Sharp increase in gonorrhoea notifications among young people, EU/EEA, July 2022 to June 2023.

Gonorrhoea cases increased steeply in women aged 20 to 24 years across 15 EU/EEA countries in July to December 2022 and January to June 2023 with, respectively, 73% and 89% more cases reported than expected, based on historical data from 2015 to 2019. Smaller increases among men due to heterosexual transmission were observed in nine EU/EEA countries. Interventions to raise awareness among young people about sexually transmitted infection risks are needed, emphasising the benefit of safe sexual practices and testing.

Nbeal2 Deficiency Increases Organ Damage but Does Not Affect Host Defense During Gram-Negative Pneumonia-Derived Sepsis.

Objective- Nbeal2-/- mice, a model of human gray platelet syndrome, have reduced neutrophil granularity and impaired host defense against systemic Staphylococcus aureus infection. We here aimed to study the role of Nbeal2 deficiency in both leukocytes and platelets during gram-negative pneumonia and sepsis. Approach and Results- We studied the role of Nbeal2 in platelets and leukocytes during murine pneumonia and sepsis by Klebsiella pneumoniae. Apart from platelet α-granule deficiency and reduced neutrophil granularity, also monocyte granularity was reduced in Nbeal2-/- mice, whereas plasma levels of MPO (myeloperoxidase), elastase, NGAL (neutrophil gelatinase-associated lipocalin), and MMP-9 (matrix metalloproteinase 9), and leukocyte CD11b expression were increased. Nbeal2-/- leukocytes showed unaltered in vitro antibacterial response and phagocytosis capacity against Klebsiella, and unchanged reactive nitrogen species and cytokine production. Also during Klebsiella pneumonia and sepsis, Nbeal2-/- mice had similar bacterial growth in lung and distant body sites, with enhanced leukocyte migration to the bronchoalveolar space. Despite similar infection-induced inflammation, organ damage was increased in Nbeal2-/- mice, which was also seen during endotoxemia. Platelet-specific Nbeal2 deficiency did not influence leukocyte functions, indicating that Nbeal2 directly modifies leukocytes. Transfusion of Nbeal2-/- but not of Nbeal2+/+ platelets into thrombocytopenic mice was associated with bleeding in the lung but similar host defense, pointing at a role for platelet α-granules in maintaining vascular integrity but not host defense during Klebsiella pneumosepsis. Conclusions- These data show that Nbeal2 deficiency-resulting in gray platelet syndrome-affects platelets, neutrophils, and monocytes, with intact host defense but increased organ damage during gram-negative pneumosepsis.

Protease-Activated Receptor 2 Facilitates Bacterial Dissemination in Pneumococcal Pneumonia.

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Protease-activated receptor 2 (PAR2) is expressed by different cell types in the lungs and can mediate inflammatory responses. We sought to determine the role of PAR2 during pneumococcal pneumonia. Pneumococcal pneumonia or sepsis was induced in wild-type and PAR2 knock-out (Par2-/-) mice by infection with viable S. pneumoniae. Par2-/- mice demonstrated improved host defense, a largely preserved lung barrier integrity, and reduced mortality during pneumococcal pneumonia. PAR2 deficiency did not influence bacterial growth after intravenous infection. Inhibition of the endogenous PAR2 activating proteases tissue factor/factor VIIa or tryptase did not impact on bacterial burdens during pneumonia. In a PAR2 reporter cell line it was demonstrated that S. pneumoniae-derived proteases are able to cleave PAR2. These results show that S. pneumoniae is able to cleave and exploit PAR2 to disseminate systemically from the airways.

Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice.

Thrombocytopenia is a common finding in sepsis and associated with a worse outcome. We used a mouse model of pneumonia-derived sepsis caused by the human pathogen Klebsiella pneumoniae to study the role of platelets in host response to sepsis. Platelet counts (PCs) were reduced to less than a median of 5 × 10(9)/L or to 5 to 13 × 10(9)/L by administration of a depleting antibody in mice infected with Klebsiella via the airways. Thrombocytopenia was associated with strongly impaired survival during pneumonia-derived sepsis proportional to the extent of platelet depletion. Thrombocytopenic mice demonstrated PC-dependent enhanced bacterial growth in lungs, blood, and distant organs. Severe thrombocytopenia resulted in hemorrhage at the primary site of infection, but not in distant organs. PCs of 5 to 13 × 10(9)/L were sufficient to largely maintain hemostasis in infected lungs. Thrombocytopenia did not influence lung inflammation or neutrophil recruitment and did not attenuate local or systemic activation of coagulation or the vascular endothelium. PCs <5 × 10(9)/L even resulted in enhanced coagulation and endothelial cell activation, which coincided with increased proinflammatory cytokine levels. In accordance, low PCs in whole blood enhanced Klebsiella-induced cytokine release in vitro. These data suggest that platelets play an important role in host defense to Klebsiella pneumosepsis.

Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice.

Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.

Thrombocytopenia impairs host defense during murine Streptococcus pneumoniae pneumonia.

OBJECTIVES: Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. In patients, thrombocytopenia is correlated with an adverse outcome of pneumonia. Platelets can modulate the host response to infection in several ways, that is, by facilitating clot formation, production of antimicrobial proteins, and interaction with neutrophils. We studied the effect of thrombocytopenia during murine pneumococcal pneumonia. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Mice. INTERVENTIONS: Pneumonia was induced by intranasal inoculation of S. pneumoniae. Platelets were depleted by anti-mouse thrombocyte serum; controls received nonimmunogenic serum. In separate studies, mice were treated with the platelet P2Y12 receptor inhibitor clopidogrel or placebo. MEASUREMENTS AND MAIN RESULTS: Thrombocytopenic mice (platelet counts < 1% of uninfected controls) showed a reduced survival during pneumococcal pneumonia (27% vs 75% among controls; p = 0.003), which was associated with higher bacterial loads in lungs, spleen, and blood. Thrombocytopenic mice showed enhanced coagulation activation (thrombin-antithrombin complexes) in plasma. Proinflammatory cytokine levels were higher in plasma but not in lungs of thrombocytopenic mice. Although clopidogrel treatment strongly prolonged the bleeding time, it did not impact on bacterial loads during pneumococcal pneumonia. CONCLUSIONS: Platelets play a protective role during pneumococcal pneumonia independent of their aggregation.

Diagnostic value of Chest X-Ray in Febrile Patients without Localizing Signs or Symptoms at the Emergency Department.

BACKGROUND: The chest X-ray (CXR) remains a widely used examination in the evaluation of patients with fever, to diagnose or rule out pneumonia. Recently, a study by our group suggested that it has no diagnostic value in patients with fever without respiratory signs and/or symptoms. OBJECTIVE: The objective of this study is to validate the results of our previous study. Design A retrospective study was conducted in two hospitals in the Netherlands. Patients All patients that were referred to the internal medicine emergency department between May 2018 and May 2019 with a suspected infection defined as fever (temperature ≥38°C) or hypothermia (temperature <36°C) or CRP ≥100µg/mL. Main measures We defined our primary outcome as the number of newly diagnosed pneumonia by CXR in cases of suspected infection with no obvious site of infection and nor localizing symptoms or signs. Key results We included 1052 patients, of which 106 did not have respiratory signs or symptoms. In this group, none of the CXRs (95% CI 0-2.36%) showed an infiltrate. Combined with our previous study, 176 CXRs were performed in patients with no respiratory signs or symptoms. None (95% CI 0-1.42%) showed an infiltrate. Conclusion Our results confirm that a CXR has no diagnostic value in the workup of fever without localizing signs or symptoms.

Description of a nationwide structure for monitoring nosocomial outbreaks of (highly resistant) microorganisms in the Netherlands: characteristics of outbreaks in 2012-2021.

BACKGROUND: Before 2012, established national surveillance systems in the Netherlands were not able to provide a timely, comprehensive epidemiological view on nosocomial outbreaks. The Healthcare-associated Infections and AntiMicrobial Resistance Monitoring Group (SO-ZI/AMR) was initiated in 2012 for timely national nosocomial outbreak monitoring and risk assessment. This paper aims to describe the achievements of the SO-ZI/AMR by presenting characteristics of outbreaks reported in 2012-2021. METHODS: Hospitals and, since 2015, long-term care facilities (LTCF) were requested to report outbreaks when (1) continuity of care was threatened, or (2) transmission continued despite control measures. A multi-disciplinary expert panel (re-)assessed the public health risk of outbreaks during monthly meetings, using 5 severity phases and based on data collected via standardised questionnaires. We descriptively studied the panel's consensus-based severity classification, distribution of (highly resistant) microorganisms, and duration and size of outbreaks between April 2012 and December 2021. RESULTS: In total, 353 hospital outbreaks and 110 LTCF outbreaks were reported. Most outbreaks (hospitals: n = 309 (88%), LTCF: n = 103 (94%)) did not progress beyond phase 1 (no public health implications, outbreak expected to be controlled within two months), one hospital outbreak reached phase 4 (insufficient/ineffective response: possible public health threat, support offered). Highly resistant microorganisms (HRMO) were involved in 269 (76%) hospital and 103 (94%) LTCF outbreaks. Most outbreaks were caused by methicillin-resistant Staphylococcus aureus (MRSA; n = 93 (26%) in hospitals, n = 80 (72%) in LTCF), vancomycin-resistant Enterococcus faecium (VRE; n = 116 (33%) in hospitals, n = 2 (2%) in LTCF) and highly resistant Enterobacterales (n = 41 (12%) in hospitals, n = 20 (18%) in LTCF). Carbapenemase-producing gram-negative bacteria were involved in 32 (9.1%) hospital and five (4.5%) LTCF outbreaks. In hospitals, VRE outbreaks had the longest duration (median 2.3; range 0.0-22.8 months) and widest range of affected patients (median 9; range 2-483). CONCLUSIONS: The SO-ZI/AMR provided national insight into the characteristics of nosocomial outbreaks over the past decade. HRMO outbreaks - mostly caused by MRSA, VRE (in hospitals) and highly resistant Enterobacterales - occurred regularly, but most of them were controlled quickly and did not develop into a public health threat. The SO-ZI/AMR has become a solid monitoring body, essential to assess risks and raise awareness of potential HRMO threats.

[Carbapenems: take it when needed but leave it if you can]. / Carbapenems: inzetten als het moet, vermijden als het kan.

Surveillance data and literature have shown a worldwide increase in infections with resistant bacteria, which has led to increased prescriptions of carbapenems, which in turn has led to increased carbapenem resistance. There is also an increasing use of carbapenems in the Netherlands, a county usually very conservative in antibiotic use. Carbapenem sparing strategies are essential in an attempt to prevent further rise of infections caused by carbapenem resistant bacteria. This article discusses carbapenem sparing strategies with old forgotten antibiotics and novel antibiotics from a Dutch perspective.

[Monkeypox, a new pandemic?] / Uitbraak van monkeypox: een nieuwe pandemie?

Monkeypox (MPX) is a disease caused by the monkeypox virus. It is a viral zoonotic disease, endemic in Central and West Africa. Human-to-human spread also occurs and is a feature of the current global outbreak. As far as we know, exponential transmission during this outbreak is not related to changed viral characteristics but due to multiple high-risk contacts in a subset of people that have contracted the virus, so far almost exclusively affecting men who have sex with men (MSM). Appropriate public health measures and increased alertness of all health care providers is needed to increase case-finding and decrease transmission. There is a real chance of MPX to become endemic in large parts of the world.

Diagnostic Value of Chest X-Ray in Patients With Suspected Infection and No Respiratory Signs or Symptoms.

Suspicion of an infection without localizing signs or symptoms is a common problem. A chest x-ray (CXR) is often performed to rule out pneumonia. Our prospective cross-sectional study suggests that a CXR has no diagnostic value in patients without respiratory signs or symptoms, if a reliable medical history can be obtained.

[Chest X-ray in patients with fever and no localizing symptoms?] / Thoraxfoto bij koorts zonder duidelijk focus?

Fever without localizing symptoms is a clinical problem that is frequently encountered on the emergency department. According to the NICE sepsis guideline, a chest X-ray should be considered in such patients. However, the evidence supporting this recommendation is limited to patients with neutropenic fever. We performed a telephone survey among the internists and residents at every Dutch hospital. Of the 141 physicians that responded, 88% considered a chest X-ray a valuable diagnostic tool and one that is indicated in patients with fever without localizing symptoms. In view of rising health costs, diagnostics should be chosen wisely. A clinical study on the diagnostic value of a chest X-ray in patients with fever without localizing symptoms is needed.

Toll-Like Receptor Signalling Is Not Involved in Platelet Response to Streptococcus pneumoniae In Vitro or In Vivo.

Streptococcus (S.) pneumoniae strains vary considerably in their ability to cause invasive disease in humans, which is at least in part determined by the capsular serotype. Platelets have been implicated as sentinel cells in the circulation for host defence. One of their utensils for this function is the expression of Toll-like receptors (TLRs). We here aimed to investigate platelet response to S. pneumoniae and a role for TLRs herein. Platelets were stimulated using four serotypes of S. pneumonia including an unencapsulated mutant strain. In vitro aggregation and flow cytometry assays were performed using blood of healthy volunteers, or blood of TLR knock out and WT mice. For in vivo pneumonia experiments, platelet specific Myd88 knockout (Plt-Myd88-/-) mice were used. We found that platelet aggregation was induced by unencapsulated S. pneumoniae only. Whole blood incubation with all S. pneumoniae serotypes tested resulted in platelet degranulation and platelet-leukocyte complex formation. Platelet activation was TLR independent, as responses were not inhibited by TLR blocking antibodies, not induced by TLR agonists and were equally induced in wild-type and Tlr2-/-, Tlr4-/-, Tlr2/4-/-, Tlr9-/- and Myd88-/- blood. Plt-Myd88-/- and control mice displayed no differences in bacterial clearance or immune response to pneumonia by unencapsulated S. pneumoniae. In conclusion, S. pneumoniae activates platelets through a TLR-independent mechanism that is impeded by the bacterial capsule. Additionally, platelet MyD88-dependent TLR signalling is not involved in host defence to unencapsulated S. pneumoniae in vivo.

Chronic antiplatelet therapy is not associated with alterations in the presentation, outcome, or host response biomarkers during sepsis: a propensity-matched analysis.

PURPOSE: Sepsis is a major health burden worldwide. Preclinical investigations in animals and retrospective studies in patients have suggested that inhibition of platelets may improve the outcome of sepsis. In this study we investigated whether chronic antiplatelet therapy impacts on the presentation and outcome of sepsis, and the host response. METHODS: We performed a prospective observational study in 972 patients admitted with sepsis to the mixed intensive care units (ICUs) of two hospitals in the Netherlands between January 2011 and July 2013. Of them, 267 patients (27.5%) were on antiplatelet therapy (95.9% acetylsalicylic acid) before admission. To account for differential likelihoods of receiving antiplatelet therapy, a propensity score was constructed, including variables associated with use of antiplatelet therapy. Cox proportional hazards regression was used to estimate the association of antiplatelet therapy with mortality. RESULTS: Antiplatelet therapy was not associated with sepsis severity at presentation, the primary source of infection, causative pathogens, the development of organ failure or shock during ICU stay, or mortality up to 90 days after admission, in either unmatched or propensity-matched analyses. Antiplatelet therapy did not modify the values of 19 biomarkers providing insight into hallmark host responses to sepsis, including activation of the coagulation system, the vascular endothelium, the cytokine network, and renal function, during the first 4 days after ICU admission. CONCLUSIONS: Pre-existing antiplatelet therapy is not associated with alterations in the presentation or outcome of sepsis, or the host response.

The role of platelets in sepsis.

Platelets are small circulating anucleate cells that are of crucial importance in haemostasis. Over the last decade, it has become increasingly clear that platelets play an important role in inflammation and can influence both innate and adaptive immunity. Sepsis is a potentially lethal condition caused by detrimental host response to an invading pathogen. Dysbalanced immune response and activation of the coagulation system during sepsis are fundamental events leading to sepsis complications and organ failure. Platelets, being major effector cells in both haemostasis and inflammation, are involved in sepsis pathogenesis and contribute to sepsis complications. Platelets catalyse the development of hyperinflammation, disseminated intravascular coagulation and microthrombosis, and subsequently contribute to multiple organ failure. Inappropriate accumulation and activity of platelets are key events in the development of sepsis-related complications such as acute lung injury and acute kidney injury. Platelet activation readouts could serve as biomarkers for early sepsis recognition; inhibition of platelets in septic patients seems like an important target for immune-modulating therapy and appears promising based on animal models and retrospective human studies.

Streptococcus pneumoniae serine protease HtrA, but not SFP or PrtA, is a major virulence factor in pneumonia.

Streptococcus (S.) pneumoniae is a common causative pathogen in pneumonia. Serine protease orthologs expressed by a variety of bacteria have been found of importance for virulence. Previous studies have identified two serine proteases in S. pneumoniae, HtrA (high-temperature requirement A) and PrtA (cell wall-associated serine protease A), that contributed to virulence in models of pneumonia and intraperitoneal infection respectively. We here sought to identify additional S. pneumoniae serine proteases and determine their role in virulence. The S. pneumoniae D39 genome contains five putative serine proteases, of which HtrA, Subtilase Family Protein (SFP) and PrtA were selected for insertional mutagenesis because they are predicted to be secreted and surface exposed. Mutant D39 strains lacking serine proteases were constructed by in-frame insertion deletion mutagenesis. Pneumonia was induced by intranasal infection of mice with wild-type or mutant D39. After high dose infection, only D39ΔhtrA showed reduced virulence, as reflected by strongly reduced bacterial loads, diminished dissemination and decreased lung inflammation. D39ΔprtA induced significantly less lung inflammation together with smaller infiltrated lung surface, but without influencing bacterial loads. After low dose infection, D39ΔhtrA again showed strongly reduced bacterial loads; notably, pneumococcal burdens were also modestly lower in lungs after infection with D39Δsfp. These data confirm the important role for HtrA in S. pneumoniae virulence. PrtA contributes to lung damage in high dose pneumonia; it does not however contribute to bacterial outgrowth in pneumococcal pneumonia. SFP may facilitate S. pneumoniae growth after low dose infection.