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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.

We show a shift in the prevalence of respiratory viral pathogens in community-acquired pneumonia patients during the COVID-19 pandemic. Our data support the efficiency of non-pharmaceutical interventions on virus circulation except for rhinoviruses. The consequences of an altered circulation on subsequent winter seasons remain unclear and support the importance of systematic virological surveillance.

To determine the most relevant pathogens for CAP in Germany, patients with radiologically confirmed pulmonary infiltrates and at least one clinical sign of lung infection were prospectively recruited within the CAPNETZ cohort from 2004 until 2016. In 990 out of 4.672 patients (21%) receiving complete diagnostics the most prominent change of pathogens was a decrease of S. pneumoniae (58% in 2004 to 37.5% in 2016; p ≤ 0.001, ρ = − 0.148) and an increase of H. influenzae (12.2% to 20.8%; p = 0.001, ρ = 0.104).

Background: Neonatal sepsis is a global health problem that mainly affects low- and middle-income countries. We have previously shown that early neonatal mortality is high at the Ho Teaching Hospital (HTH) of Ghana. We sought to determine the prevalence of neonatal sepsis, sepsis-related mortality, and bacterial species patterns in neonatal and young infant sepsis in this hospital. Methods: A hospital-based study was conducted in the hospital’s neonatal intensive care unit (NICU) from March to June 2018. Blood samples from 96 babies clinically diagnosed with or at risk of sepsis were cultured using the BACTEC 9050® machine. Clinical data including gravida, parity and antibiotic medication before delivery of mother and delivery type, gestation, birth weight and antibiotic medication status were collected for analysis. MALDI-TOF MS identified bacterial isolates, and their identities were confirmed via tuf gene sequence typing. The data were analyzed using GraphPad Prism 8.0.2. Results: Blood cultures were positive in 28 of the babies, with 14 and 12 representing early-onset and late-onset neonatal sepsis, respectively, and two cases of unknown sepsis type. Of the bacterial species that caused sepsis in the babies, coagulase-negative staphylococcus (CoNS) was the most prevalent isolate in 22 cases, followed by Klebsiella pneumoniae in two and Staphylococcus aureus, Streptococcus agalactiae, the Acinetobacter species, and Escherichia coli in the rest (one each). Of the CoNS, S. haemolyticus and S. epidermidis were the most prevalent species, found in eight and six cases, respectively. Thirteen neonates died, of whom seven had positive blood cultures, and two were referred. A case fatality rate of 7/26 was estimated. Neonatal mortality caused by Gram-negative bacterial infection was higher than that caused by Gram-positive bacteria. Conclusions: These data suggest a significant burden of sepsis among neonates and young infants and are associated with substantial morbidity and mortality at the HTH. There is a need to investigate risk factors associated with the increased sepsis rate in this hospital to inform measures to reduce the neonatal sepsis rate.

ObjectivesTo analyse the rectal carriage rate and the molecular epidemiology of vancomycin-resistant Enterococcus faecium (VREfm) recovered from patients upon hospital admission.MethodsAdult patients were screened at six German university hospitals from five different federal states upon hospital admission for rectal colonization with VREfm between 2014 and 2018. Molecular characterization of VREfm was performed by WGS followed by MLST and core-genome MLST analysis.ResultsOf 16350 patients recruited, 263 were colonized with VREfm, with increasing prevalence rates during the 5 year study period (from 0.8% to 2.6%). In total, 78.5% of the VREfm were vanB positive and 20.2% vanA positive, while 1.2% harboured both vanA and vanB. The predominant ST was ST117 (56.7%) followed by ST80 (15%), ST203 (10.9%), ST78 (5.7%) and ST17 (3.2%). ST117/vanB VREfm isolates formed a large cluster of 96 closely related isolates extending across all six study centres and four smaller clusters comprising 13, 5, 4 and 3 isolates each. In contrast, among the other STs inter-regional clonal relatedness was rarely observed.ConclusionsTo our knowledge, this is the largest admission prevalence and molecular epidemiology study of VREfm. These data provide insight into the epidemiology of VREfm at six German university hospitals and demonstrate the remarkable inter-regional clonal expansion of the ST117/vanB VREfm clone.

Purpose The Choosing Wisely® initiative is an international campaign addressing over- and underuse of diagnostic and therapeutic measures in infectious diseases among others. Since 2016, the German Society for Infectious Diseases (DGI) has constantly designed new items in this regard. Here we report the most recent recommendations. Methods The recommendations of the DGI are part of the “Klug entscheiden” initiative of the German Society of Internal Medicine (DGIM). Topics for the new items were suggested by members of the DGI, checked for scientific evidence and consented within the DGI and the DGIM before publication. Results The new recommendations are: (1) individuals with immune-suppression, advanced liver cirrhosis or renal insufficiency should receive a dual pneumococcal vaccination. (2) In case of positive blood cultures with Candida spp. thorough diagnostics and treatment should be initiated. (3) In case of suspected meningitis, adult patients should receive dexamethasone and antibiotics immediately after venipuncture for blood cultures and before potential imaging. (4) In case of suspected meningitis a CT scan before lumbar puncture should not be ordered—except for symptoms indicating high CSF pressure or focal brain pathology or in cases of severe immune-suppression. (5) In patients with suspected severe infections, a minimum of two pairs of blood cultures should be drawn using separate venipunctures prior to antibiotic therapy—regardless of body temperature. There is no need of a minimum time interval in between the blood draws. Conclusion Applying these new Choosing Wisely® recommendations will increase patient safety and the value of health care.

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.

Zusammenfassung Epidemiologische Daten zur Erregerverteilung stellen bei respiratorischen Infektionen noch immer die Grundlage für empirische Therapieempfehlungen dar. Durch rasante technologische Entwicklungen im Bereich der Multiplex- und Sequenzierverfahren erweitert sich zunehmend das Spektrum potenziell relevanter Erreger und stellt bisherige Dogmen zur Virulenz und Pathogenität einzelner Erreger auf die Probe. Dabei behalten klassische pathogene Erreger der Lunge ihre Bedeutung, werden jedoch zunehmend in einen Kontext gesetzt, der virale Koinfektionen und Veränderungen des lokalen Mikrobioms berücksichtigt. Neuere Daten legen nahe, dass es erst durch die Integration dieser Informationen möglich sein wird, saisonale Unterschiede in der Häufigkeit bestimmter Lungeninfektionen zu erklären und neue Ansätze zur Stratifizierung von Risikopatienten zu finden. Dies wird besonders offensichtlich bei immunsupprimierten Patienten, bei denen Infektionen mit Viren und fakultativ pathogenen Erregern wie nichttuberkulösen Mykobakterien (NTM) zu schweren Krankheitsverläufen mit hoher Morbidität und Letalität führen können. Auf der Basis grundlegender Kenntnisse zum Erregerspektrum von ambulant und nosokomial erworbenen Pneumonien werden neue Ansätze in der Erregerdiagnostik und der Analytik des Lungenmikrobioms diskutiert und hinsichtlich der aktuellen Anwendbarkeit im Alltag hinterfragt.

Background Intravascular catheters are essential for care in Neonatal Intensive Care Units (NICUs) but predispose infants to catheter-associated infections including late-onset sepsis, commonly caused by CoNS. Antiseptics are applied to prevent infection with chlorhexidine (CHG) and octenidine (OCT) the most common agents used. Objectives To investigate the association between antiseptic use and bacterial susceptibility. Methods CoNS isolates were collected from two NICUs with differing antiseptic regimens: Norwich, UK (using CHG) and Lubeck, Germany (using OCT). CoNS were isolated from different body sites of babies upon admission, and weekly thereafter. Antiseptic susceptibility testing was performed, and a selection underwent genome sequencing. Results A total of 1274 isolates were collected. UK isolates (n = 863) were significantly less susceptible than German isolates (n = 411) to both CHG (mean MIC: 20.1 mg/L versus 8.9 mg/L) and OCT (mean MIC: 2.3 mg/L versus 1.6 mg/L). UK isolates taken on admission were more susceptible to CHG than subsequent isolates. No cross-resistance between the agents was seen. Genome sequencing of 122 CoNS showed the most common species to be Staphylococcus epidermidis and Staphylococcus haemolyticus and phylogenetic analysis suggested antiseptic tolerance evolved multiple times in independent lineages. There was no evidence of dominant antiseptic tolerant clones and carriage of genes previously implicated in antimicrobial susceptibility (qac, smr, norA/B), did not correlate with CHG or OCT susceptibility. Conclusions Long-term CHG use may select for CHG and OCT tolerance in CoNS. This highlights the different potential for separate antiseptic regimens to select for resistance development. This could be an important factor in developing future infection control policies.

Urogenital infections with Chlamydia trachomatis (C. trachomatis) are the most common bacterial sexually transmitted diseases worldwide. As an obligate intracellular bacterium, chlamydial replication and pathogenesis depends on the host metabolic activity. First-line antimicrobials such as doxycycline (DOX) and azithromycin (AZM) have been recommended for the treatment of C. trachomatis infection. However, accumulating evidence suggests that treatment with AZM causes higher rates of treatment failure than DOX. Here, we show that an inferior efficacy of AZM compared to DOX is associated with the metabolic status of host cells. Chlamydial metabolism and infectious progeny of C. trachomatis were suppressed by therapeutic relevant serum concentrations of DOX or AZM. However, treatment with AZM could not suppress host cell metabolic pathways, such as glycolysis and mitochondrial oxidative phosphorylation, which are manipulated by C. trachomatis. The host cell metabolic activity was associated with a significant reactivation of C. trachomatis after removal of AZM treatment, but not after DOX treatment. Furthermore, AZM insufficiently attenuated interleukin (IL)-8 expression upon C. trachomatis infection and higher concentrations of AZM above therapeutic serum concentration were required for effective suppression of IL-8. Our data highlight that AZM is not as efficient as DOX to revert host metabolism in C. trachomatis infection. Furthermore, insufficient treatment with AZM failed to inhibit chlamydial reactivation as well as C. trachomatis induced cytokine responses. Its functional relevance and the impact on disease progression have to be further elucidated in vivo.

The etiopathogenesis of chronic otitis media epitympanalis/cholesteatoma and its proliferative destructive course with possible complications such as destruction of bony structures with hearing loss, vestibular dysfunction, facial nerve paralysis and intracranial complications are still unexplained. Surgery is still the way to go. New studies are increasingly looking at the innate immune system.Our studies were carried out in a mouse model in WT mice and immundeficient KO-mice, as well as in cholesteatoma and healthy ear canal skin and middle ear tissue, which was removed during ear surgery. The expression analyses were carried out at the gene and protein level using TNF as the major target for therapy evaluation. By means of TUNEL staining and immunohistochemistry the level of apoptosis was evaluated.The uncontrolled undirected cholesteatoma growth shows an immunomodulatory profile with up and down-regulation of various gene networks, especially those involved in TNF downstream and upstream signaling pathways. TNF in cholesteatoma is modulated both inflammatorily and apoptotically and therefore is suitable as a possible therapeutic approach in various models.Cholesteatoma might be immunomodulatory regulated.Die Ätiopathogenese der chronischen Otitis media epitympanalis bzw. des Cholesteatoms und ihr proliferierender destruierender Verlauf mit möglichen Komplikationen wie Destruktion der knöchernen Strukturen mit Hörverlust, vestibulärer Dysfunktion, Gesichtsnervenlähmung und intrakraniellen Komplikationen sind immer noch ungeklärt. Die Therapie der Wahl ist nach wie vor die operative Sanierung. Aktuelle Studien befassen sich immer mehr mit dem angeborenen Immunsystem.Unsere Untersuchungen erfolgten im Mausmodell an WT-Mäusen und immundefizienten KO-Mäusen sowie an Gewebeproben vom Cholesteatom, gesunder Gehörgangshaut und gesunder Mittelohrschleimhaut, die während sanierenden Ohroperationen entnommen wurden. Die Expressionsanalysen erfolgten auf Gen- und Proteinebene mit TNF als Major Target zur Therapieevaluation. Mittels TUNEL-Färbung und Immunhistochemie an Kryoschnitten wurde die Apoptose-Rate durch TNF bestimmt.Das ungerichtet-expansive Cholesteatomwachstum zeigt ein immunmodulatorisches Profil mit Hoch- und Runterregulation von verschiedenen Gen-Netzwerken, vor allem Molekülen der TNF-Down- und -Upstream-Signalwege. Dabei wird TNF sowohl inflammatorisch als auch apoptotisch moduliert und eignet sich als möglicher Therapieansatz in verschiedenen Modellen.Es gibt Hinweise auf eine immunmodulatorische Regulation im Cholesteatom.

Urinary tract infections (UTIs) are frequent in humans, affecting the upper and lower urinary tract. Present diagnosis relies on the positive culture of uropathogenic bacteria from urine and clinical markers of inflammation of the urinary tract. The bladder is constantly challenged by adverse environmental stimuli which influence urinary tract physiology, contributing to a dysbiotic environment. Simultaneously, pathogens are primed by environmental stressors such as antibiotics, favoring recurrent UTIs (rUTIs), resulting in chronic illness. Due to different confounders for UTI onset, a greater understanding of the fundamental environmental mechanisms and microbial ecology of the human urinary tract is required. Such advancements could promote the tandem translation of bench and computational studies for precision treatments and clinical management of UTIs. Therefore, there is an urgent need to understand the ecological interactions of the human urogenital microbial communities which precede rUTIs. This review aims to outline the mechanistic aspects of rUTI ecology underlying dysbiosis between both the human microbiome and host physiology which predisposes humans to rUTIs. By assessing the applications of next generation and systems level methods, we also recommend novel approaches to elucidate the systemic consequences of rUTIs which requires an integrated approach for successful treatment. To this end, we will provide an outlook towards the so-called ‘uncomplicated environment of UTIs’, a holistic and systems view that applies ecological principles to define patient-specific UTIs. This perspective illustrates the need to withdraw from traditional reductionist perspectives in infection biology and instead, a move towards a systems-view revolving around patient-specific pathophysiology during UTIs.

OBJECTIVE: To perform a nationwide inventory of diagnostic mycobacteriology services in Germany.METHOD: A survey was conducted among participants of the national mycobacteriology external quality assurance scheme asking for smear microscopy techniques, molecular assays, culture systems and drug susceptibility testing (DST) capacities for Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM), and numbers of processed/culture-positive samples, and DSTs performed in 2016.RESULTS: We found that 170/238 laboratories (71.4%) provided data. Numbers of samples processed for culture varied between 35 and 40 000 (median 1856, interquartile range [IQR] 761-3500). Specimen numbers culture-positive for MTBC or NTM ranged from 0 to 1895 (median 46, IQR 17-116), and from 0 to 833 (median 30, IQR 13-71), respectively. Numbers of performed first-line susceptibility tests varied between 3 and 1400 (median 36, IQR 28-78). Eight laboratories performed DST for NTM. Also, 26.9% of all laboratories did not offer rapid genotypic DST (gDST) from primary samples.CONCLUSION: The landscape of diagnostic mycobacteriology in Germany is highly heterogenic with considerable variations in sample numbers and testing methodologies. Shortcomings exist with respect to fluorochrome staining of primary samples, rapid gDST of MTBC, and DST of NTM. National guidelines need to be adapted accordingly.

COPD patients have an increased susceptibility to bacterial airway infections that can induce exacerbations. In response to infections, circulating monocytes become recruited to the infected tissue and secrete cytokines. We hypothesized that this cytokine response is reduced in COPD. Cultured peripheral blood monocytes of never smokers (NS) and smokers without (S) and with COPD (3 study populations, n = 36-37) were stimulated with extracts of Haemophilus influenzae, Staphylococcus aureus, or Streptococcus pneumoniae or with four different pathogen-associated molecular patterns (PAMPs). Four cytokines and 9 PAMP-related signaling molecules were measured and compared between the groups. Granulocyte-macrophage-colony-stimulating-factor responses to all stimulants were reduced in S and COPD compared to NS. Tumor-necrosis-factor-α responses to all bacterial extracts, peptidoglycan, and lipopolysaccharide were reduced in S and/or COPD. Interleukin-10 responses to S. aureus and lipoteichoic acid were increased in COPD. Correlations to pack-years and lung function were found. The peptidoglycan-receptor NOD2 and the mRNA of the lipopolysaccharide-receptor TLR4 were reduced in S and COPD. Cytokine responses of monocytes to bacteria are suppressed by smoking and in COPD possibly due to NOD2 and TLR4 reduction and/or interleukin-10 increase. This might help to explain the increased susceptibility to bacterial infections. These systemic molecular pathologies might be targets for therapeutic strategies to prevent infection-induced exacerbations. KEY MESSAGES: COPD subjects have an increased susceptibility to bacterial infections. This implies defects in the immune response to bacteria and is critical for disease progression. The cytokine response of monocytes to bacteria is reduced in COPD. This might be due to a reduced NOD2 and TLR4 and an increased IL-10 expression. This can explain the increased susceptibility to infections and help to identify drug targets.

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.

BackgroundMore than one year into the COVID-19 pandemic, important data gaps remain on longitudinal prevalence of SARS-CoV-2 infection at the population level and in defined risk groups, efficacy of specific lockdown measures, and on (cost-)effective surveillance.MethodsThe ELISA (LübeckLongitudinalInvestigation ofSARS-CoV-2 Infection) study invited adult inhabitants (n=∼300,000) from the Lübeck area (Northern Germany) and enrolled 3051 participants (∼1%); 1929 population-matched and 1645 with high-exposure based on profession. The one-year study period (03/2020-02/2021) spanned massive influx of tourism in the summer, rise of infection rates in the fall/winter 2020/2021, and two lockdowns. Participants were screened seven times for SARS-CoV-2 infection using PCR and antibody testing and monitored with an app-based questionnaire (n=∼91,000).ResultsCohort (56% female; mean age: 45.6 years) retention was 75%-98%; 89 persons (3.5%) were antibody- and/or PCR-positive. Seropositivity was almost 2-fold higher in men and increased risk detected in several high-exposure groups (highest for nurses, followed by police, army, firemen, and students). In May 2020, 92% of the infections were missed by PCR testing; by February 2021, only 29% remained undiagnosed. “Contact to COVID-19-affected” was the most relevant risk factor. Other factors, such as frequent use of public transportation, shopping, close contacts at work, and extensive tourism in the summer did not impact infection rates.ConclusionsWe i) provide a model for effective, regional surveillance; ii) identify infection risk factors informing public health measures; iii) demonstrate that easing of lockdown measures appears safe at times of low prevalence in the presence of continuous monitoring.

ObjectiveTo provide epidemiological data of infants < 90 days of age with suspected late-onset sepsis (LOS) and evaluate distinct immunological specificities. We hypothesized that previously healthy infants < 3 months of age with sepsis have a yet undefined immunological predisposition; e.g. differences in lymphocyte subsets including regulatory T cells.MethodsWe performed an exploratory, single center study between January 1st, 2019 and June 1st, 2021. Routine diagnostics included conventional culture (blood, cerebrospinal fluid, urine), PCR and inflammatory markers in infants < 90 days of age with suspected sepsis. We additionally analyzed lymphocyte subsets and CD4+ CD25+ forkhead box protein (FoxP3)+ Tregs at admission for sepsis workup as compared to age-matched controls.ResultsA convenience sample cohort of n= 51 infants with sepsis workup was enrolled. Invasive bacterial infection (IBI) was diagnosed in 25 (49.0%) patients including two infants with a rhinovirus co-infection and viral infection in 14 (27.5%) neonates. No infectious cause was found in 12 cases. Infants with suspected LOS displayed a decreased abundance of CD4+ FoxP3+ T cells as compared to controls, which was most pronounced in the subgroup of infants with IBI. We also noticed elevated HLA-DR-positive CD3+ cells in infants with LOS and a higher CD4/CD8-ratio in infants with viral infection as compared to healthy controls. Infants with viral infections had a higher number of natural killer cells as compared to infants with IBI.ConclusionOur exploratory data support the concept of a potential immaturity state and failed immune tolerance development for young infants with LOS. Future large-scale studies are needed to elucidate pre-sepsis conditions and to target the microbiome-immunity interplay as a potential risk pattern.

Coronavirus disease 2019 (COVID-19) is a viral infection affecting multiple organ systems of great significance for metabolic processes. Thus. there is increasing interest in metabolic and lipoprotein signatures of the disease and early analyses have demonstrated metabolic pattern typical for atherosclerotic and hepatic damage in COVID-19 patients. However, it remains unclear whether these are specific for COVID-19 or a general marker of critical illness. To answer this question, we have analyzed 276 serum samples from 92 individuals using NMR metabolomics, including longitudinally collected samples from 5 COVID-19 and 11 cardiogenic shock intensive care patients, 18 SARS-CoV-2 antibody-positive individuals, and 58 healthy controls.COVID-19 patients showed a distinct metabolic serum profile, including changes typical for severe dyslipidemia and a deeply altered metabolic status compared to healthy controls. Specifically, VLDL parameters, IDL particles, large-sized LDL particles, and the ApoB100/ApoA1 ratio were significantly increased, whereas HDL fractions were decreased. Moreover, a similarly perturbed profile was apparent, even when compared to other ICU patients suffering from cardiogenic shock, highlighting the impact of COVID-19 especially on lipid metabolism and energy status. COVID-19 patients were separated with an AUROC of 1.0 when compared to both healthy controls and cardiogenic shock patients. Anti-SARS-CoV-2 antibody-positive individuals without acute COVID-19 did not show a significantly perturbed metabolic profile compared to age- and sex-matched healthy controls, but SARS-CoV-2 antibody-titers correlated significantly with metabolic parameters, including levels of glycine, ApoA2, and small-sized LDL and HDL subfractions. Our data suggest that NMR metabolic profiles are suitable for COVID-19 patient stratification and post-treatment monitoring.

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.

Background Asymptomatic C. difficile colonization is believed to predispose to subsequent C. difficile infection (CDI). While emerging insights into the role of the commensal microbiota in mediating colonization resistance against C. difficile have associated CDI with specific microbial components, corresponding prospectively collected data on colonization with C. difficile are largely unavailable. Methods C. difficile status was assessed by GDH EIA and real-time PCR targeting the toxin A (tcdA) and B (tcdB) genes. 16S V3 and V4 gene sequencing results from fecal samples of patients tested positive for C. difficile were analyzed by assessing alpha and beta diversity, LefSe, and the Piphillin functional inference approach to estimate functional capacity. Results 1506 patients were recruited into a prospective observational study (DRKS00005335) upon admission into one of five academic hospitals. 936 of them provided fecal samples on admission and at discharge and were thus available for longitudinal analysis. Upon hospital admission, 5.5% (83/1506) and 3.7% (56/1506) of patients were colonized with toxigenic (TCD) and non-toxigenic C. difficile (NTCD), respectively. During hospitalization, 1.7% (16/936) acquired TCD. Risk factors for acquisition of TCD included pre-existing lung diseases, lower GI endoscopy and antibiotics. Species protecting against hospital-related C. difficile acquisition included Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococcus spp. Metagenomic pathway analysis identified steroid biosynthesis as the most underrepresented metabolic pathway in patients who later acquire C. difficile colonization. Conclusions Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococci were associated with a decreased risk of C. difficile acquisition. Clinical Trials Registration DRKS00005335.

Background Corona virus disease 2019 (COVID‐19) patients are at increased risk for thromboembolic events. It is unclear whether the risk for gastrointestinal (GI) bleeding is also increased. Methods We considered 4128 COVID‐19 patients enrolled in the Lean European Open Survey on SARS‐CoV‐2 (LEOSS) registry. The association between occurrence of GI bleeding and comorbidities as well as medication were examined. In addition, 1216 patients from COKA registry were analyzed focusing on endoscopy diagnostic findings. Results A cumulative number of 97 patients (1.8%) with GI bleeding were identified in the LEOSS registry and COKA registry. Of 4128 patients from the LEOSS registry, 66 patients (1.6%) had a GI bleeding. The rate of GI bleeding in patients with intensive care unit (ICU) admission was 4.5%. The use of therapeutic dose of anticoagulants showed a significant association with the increased incidence of bleeding in the critical phase of disease. The Charlson comorbidity index and the COVID‐19 severity index were significantly higher in the group of patients with GI bleeding than in the group of patients without GI bleeding (5.83 (SD = 2.93) vs. 3.66 (SD = 3.06), p

Background: Aspiration community-acquired pneumonia (ACAP) and community-acquired pneumonia (CAP) in patients with aspiration risk factors (AspRFs) are infections associated with anaerobes, but limited evidence suggests their pathogenic role. Research Question: What are the aspiration risk factors, microbiology patterns, and empiric anti-anaerobic use in patients hospitalized with CAP? Study Design and Methods: This is a secondary analysis of GLIMP, an international, multicenter, point-prevalence study of adults hospitalized with CAP. Patients were stratified into three groups: (1) ACAP, (2) CAP/AspRF+ (CAP with AspRF), and (3) CAP/AspRF- (CAP without AspRF). Data on demographics, comorbidities, microbiological results, and anti-anaerobic antibiotics were analyzed in all groups. Patients were further stratified in severe and nonsevere CAP groups. Results: We enrolled 2,606 patients with CAP, of which 193 (7.4%) had ACAP. Risk factors independently associated with ACAP were male, bedridden, underweight, a nursing home resident, and having a history of stroke, dementia, mental illness, and enteral tube feeding. Among non-ACAP patients, 1,709 (70.8%) had CAP/AspRF+ and 704 (29.2%) had CAP/AspRF-. Microbiology patterns including anaerobes were similar between CAP/AspRF-, CAP/AspRF+ and ACAP (0.0% vs 1.03% vs 1.64%). Patients with severe ACAP had higher rates of total gram-negative bacteria (64.3% vs 44.3% vs 33.3%, P =.021) and lower rates of total gram-positive bacteria (7.1% vs 38.1% vs 50.0%, P 50% in all groups) independent of AspRFs or ACAP received specific or broad-spectrum anti-anaerobic coverage antibiotics. Interpretation: Hospitalized patients with ACAP or CAP/AspRF+ had similar anaerobic flora compared with patients without aspiration risk factors. Gram-negative bacteria were more prevalent in patients with severe ACAP. Despite having similar microbiological flora between groups, a large proportion of CAP patients received anti-anaerobic antibiotic coverage.

Background & Aims After birth, the immune system matures via interactions with microbes in the gut. The S100 calcium binding proteins S100A8 and S100A9, and their extracellular complex form, S100A8–A9, are found in high amounts in human breast milk. We studied levels of S100A8–A9 in fecal samples (also called fecal calprotectin) from newborns and during infancy, and their effects on development of the intestinal microbiota and mucosal immune system. Methods We collected stool samples (n = 517) from full-term (n = 72) and preterm infants (n = 49) at different timepoints over the first year of life (days 1, 3, 10, 30, 90, 180, and 360). We measured levels of S100A8–A9 by enzyme-linked immunosorbent assay and analyzed fecal microbiomes by 16S sRNA gene sequencing. We also obtained small and large intestine biopsies from 8 adults and 10 newborn infants without inflammatory bowel diseases (controls) and 8 infants with necrotizing enterocolitis and measured levels of S100A8 by immunofluorescence microscopy. Children were followed for 2.5 years and anthropometric data and medical information on infections were collected. We performed studies with newborn C57BL/6J wild-type and S100a9–/– mice (which also lack S100A8). Some mice were fed or given intraperitoneal injections of S100A8 or subcutaneous injections of Staphylococcus aureus. Blood and intestine, mesenterial and celiac lymph nodes were collected; cells and cytokines were measured by flow cytometry and studied in cell culture assays. Colon contents from mice were analyzed by culture-based microbiology assays. Results Loss of S100A8 and S100A9 in mice altered the phenotypes of colonic lamina propria macrophages, compared with wild-type mice. Intestinal tissues from neonatal S100-knockout mice had reduced levels of CX3CR1 protein, and Il10 and Tgfb1 mRNAs, compared with wild-type mice, and fewer T-regulatory cells. S100-knockout mice weighed 21% more than wild-type mice at age 8 weeks and a higher proportion developed fatal sepsis during the neonatal period. S100-knockout mice had alterations in their fecal microbiomes, with higher abundance of Enterobacteriaceae. Feeding mice S100 at birth prevented the expansion of Enterobacteriaceae, increased numbers of T-regulatory cells and levels of CX3CR1 protein and Il10 mRNA in intestine tissues, and reduced body weight and death from neonatal sepsis. Fecal samples from term infants, but not preterm infants, had significantly higher levels of S100A8–A9 during the first 3 months of life than fecal samples from adults; levels decreased to adult levels after weaning. Fecal samples from infants born by cesarean delivery had lower levels of S100A8–A9 than from infants born by vaginal delivery. S100 proteins were expressed by lamina propria macrophages in intestinal tissues from infants, at higher levels than in intestinal tissues from adults. High fecal levels of S100 proteins, from 30 days to 1 year of age, were associated with higher abundance of Actinobacteria and Bifidobacteriaceae, and lower abundance of Gammaproteobacteria—particularly opportunistic Enterobacteriaceae. A low level of S100 proteins in infants' fecal samples associated with development of sepsis and obesity by age 2 years. Conclusion S100A8 and S100A9 regulate development of the intestinal microbiota and immune system in neonates. Nutritional supplementation with these proteins might aide in development of preterm infants and prevent microbiota-associated disorders in later years.

Purpose Thorough knowledge of the nature and frequency of co-infections is essential to optimize treatment strategies and risk assessment in cases of coronavirus disease 2019 (COVID-19). This study aimed to evaluate the multiplex polymerase chain reaction (PCR) screening approach for community-acquired bacterial pathogens (CABPs) at hospital admission, which could facilitate identification of bacterial co-infections in hospitalized COVID-19 patients. Methods Clinical data and biomaterials from 200 hospitalized COVID-19 patients from the observational cohort of the Competence Network for community-acquired pneumonia (CAPNETZ) prospectively recruited between March 17, 2020, and March 12, 2021 in 12 centers in Germany and Switzerland, were included in this study. Nasopharyngeal swab samples were analyzed on hospital admission using multiplex real-time reverse transcription (RT)-PCR for a broad range of CABPs. Results In total of 200 patients Staphylococcus aureus (27.0%), Haemophilus influenzae (13.5%), Streptococcus pneumoniae (5.5%), Moraxella catarrhalis (2.5%), and Legionella pneumophila (1.5%) were the most frequently detected bacterial pathogens. PCR detection of bacterial pathogens correlated with purulent sputum, and showed no correlation with ICU admission, mortality, and inflammation markers. Although patients who received antimicrobial treatment were more often admitted to the ICU and had a higher mortality rate, PCR pathogen detection was not significantly related to antimicrobial treatment. Conclusion General CABP screening using multiplex PCR with nasopharyngeal swabs may not facilitate prediction or identification of bacterial co-infections in the early phase of COVID-19-related hospitalization. Most patients with positive PCR results appear to be colonized rather than infected at that time, questioning the value of routine antibiotic treatment on admission in COVID-19 patients.

The coronavirus disease 2019 (COVID-19) pandemic comprises approximately 50 million confirmed cases and over 1.2 million deaths as of November 10, 2020 [1], affecting health care systems worldwide in an unprecedented way. In the absence of effective treatments or preventive measures, all attempts to control the pandemic are based on reliable diagnostic procedures, particularly RT-PCR of upper respiratory specimens, which is considered the diagnostic gold standard [2]. A previously unimaginable number of these diagnostic procedures has been performed since the beginning of the pandemic and there is a clear trend towards further expanding the number of tests [3]. Although specimens are frequently obtained by semi-skilled temporary staff, the collection is generally considered safe. However, possible adverse events (AEs) of the procedure have largely escaped systematic recording and reporting to date. A Pubmed search, performed on October 10, 2020, using every possible combination of the search terms “complications”, “adverse events”, “adverse effects” and “nasal swab”, “oral swab”, “nasopharyngeal swab”, “oropharyngeal swab”, revealed only three publications relevant for the question of AEs caused by pharyngeal swab procedures. The first one represents a case report describing the break of a nasal swab by triggering the swab's breakpoint mechanism during the examination of an uncooperative patient [4]. The second publication compared commercially available swabs with three-dimensional printed nasopharyngeal swabs, reporting different mild complications in several individuals, and one individual with severe epistaxis needing medical help [5]. Lastly, one case of cerebrospinal fluid leak requiring endoscopic surgical repair was reported after a nasal COVID-19 test [6]. Of note, even the second study investigated AEs in only 176 individuals [5]., Although swab procedures during SARS-CoV-2 testing are generally safe (3 adverse events in 11 476 swab procedures; 0.026%), increased awareness of complications is necessary, considering approximately 5.1 million tests conducted worldwide daily.

The reason for the apparently lower infection rate of children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to adults is still unclear. Here, we report on 4 schoolchildren with heavy exposure to SARS-CoV-2 with no clinical signs of coronavirus disease 2019, repeated negative nasopharyngeal swabs for SARS-CoV-2 RNA, and no seroconversion.

Background In 2013 German infection surveillance guidelines recommended weekly colonization screening for multidrug-resistant (MDRO) or highly epidemic organisms for neonatal intensive care units (NICUs) and extended hygiene measures based on screening results. It remains a matter of debate whether screening is worth the effort. We therefore aimed to evaluate sepsis related outcomes before and after the guideline update. Methods The German Neonatal Network (GNN) is a prospective cohort study including data from extremely preterm infants between 22 + 0 and 28 + 6 gestational weeks born in 62 German level III NICUs. Results Infants treated after guideline update (n = 8.903) had a lower mortality (12.5% vs. 13.8%, p = 0.036), reduced rates for clinical sepsis (31.4 vs. 42.8%, p p = 0.003) as compared to infants treated before update (n = 3.920). In a multivariate logistic regression analysis, nine pathogens of culture-proven sepsis were associated with sepsis-related death, e.g. Pseudomonas aeruginosa [OR 59 (19–180), p p p Conclusions The introduction of weekly screening and extended hygiene measures is associated with reduced sepsis rates, but has no effects on sepsis-related mortality and sepsis with screening-relevant pathogens. The high exposure rate to meropenem should be a target of antibiotic stewardship programs.

Objective: To evaluate the nutrition-related effects of prophylactic Lactobacillus acidophilus/Bifidobacterium infantis probiotics on the outcomes of preterm infants &lt, 29 weeks of gestation that receive human milk and/or formula nutrition. We hypothesize that human-milk-fed infants benefit from probiotics in terms of sepsis prevention and growth. Methods: We performed an observational study of the German Neonatal Network (GNN) over a period of six years, between 1 January, 2013 and 31 December, 2018. Prophylactic probiotic use of L. acidophilus/B. infantis was evaluated in preterm infants &lt, 29 weeks of gestation (n = 7516) in subgroups stratified to feeding type: (I) Exclusively human milk (HM) of own mother and/or donors (HM group, n = 1568), (II) HM of own mother and/or donor and formula (Mix group, n = 5221), and (III) exclusive exposure to formula (F group, n = 727). The effect of probiotics on general outcomes and growth was tested in univariate models and adjusted in linear/logistic regression models. Results: 5954 (76.5%) infants received L. acidophilus/B. infantis prophylactically for the prevention of necrotizing enterocolitis (NEC). Probiotic use was associated with improved growth measures in the HM group (e.g., weight gain velocity in g/day: effect size B = 0.224, 95% CI: 2.82&ndash, 4.35, p &lt, 0.001) but not in the F group (effect size B = &minus, 0.06, 95% CI: &minus, 3.05&ndash, 0.28, p = 0.103). The HM group had the lowest incidence of clinical sepsis (34.0%) as compared to the Mix group (35.5%) and the F group (40.0%). Only in the Mix group, probiotic supplementation proved to be protective against clinical sepsis (OR 0.69, 95% CI: 0.59&ndash, 0.79, 0.001). Conclusion: Our observational data indicate that the exposure to L. acidophilus/B. infantis probiotics may promote growth in exclusively HM-fed infants as compared to formula-fed infants. To exert a sepsis-preventive effect, probiotics seem to require human milk.

Background Febrile neutropenia is a common and serious complication during treatment of childhood cancer. Empirical broad-spectrum antibiotics are usually administered until neutrophil cell count recovery. It was the aim of this study to investigate cytokine profiles as potential biomarkers using in-vitro sepsis models to differentiate between distinct clinical courses of febrile neutropenia (FN). Methods We conducted an observational study in FN episodes of pediatric oncology patients. Courses of neutropenia were defined as severe in case of proven blood stream infection or clinical evidence of complicated infection. We collected blood samples at various time points from the onset of FN and stimulated ex vivo with lipopolysaccharide (LPS) and Staphylococcus epidermidis (SE) for 24 h. Twenty-seven cytokine levels were measured in the whole blood culture supernatants by a multiplex immunoassay system. Results Forty-seven FN episodes from 33 children were investigated. IL-8, IL-1β, and MCP-1 expression increased significantly over time. IL-8, MIP-1α, MIP-1β, MCP-1, and TNF-α showed significantly lower concentration in patients with a clinically severe course of the FN. Conclusions Distinct patterns of cytokine profiles seem to be able to determine infectious FN and to predict the severity of its clinical course. If these data can be verified in a multi-centre setting, this may finally lead to an individualized treatment strategy facilitating antibiotic stewardship in these patients.

We read with great interest the article by Fernandez and colleagues1 which identifies bacterial infections, including pneumonia, not only as a trigger, but also as a common complication of acute-on-chronic liver failure with severe consequences. Moreover, in this and other studies the role of respiratory infections and failure has been shown to be detrimental in patients with chronic liver disease (CLD).2–4 While it is well established that respiratory infections aggravate the clinical outcome and increase mortality in CLD, there are little to no data from large cohorts analysing the role of CLD in patients with community-acquired pneumonia (CAP). This prompted us to analyse the impact of CLD on the severity of CAP using data from the German Competence Network for Community-acquired pneumonia (CAPNETZ) study, a large multicentre study on CAP conducted between 2001 and 2017.5 6 The CAPNETZ study included a total of 11 832 patients with episodes of CAP, of whom 5449 hospitalised patients had information available on the presence or absence of CLD. In this cohort, 289 patients with CAP (5.3%; online supplementary figure S1) were identified with CLD. CAP patients with CLD were significantly younger than those without; their median age (IQR) was 64 years (50–73) vs 73 years (64–80) (p

The diagnostic proof of fungal infection in preterm infants is difficult. Antifungal treatment (AFT) is often initiated empirically when infants with suspected infection do not improve despite broad-spectrum antibiotic therapy. It was the aim of our study to determine the rate of exposure to empirical AFT in a large cohort of very low birth weight infants (VLBWI) of the German Neonatal Network and to address associated risks and outcomes.The epidemiologic database consisted of n = 13,343 VLBWI born in 54 German Neonatal Network centers between 2009 and 2015. AFT was defined as number of neonates who got any dose of at least one of the following antifungal drugs: fluconazole, amphotericin B, voriconazole and caspofungin (denominator: number of infants enrolled in German Neonatal Network) for treatment (not prophylaxis) of (suspected) fungal infection. Univariate and logistic regression analyses were used to identify risk factors for exposure to AFT and associated short-term morbidities and long-term outcomes at 5-year follow-up.In our cohort, 724 out of 13,343 (5.4%) VLBWI were exposed to empiric AFT and had a mean gestational age of 25.7 (±2.1) weeks. Forty-four out of 13,343 (0.3%) had proven bloodstream infection with Candida spp. The main risk factors for exposure to AFT were gestational age, postnatal steroid treatment, need for abdominal surgery and use of carbapenems. Notably, AFT was associated with adverse outcomes such as bronchopulmonary dysplasia [adjusted odds ratio (OR): 1.9; 95% confidence interval (CI): 1.6-2.3; P0.001) and retinopathy of prematurity requiring intervention (adjusted OR: 1.69; 95% CI: 1.3-2.3; P0.001) but not mortality. In the subgroup of infants available for 5-year follow-up (n = 895), exposure to AFT was associated with a risk for cerebral palsy (adjusted OR: 2.79; 95% CI: 1.11-7.04; P = 0.04) and intelligence quotient85 (adjusted OR: 2.07; 95% CI: 1.01-4.28; P = 0.049).A significant proportion of VLBWI is exposed to AFT, specifically those born26 weeks. Exposed infants were found to have a higher risk for adverse outcomes, which may reflect their significant vulnerability in general. Given the observational design of our study, it remains unclear whether potential side effects of empirical or target AFT itself contribute to adverse outcome. Future studies need to include risk-based strategies and stewardship programs to restrict the use of antifungal management in VLBWI.

Infections are a major problem in patients with burn diseases. Mortality is high despite antibiotic therapy as studies are controversial concerning drug underdosing. The aims of this prospective, observational study were to monitor plasma concentrations of piperacillin during standard piperacillin/tazobactam treatment in 20 burn patients and 16 controls from the intensive care unit (ICU) and to optimize doses by in silico analyses. Piperacillin/tazobactam (4/0.5 g, tid) was administered over 0.5 h. Blood samples were taken at 1, 4, and 7.5 h after the end of the infusion. Free piperacillin plasma concentrations were determined. Pharmacokinetic parameters and in silico analysis results were calculated using the freeware TDMx. The primary target was defined as percentage of the day (fT>1xMIC; fT>4xMIC) when piperacillin concentrations exceeded 1xMIC/4xMIC (minimum inhibitory concentration), considering a MIC breakpoint of 16 mg/L for Pseudomonas aeruginosa. In an off-label approach, two burn patients were treated with 8/1 g piperacillin/tazobactam, 3 h qid. fT>1xMIC (55 ± 22% vs. 77 ± 24%) and fT>4xMIC (17 ± 11% vs. 30 ± 11%) were lower in burn than in ICU patients after 4/0.5 g, 0.5 h, tid. In silico analyses indicated that fT>1xMIC (93 ± 12% burn, 97 ± 4% ICU) and fT>4xMIC (62 ± 23% burn, 84 ± 19% ICU) values increase by raising the piperacillin dosage to 8/1 g qid and prolonging the infusion time to 3 h. Off-label treatment results were similar to in silico data for burn patients (84%fT>1xMIC and 47%fT>4xMIC). Standard dosage regimens for piperacillin/tazobactam resulted in subtherapeutic piperacillin concentrations in burn and ICU patients. Dose adjustments via in silico analyses can help to optimize antibiotic therapy and to predict respective concentrations in vivo. Trial registration: NCT03335137, registered 07.11.2017, retrospectively.

This study aimed to describe real-life microbiological testing of adults hospitalised with community-acquired pneumonia (CAP) and to assess concordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) and 2011 European Respiratory Society (ERS) CAP guidelines. This was a cohort study based on the Global Initiative for Methicillin-resistant Staphylococcus aureus Pneumonia (GLIMP) database, which contains point-prevalence data on adults hospitalised with CAP across 54 countries during 2015. In total, 3702 patients were included. Testing was performed in 3217 patients, and included blood culture (71.1%), sputum culture (61.8%), Legionella urinary antigen test (30.1%), pneumococcal urinary antigen test (30.0%), viral testing (14.9%), acute-phase serology (8.8%), bronchoalveolar lavage culture (8.4%) and pleural fluid culture (3.2%). A pathogen was detected in 1173 (36.5%) patients. Testing attitudes varied significantly according to geography and disease severity. Testing was concordant with IDSA/ATS and ERS guidelines in 16.7% and 23.9% of patients, respectively. IDSA/ATS concordance was higher in Europe than in North America (21.5% versus 9.8%; p, Testing practices vary based on geography and disease severity, and IDSA/ATS/ERS testing recommendations are rarely followed http://ow.ly/80Iy30lxo1c

Sexually transmitted infections (STIs) are a major health concern with clinical manifestations being acknowledged to cause severe reproductive impairment. Research in infectious diseases has been centered around the known major pathogens for decades. However, we have just begun to understand that the microbiota of the female genital tract is of particular importance for disease initiation, infection progression, and pathological outcome. Thus, we are now aware that many poorly described, partially not yet known, or cultured bacteria may pave the way for an infection and/or contribute to disease severity. While sequencing-based methods are an important step in diagnosing STIs, culture-based methods are still the gold-standard method in diagnostic routine, providing the opportunity to distinguish phenotypic traits of bacteria. However, current diagnostic culture routines suffer from several limitations reducing the content of information about vaginal microbiota. A detailed characterization of microbiota-associated factors is needed to assess the impact of single-bacterial isolates from the vaginal community on vaginal health and the containment of STIs. Here we provide current concepts to enable modern culture routines and create new ideas to improve diagnostic approaches with a conjunct usage of bioinformatics. We aim to enable scientists and physicians alike to overcome long-accepted limitations in culturing bacteria of interest to the human health. Eventually, this may improve the quality of culture-based diagnostics, facilitate a research interface, and lead to a broader understanding of the role of vaginal microbiota in reproductive health and STIs.

Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.

Ziel der Studie Nach Angaben des Robert-Koch-Instituts leben in Deutschland circa 84.700 Menschen mit einer HIV-Infektion. Ein Drittel dieser Menschen sind uber 50 Jahre alt. Die ambulant erworbene Pneumonie (CAP) ist mit mehr als 250 000 Fallen pro Jahr in Deutschland eine Volkserkrankung deren Inzidenz und Mortalitat mit zunehmendem Alter der Betroffenen steigt. Aus diesem Grund sind diagnostische und therapeutische Strategien zur Versorgung von HIV-positiven Patienten mit CAP dringend erforderlich. Methodik Mithilfe eines Fragebogens wurden Arzte in HIV-Schwerpunktpraxen und -ambulanzen zu ihrem diagnostischen und therapeutischen Vorgehen bei HIV-assoziierten ambulant erworbenen Pneumonien (HIV +/CAP) befragt. Es konnten Fragebogen von insgesamt 56 Behandlern ausgewertet werden. Ergebnisse Die Halfte der HIV-Schwerpunktarzte ist der Meinung, dass die CAP mit einem jahrlichen Auftreten bei 1 bis 5 % aller HIV-Patienten in Deutschland (84 700) mit bis zu 4200 Fallen pro Jahr deutlich haufiger ist als bisher angenommen wird. 58,9 % der befragten Arzte sind der Auffassung, dass sich das Erregerspektrum bei HIV +/CAP nicht von non-HIV/CAP unterscheidet. 80,3 % der Befragten verwenden die gleichen antibiotischen Therapieregime, wie sie bei non-HIV/CAP zum Einsatz kommen. Schlussfolgerung Obwohl uber 40 % der HIV-Behandler der Ansicht sind, dass sich das Erregerspektrum bei HIV +/CAP von non-HIV/CAP unterscheidet, behandeln uber 80 % diese Patienten in Ermangelung spezifischer Empfehlungen entsprechend der Therapieempfehlung der S3-Leitlinie fur nicht immunsupprimierte CAP-Patienten. Da spezifische Daten zur Atiologie und zum Verlauf von HIV +/CAP z. B. in Abhangigkeit von CD4-Zellzahl und HIV-Therapie fehlen, sollte der Verlauf von HIV +/CAP im Rahmen von Kohortenstudien weiter untersucht werden.

BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality, and chronic obstructive pulmonary disease (COPD) is a frequent comorbidity. The bacterial aetiology of CAPCOPD and its possible associations with serum markers and mortality are incompletely understood.OBJECTIVES: 1) To assess the bacterial aetiology of CAP only and CAP-COPD, and 2) to study the association between bacterial aetiology, empirical antibiotic treatment, serum markers and mortality.METHODS: Of 1288 patients with CAP (57.0% males, age 59.0 years +/- 18.5), 262 (20.3%) fulfilled the diagnostic criteria for COPD. Differences between subgroups were investigated using univariate analyses and corrected for multiple comparisons.RESULTS: Streptococcus pneumoniae was the most common pathogen (30.8% CAP only vs. 26.0% CAPCOPD, not significant). Haemophilus influenzae was significantly more frequent in CAP-COPD (5.6% CAP-SUMMARY only vs. 26.0% CAP-COPD, P 0.05). The CAP-COPD group had worse CURB-65 and partial pressure of arterial oxygen levels than the CAP only group (P CONCLUSION: It is important to identify COPD patients with CAP. In particular, those without bacterial pathogen detection have more severe CAP and are at higher risk of dying. Better understanding of the aetiology could contribute to improved management and treatment of CAP in COPD patients.

Introduction Implementation of the 7-valent pneumococcal conjugate vaccine (PCV7) in infant vaccination programs has substantially reduced the burden of PCV7 serotypes also in adult community-acquired pneumonia (CAP). Currently, it is unclear, if this extensive herd protection effect can be extrapolated to the additional 6 serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13), which replaced PCV7 in Germany in 2010. Objectives We investigated changing trends for PCV13 serotypes in adult CAP patients between three to seven years after implementation of PCV13 infant immunization in Germany. Methods Between December 2012 and January 2017, urine samples from German adult patients with radiologically confirmed CAP were prospectively collected by the multi-center cohort study CAPNETZ and analyzed by the serotype-specific multiplex urinary antigen detection assay (SSUAD) allowing for the detection of PCV13 serotypes. Results PCV13 serotypes were found in 59 of 796 (7.4%) patients with all-cause CAP, most prevalent was serotype 3 (30 of 59 patients, 50.8%). All patients with serotype 3-CAP were admitted to hospital and the majority required oxygen at admission (83.3% of patients with serotype 3-CAP versus 50.9% of patients with pneumococcal CAP by other serotypes, p = 0.005). Compared to SSUAD testing, conventional microbiological workup missed 27 of 30 (90.0%) serotype 3-CAP cases. We could not observe a time trend in the proportions of PCV13 serotypes and serotype 3 in all-cause CAP between 2013 and 2016 (OR trend per year 0.84, 95% CI 0.64–1.11 for PCV13 serotypes and OR trend per year 0.95, 95% CI 0.70–1.28 for serotype 3). Conclusions: Conventional methods underestimate serotype 3-CAP that can cause severe disease. Changes in overall PCV13 coverage were not detected during the years 2013 to 2016, mostly driven by a high proportion of serotype 3.

BackgroundThe role of macrolide/β-lactam combination therapy in community-acquired pneumonia (CAP) of moderate severity is a matter of debate. Macrolides expand the coverage to atypical pathogens and attenuate pulmonary inflammation, but have been associated with cardiovascular toxicity and drug interactions. We developed a decision tree based on aetiological and clinical parameters, which are available ex ante to support a personalised decision for or against macrolides for the best clinical outcome of the individual patient.MethodsWe employed machine learning in a cross-validation scheme based on a well-balanced selection of 4898 patients after propensity score matching to data available on admission of 6440 hospitalised patients with moderate severity (non-intensive care unit patients) from the observational, prospective, multinational CAPNETZ study. We aimed to improve the primary outcome of 180-day survival.ResultsWe found a simple decision tree of patient characteristics comprising chronic cardiovascular and chronic respiratory comorbidities as well as leukocyte counts in the respiratory secretion at enrolment. Specifically, we found that patients without cardiovascular or patients with respiratory comorbidities and high leukocyte counts in the respiratory secretion benefit from macrolide treatment. Patients identified to be treated in compliance with our treatment suggestion had a lower mortality of 27% (OR 1.83, 95% CI 1.48–2.27; pConclusionStratifying macrolide treatment in patients following a simple treatment rule may lead to considerably reduced mortality in CAP. A future randomised controlled trial confirming our result is necessary before implementing this rule into the clinical routine.

In Caribbean poetry, it is time and again the sea, as site of the Middle Passage and as a marker of island experiences, of displacement and belonging, which gives shape to an inherently polyvalent poetics of location. The sea pervades many Caribbean poems, both as a historical contact zone and as an imaginative principle of a new kind of nomadic and mobile epistemology. While the “Black Atlantic” paradigm fruitfully emphasizes transit and transcultural exchange, recent scholarship has also explored the sea as a site of dwelling and a more localized Caribbean place. Ecocritical readings in particular have highlighted the role of regional environments. Moreover, they have pinpointed a long-standing intellectual concern by which Caribbean writers have turned to land and sea as a way of reconstituting poetic traditions and historical narratives. Similarly, this article will discuss “sea passages” in a double, though always complementary, sense: passages across and to the sea, that is, precisely in ord...

Summary The predisposition of preterm neonates to invasive infection is, as yet, incompletely understood. Regulatory T cells (Tregs) are potential candidates for the ontogenetic control of immune activation and tissue damage in preterm infants. It was the aim of our study to characterize lymphocyte subsets and in particular CD4+CD25+forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 117; 23 + 0 – 36 + 6 weeks of gestational age) in the first 3 days of life in comparison to term infants and adults. We demonstrated a negative correlation of Treg frequencies and gestational age. Tregs were increased in blood samples of preterm infants compared to term infants and adults. Notably, we found an increased Treg frequency in preterm infants with clinical early-onset sepsis while cause of preterm delivery, e.g. chorioamnionitis, did not affect Treg frequencies. Our data suggest that Tregs apparently play an important role in maintaining maternal-fetal tolerance, which turns into an increased sepsis risk after preterm delivery. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.

BACKGROUNDBetween 2010 and 2012, 3 outbreaks of nosocomial infections in German neonatal intensive care units (NICUs) attracted considerable public interest. Headlines on national television channels and in newspapers had important consequences for the involved institutions and a negative impact on the relationship between families and staff in many German NICUs.OBJECTIVETo determine whether NICU outbreaks reported in the media influenced provider behavior in the community of neonatal care and led to more third-line antibiotic prescribing.DESIGNObservational cohort study.METHODSTo investigate secular trends, we evaluated data for very-low-birth-weight infants (VLBWIs, birth weight RESULTSThe exposure of all VLBWIs to third-line antibiotics increased after outbreaks (19.4% before vs 22.5% after; P=.007). This trend particularly affected male infants (4.6% increase; P=.005) and infants with a birth weight between 1,000 and 1,499 g (3.5% increase; P=.001)In a logistic regression analysis, month of discharge as linear variable of time was associated with increased exposure to third-line antibiotics (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.009–1.014; PP=.024).CONCLUSIONSMedia reports directly affect medical practice, eg, overuse of third-line antibiotics. Future communication and management strategies must be based on objective dialogues between the scientific community and investigative journalists.Infect Control Hosp Epidemiol 2016;37:924–930

The aim of the study was to compare the distribution of the vaccine-serotypes covered by pneumococcal conjugate vaccines (PCV7 and PCV13) in adult patients with pneumococcal community-acquired pneumonia in Germany between the periods 2002-2006 and 2007-2011 using a novel serotype-specific multiplex urinary antigen detection assay (SSUA). Vaccination of children started with PCV7 in 2007, which was replaced by PCV13 in 2010. Following confirmation of the accuracy of SSUA in long-term stored urine samples from 112 patients with confirmed pneumonia and known pneumococcal serotype, urine samples of 391 CAPNETZ patients with documented pneumococcal pneumonia (i.e. positive BinaxNOW (R) Streptococcus pneumoniae urine antigen test) but unknown serotype were tested for the 13 vaccine-serotypes using SSUA. The proportion of PCV7-serotypes significantly decreased in adult patients with pneumonia from 30.6% (2002-6) to 13.3% (2007-11, p

CAPNETZ is a medical competence network for community-acquired pneumonia (CAP), which was funded by the German Ministry for Education and Research. It has accomplished seminal work on pneumonia over the last 15 years. A unique infrastructure was established which has so far allowed us to recruit and analyze more than 11,000 patients. The CAPNETZ cohort is the largest cohort worldwide and the results obtained relate to all relevant aspects of CAP management (epidemiology, risk stratification via biomarkers or clinical scores, pathogen spectrum, pathogen resistance, antibiotic management, prevention and health care research). Results were published in more than 150 journals and informed the preparation and update of the national S3-guideline. CAPNETZ was also the foundation for further networks like the Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) (PROGRESS), the Systems Medicine of Community Acquired Pneumonia Network (CAPSyS) and SFB-TR84 (Sonderforschungsbereich - Transregio 84). The main recipients (Charit, Berlin, University Clinic Ulm and the Hannover Medical School) founded the CAPNETZ foundation and transferred all data and materials rights to this foundation. Moreover, the ministry granted the CAPNETZ foundation the status of being eligible to apply for research proposals and receive research funds. Since 2013 the CAPNETZ foundation has been an associated member of the German Center for Lung Research (DZL). Thus, a solid foundation has been set up for CAPNETZ to continue its success story.

BACKGROUND NOD2 loss-of-function mutations, that is, R702W [rs2066844], G908R [rs2066845], and Leu1007fsinsC [rs5743293], have been linked to inflammatory bowel diseases. It is yet unknown whether these variants are also associated with necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) in infants of very low birth weight (VLBW). METHODS To test this hypothesis, we genotyped 9082 VLBW infants with European ancestry enrolled in a prospective, population-based cohort study of the German Neonatal Network. We assessed the effect of the NOD2 gene variants on the risk for major morbidities of the gastrointestinal tract, that is, NEC/FIP requiring surgery in multivariable logistic regression analyses. RESULTS In the whole cohort of VLBW infants, carriers of ≥ 2 NOD2 variant alleles had an increased risk for NEC requiring surgery (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.27-10.04; P = 0.03) and NEC or FIP requiring surgery (OR, 3.81; 95% CI, 1.70-8.51; P = 0.004) as compared with wild-type genotypes. In a multivariable logistic regression analysis including gestational age, birth weight, gender, multiple birth, and inborn delivery, the association between ≥ 2 NOD2 variant alleles and NEC surgery (OR, 4.14; 95% CI, 1.41-12.12; P = 0.009), FIP surgery (OR, 3.50; 95% CI, 1.02-12.04; P = 0.047), and NEC or FIP surgery (OR, 4.10; 95% CI, 1.74-9.73; P = 0.001) proved to be independent. We also performed a regression analysis in the subgroup of infants with available information on Lactobacillus acidophilus/Bifidobacterium infantis probiotic supplementation (n = 3638). Although probiotics had a protective effect on NEC and NEC or FIP requiring surgery, the NOD2 variants had no significant impact in this subgroup. CONCLUSIONS VLBW infants carrying ≥ 2 NOD2 genetic risk factors of inflammatory bowel disease in adults have an increased risk for severe gastrointestinal complications, such as NEC requiring surgery. Therefore, infants might benefit from NOD2 genotyping followed by supplementation with probiotics. Replication studies are needed along with genome-wide arrays to allow risk-adapted prevention and therapeutic strategies.

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.

Human airways are continuously colonized by microaspiration of microbiota. Less is known about the presence, origin and composition of microbiota in the lung parenchyma. In a study of 13 patients undergoing surgery for peripheral lung cancer microbiota composition was comparatively evaluated in upper airway, lower airway and lung tissue samples using 16S rDNA analysis. Bacterial density decreased stepwise from upper to lower airways and tissue. On a taxonomic level upper and lower airway microbiota were similar whereas lung tissue showed marked dissimilarities compared to lower airways that may reflect different environmental conditions shaping local microbiota and host immunity.