CURB-65 score of 0 to 17.1% in patients with CURB-65 score of 4. Patients with afebrile bacteremia exhibited the highest 28-day mortality rate (9.9%). Positive pneumococcal urinary antigen test (adjusted OR [AOR], 4.6; 95% CI, 2.6-8.2), C-reactive protein level > 200 mg/L (AOR, 3.1; 95% CI, 1.9-5.2), and BUN level ≥ 30 mg/dL (AOR, 3.1; 95% CI, 1.9-5.3) were independent positive predictors, and antibiotic pretreatment (AOR, 0.3; 95% CI, 0.1-0.6) was an independent negative predictor of bacteremia in patients who were afebrile. Conclusions A relevant proportion of patients with bacteremic CAP was afebrile. These patients had an increased mortality rate compared with patients with febrile bacteremia or nonbacteremic pneumonia. Therefore, the relevance of fever as an indicator for BC necessity merits reconsideration.

Tuberculosis, the leading cause of infection-related death in developing regions, is a leading cause of morbidity and mortality worldwide. Screening for, and treatment of, latent Mycobacterium tuberculosis infection is routine before initiation of anti-tumour necrosis factor α (anti-TNFα) agents in the management of psoriasis, Crohn's disease, and rheumatoid arthritis. By contrast, screening for latent tuberculosis before immune checkpoint inhibitor treatment in cancer is not routine, despite the increasing number of reports of primary infection with M tuberculosis or reactivation of latent M tuberculosis infection during such treatment. We present our experience with M tuberculosis screening in 70 patients who underwent immune checkpoint inhibitor therapy for metastatic skin cancer. Based on our understanding of the interaction between M tuberculosis and the immune system, we present the argument for tuberculosis screening before immune checkpoint inhibitor therapy and its use when considering anti-TNFα treatment for severe immune-related adverse events. We call for increased vigilance during immune checkpoint inhibition until its effects on tuberculosis pathophysiology are fully ascertained.

Background Tuberculosis (TB), especially drug-resistant TB, is a global public health problem. This study aimed to validate a new molecular diagnostic test, the FluoroType® MTBDR. Method Samples underwent routine diagnostic procedures (fluorescence microscopy, culture, species differentiation and phenotypic drug susceptibility testing). Left over samples stored at −20° underwent DNA extraction using the Fluorolyse® kit, followed by FluoroType® MTBDR and Genotype MTBDRplus testing. Results A total of 350 respiratory and 59 lymph node samples were included in the study; 71 respiratory and 16 lymph node samples were culture positive for M. tuberculosis complex (MTBC). The sensitivity of the FluoroType® MTBDR to detect MTBC DNA was 91.4% (95%CI 82.3–96.8%), 68.4% (95%CI 43.4–87.4%) and 62.5%, (95%CI 35.4–84.8%) for respiratory, smear negative respiratory and lymph node samples respectively. The correlating sensitivities of the GenoType MTBDRplus were 85.9% (95%CI 75.6–93.0%), 52.6% (95%CI 28.9–75.6%) and 56.3% (29.9–80.2). Sensitivity of the FluoroType® MTBDR to detect RMP and INH resistance for respiratory samples was 96.5% (95%CI 82.2–99.9) and 70% (95%CI 45.7–88.1), respectively. The GenoType MTBDRplus revealed sensitivities of 97.1% (95% 85.1–99.9) 70.6% (95%CI 52.5–84.9) for detection of RMP and INH resistance. Indeterminate results were 13/64 (20.3%), 23/64 (35.9%) and 16/64 (25.0%) for rpoB, katG and inhA using the FluoroType® MTBDR. Conclusion The FluoroType® MTBDR has a high sensitivity to detect MTBC DNA. However, the high proportion of indeterminate results across all three genes needs to be addressed.

Background: Housing and access to healthcare pose particular challenges to asylum seekers and refugees. The study aim was to assess their infection risk during the COVID-19 pandemic. Methods: We provide the first event-free, prospective study on SARS-CoV-2 cases among adult asylum seekers/refugees in Europe. SARS-CoV-2 genome and antibody titers were determined in adult asylum seekers/refugees living in shared accommodation in Lubeck, Germany at two time-points and compared to the results from a local population-based cohort. Findings: In November/December 2020, we detected 2/97 PCR- (2·1%; 95% confidence interval [CI]: 0·4-6·3%) and 4/97 (4·1%; CI: 1·4-9·2%) seropositive asylum seekers/refugees compared to 3/2547 (0·1%; CI: 0·0-0·3%) PCR-positive and 12/2547 (0·5%; CI: 0·3-0·8%) seropositive probands in the control sample. In February 2021, 2/67 (3·0%; CI: 0·5-9·1%) PCR-, and 25/67 (37·3%; CI: 27·4-48·1) antibody-positive individuals were found in the study group in comparison to 2/2371 (0·1%; CI: 0·0-0·3% and 38/2371 (1·6%; CI: 1·2-2·1%) in the control group. Age, sex, or facility equipment did not impact the results. "Living-with-own-children-in-the-shelter” was significantly positively correlated with infection risk. Importantly, none of the PCR-positive refugees were aware of their infection. Only 32·9% of the asylum seekers were willing to be vaccinated compared to 85·5% in the control population. Interpretation: Refugees residing in shared accommodations represent a high-risk group for SARS-CoV-2 infection and transmission. The present study suggests a need for (i) tailored testing strategies, (ii) improved information of this subgroup, and (iii) high-priority vaccination. Funding Information: The study was funded by the Federal Ministry of Education and Research. Declaration of Interests: C.K. serves as medical advisor to Centogene for genetic testing reports in the fields of movement disorders and dementia, excluding Parkinson's disease and serves on the Scientific Advisory Board of Retromer Therapeutics. Neither activity represents a conflict of interest. Likewise, none of the other authors declares any financial conflict of interest. Ethics Approval Statement: The ethics committee of the University of Lubeck approved the study (Az. 20-150). All participants gave written informed consent. All study materials were translated into the refugees' native languages, and interpreters were available on-site at the study center.

Loss of epithelial barriers characterized by reduction of E-cadherin is a hallmark of chronic obstructive pulmonary disease (COPD). We investigated the effects of nontypeable Haemophilus influenzae (NTHi) infections, associated with acute exacerbations of chronic bronchitis, on the regulation of E-cadherin in host cells. NTHi infection decreased E-cadherin mRNA and protein-levels in lung epithelial cells. E-cadherin reduction was mediated by activation of the fibroblast growth factor 2 (FGF2), the mammalian target of rapamycin (mTOR) and Slug. These data indicate that epithelial integrity and barrier function is disturbed by NTHi infection. Mainly, the destruction of cell–cell contacts is a prominent feature in NTHi infection.

SummaryAfter birth, the immune system experiences considerable reprogramming by interacting with the colonizing microbiota. Host factors involved in this relationship are largely unknown. Our studies in two infant cohorts and newborn mice reveal that abundant enteral S100A8/A9 trains the inflammatory and regulatory phenotype of colonic lamina propria macrophages. Neonatal S100A8/A9-alarmin deficiency results in an impaired expression of Cx3cr1, Il-10 and Tgf-β, reduced expansion of regulatory T cells, and dominant gut colonization with aerobes and facultative anaerobes, translating into a higher risk of gut dysbiosis and septic diseases preventable by one-time feeding of S100A8 at birth. Our results establish S100A8/A9 as an important host factor for developing gut homeostasis and a promising target for enteral supplementation aiming to prevent dysbiosis and associated diseases.

Welders have an increased susceptibility to airway infections with non-typeable Haemophilus influenzae (NTHi), which implicates immune defects and might promote pneumonia and chronic obstructive pulmonary disease (COPD). We hypothesized that welding-fume exposure suppresses Th1-lymphocyte activity. Non-effector CD4+ T-cells from blood of 45 welders (n = 23 gas metal arc welders, GMAW; n = 16 tungsten inert gas welders, TIG; n = 6 others) and 25 non-welders were ex vivo activated towards Th1 via polyclonal T-cell receptor stimulation and IL-12 (first activation step) and then stimulated with NTHi extract or lipopolysaccharide (LPS) (second activation step). IFNγ and IL-2 were measured by ELISA. In the first activation step, IFNγ was reduced in welders compared to non-welders and in the GMAW welders with higher concentrations of respirable particles compared to the lower exposed TIG welders. IFNγ was not influenced by tobacco smoking and correlated negatively with welding-fume exposure, respirable manganese, and iron. In the second activation step, NTHi and LPS induced additional IFNγ, which was reduced in current smokers compared to never smokers in welders as well as in non-welders. Analyzing both activation steps together, IFNγ production was lowest in smoking welders and highest in never smoking non-welders. IL-2 was not associated with any of these parameters. Welding-fume exposure might suppress Th1-based immune responses due to effects of particulate matter, which mainly consists of iron and manganese. For responses to NTHi this is strongest in smoking welders because welding fume suppresses T-cell activation towards Th1 and cigarette smoke suppresses the subsequent Th1-response to NTHi via LPS. Both effects are independent from IL-2-regulated T-cell proliferation. This might explain the increased susceptibility to infections and might promote COPD development.

Disturbances in Insulin-like growth factor-I (IGF-I) and dysregulation in neonatal immune responses have been associated with typical neonatal diseases. Immunosuppression by IGF-I might be a key regulator of neonatal immune responses in infection and maturation. However, information on IGF-I serum levels, IGF-I-receptor (IGF-IR) and effects on functional properties of neonatal immune cells is scarce. Neonatal cord blood samples were stimulated with anti-CD3/anti-CD28, PMA/ionomycin or LPS in a whole-blood assay, while IGF-I serum levels and IGF-I receptor expression were assessed. Furthermore the effect of IGF-I on cytokine expression, apoptosis and the DNA binding activity of AP-1 and NFκB was evaluated. IGF-I serum levels were within normal range. The IGF-I-receptor was present on the surface of cord blood CD3+CD4+lymphocytes and cord blood CD14+monocytes. Upon stimulation the IGF-I-R expression on lymphocytes was significantly upregulated. The addition of IGF-I (100ng/ml) to whole blood cultures inhibited the secretion of IFN-γ from PMA/ionomycin-stimulated cord blood mononuclear cells (CBMC). While IGF-I did not influence apoptosis in our experimental setting, it led to a distinct decrease in anti-CD3/CD28-stimulated DNA binding activity of AP-1 and NFκB. Thus IGF-I may be a key regulator of neonatal immune responses in maturation processes and inflammation by suppressing proinflammatory Th1 responses. Future in vivo studies need to elucidate whether disturbances of the IGF-I serum level and IGF-IR expression are associated with susceptibility for infections and subsequent diseases in neonates.

Summary Given the susceptibility of newborns to infection and the potential harm of overwhelming proinflammatory immune responses, the impact of genetic variation in innate immune molecules is of increasing interest for risk stratification and prevention. We studied the functional relevance of the 159C>T CD14 single nucleotide polymorphism in cord blood samples of n = 135 healthy term neonates by investigation of sCD14, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α concentrations in whole-blood culture supernatants and intracellular assessment of IL-1β, IL-6, and TNF-α expression by flow cytometry. The 159C>T CD14 genotype frequencies were n = 42 (0.31) for homozygous CD14-159 CC, n = 69 (0.51) for heterozygous CD14-159 CT, and n = 24 (0.18) for homozygous CD14-159 TT. No genotype-associated differences were noted for ex vivo baseline expression of sCD14, IL-6, IL-10, and TNF-α. After in vitro stimulation of cord blood cultures with lipopolysaccharide, carriers of the CD14-159 T allele were determined to have higher levels of sCD14 compared with carriers of the CD14-159 C allele ( p = 0.04) and increased concentrations of IL-6 ( p = 0.009) in culture supernatants (one-way analysis of variance). The 159C>T CD14 polymorphism is associated with soluble CD14 expression and cytokine expression, which might influence the balance of pro- and anti-inflammatory immune responses in healthy term neonates. Further studies are needed to delineate whether the 159C>T CD14 genotype is a risk factor for severity of neonatal infection in the clinical setting and a potential target for prevention strategies.

Interleukin-6 (IL-6) is required for the clearance of bacteria in pneumococcal pneumonia. The abundance of endogenous IL-6 production on infectious stimuli is associated with genotypic differences in the −174 promoter region of IL-6 (−174 G→C), showing increased IL-6 levels in patients carrying the GG genotype. One hundred patients with culturally proven pneumococcal disease were analyzed for distribution of the G-/C-alleles in the IL-6 −174 promoter region in comparison to 50 age-matched controls. Extrapulmonary pneumococcal dissemination, including septic metastasis, endocardial and meningeal infection, was used as parameter for impaired clearance of the bacteria. No significant differences in the allele distribution were observed between patients and controls. Within the patient group, the interleukin-6 GG homozygous carriers were less likely to develop extrapulmonary pneumococcal infection (10.3% versus 30.9%; OR 0.26, 95% CI 0.07–0.94, p = 0.04). The IL-6 GG genotype, encoding for enhanced IL-6 secretion on bacterial stimuli, reduces the risk of bacterial spread to extrapulmonary sites in pneumococcal infection, possibly due to a more effective clearance of the pathogen from the blood and the respiratory tract.

Peripheral blood monocytes (PBMC) promote vascular inflammation and atherosclerosis. Chlamydia pneumoniae (Cp) infection of PBMC is found in atherosclerotic patients, appears refractory to antibiotics, and may predispose to vascular damage. In Cp-infected human PBMC we analyzed the role of cyclooxygenase-2 (Cox-2) for the proatherosclerotic key mediators prostaglandin E2 (PGE2) and interstitial collagenase (MMP-1). Cp infection resulted in rapid and sustained Cox-2 mRNA and protein stimulation depending on p38 and p44/42 MAPkinases. Subsequent upregulation of PGE synthase and MMP-1 was completely abrogated by the selective Cox-2 inhibitor NS398. Enhanced synthesis of PGE2 and MMP-1 in Cp infected PBMC is mediated through initiation of the p38 and p44/42 MAPK pathways and requires sustained Cox-2 activation. Selective Cox-2 inhibitors, currently under investigation for cardiovascular risk reduction, may represent a novel therapeutic option for patients with endovascular Cp infection as they target the actuated pathological signal transduction cascade in persistently infected PBMC.

The bacterium Chlamydia pneumoniae chronically infects atheromatous lesions and is linked to atherosclerosis by modifying inflammation, proliferation, and the lipid metabolism of blood monocytes. As continuous LDL modification in the vascular intima is crucial for atherogenesis we investigated the impact of endothelial infection on LDL oxidation. HUVEC were infected with a vascular C. pneumoniae strain. Supernatants of infected cells but not cell lysates increased lipid peroxidation products (6.44 vs 6.14 nmol/ml, p

Atherosclerosis is characterized by chronic inflammation and vascular cell proliferation. The intracellular bacterium Chlamydia pneumoniae has been implicated in atherogenesis as it has been recovered from atheromatous plaques. In vitro, C. pneumoniae infection initiates activation of the transcriptional factor NF-κB via small GTPases Rac1 and RhoA. This signaling cascade results in the synthesis of numerous proinflammatory and pro-coagulatory mediators (e.g., IL-6, IL-8, RANTES, MCP-1, PAI-1, TF) that are also characteristically produced in the plaque. In parallel, chlamydiae stimulate vascular cell proliferation via ERK 1/2 MAPkinase and transcription factor Egr-1. Thus, chlamydial infection may have a role in the inflammatory, as well as in the angiogenic, component of atherogenesis. The proinflammatory activity of chlamydial infection is reduced by statins, via suppression of Rho and Rac signalling, indicating a beneficial anti-inflammatory effect of lipid-lowering drugs in vascular infection. C. pneumoniae uses blood monocytes as transport vehicles for systemic dissemination. In monocytes the pathogen enters a non-replicative, but viable, state characterized by continuous production of mRNA transcripts. Release of proinflammatory mediators by circulating or transendothelially migrating infected monocytes might promote chronic inflammation and atherogenesis. Interestingly, persistent chlamydiae in monocytes appear to be refractory to conventional antichlamydial treatment, thus posing a challenge to the ongoing experimental treatment studies. The persistent state is likely to have a key role in the pathogenesis of chronic chlamydial infections and requires further examination on a molecular level.