Search

Background: Streptococcus pneumoniae is the most frequent causative pathogen of bacterial pneumonia in children worldwide. Bangladesh introduced the 10-valent pneumococcal conjugate vaccine (PCV10) in their national immunization program for infants in 2015. We assessed its potential coverage in under-fives with community-acquired pneumonia (CAP) in the years before PCV10 was introduced., Methods: A total of 1502 childhood pneumonia cases (< 5 year olds living in the urban section Kamalapur, Dhaka) were enrolled between 2011 and 2013. Acute phase and late (convalescent) serum samples were collected from 1380 cases. Serotype-specific pneumococcal antibody concentrations were measured using a 25-plex immunoassay panel. Pneumococcal CAP was diagnosed based on a serotype-specific pneumococcal antibody response., Results: S. pneumoniae was serologically identified as causative pathogen in 406/1380 (29%) cases. The five most prevalent serotypes were (in descending order) 11A, 22F, 3, 2 and 19F. Based on the percentage of pneumonia cases associated with PCV10 vaccine types, the potential PCV10 coverage was 29% (116/406)., Conclusions: In almost a third of the studied cases S. pneumoniae was identified as a causative pathogen. Because of the characteristics of the immunoassay, this might well be a gross underestimation. Nevertheless, the potential PCV10-coverage was low. Given the high serotype diversity, the region might benefit greatly from a higher-coverage PCV or recombinant protein vaccine., (© 2024. The Author(s).)

Since 2022, many countries have reported an upsurge in invasive group A streptococcal (iGAS) infections. We explored whether changes in Streptococcus pyogenes carriage rates or emergence of strains with potentially altered virulence, such as emm 1 variants M1 UK and M1 DK , contributed to the 2022/2023 surge in the Netherlands. We determined emm (sub)type distribution for 2,698 invasive and 351 S . pyogenes carriage isolates collected between January 2009 and March 2023. Genetic evolution of emm 1 was analyzed by whole-genome sequencing of 497 emm 1 isolates. The nationwide iGAS upsurge coincided with a sharp increase of emm 1.0 from 18% (18/100) of invasive isolates in Q1 2022 to 58% (388/670) in Q1 2023 (Fisher's exact test, P < 0.0001). M1 UK became dominant among invasive emm 1 isolates in 2016 and further expanded from 72% in Q1 2022 to 96% in Q1 2023. Phylogenetic comparison revealed evolution and clonal expansion of four new M1 UK clades in 2022/2023. DNase Spd1 and superantigen SpeC were acquired in 9% (46/497) of emm 1 isolates. S. pyogenes carriage rates and emm 1 proportions in carriage isolates remained stable during this surge, and the expansion of M1 UK in iGAS was not reflected in carriage isolates. During the 2022/2023 iGAS surge in the Netherlands, expansion of four new M1 UK clades was observed among invasive isolates, but not carriage isolates, suggesting increased virulence and fitness of M1 UK compared to contemporary M1 strains. The emergence of more virulent clades has important implications for public health strategies such as antibiotic prophylaxis for close contacts of iGAS patients.IMPORTANCEThis study describes the molecular epidemiology of invasive group A streptococcal (iGAS) infections in the Netherlands based on >3,000 Streptococcus pyogenes isolates from both asymptomatic carriers and iGAS patients collected before, during, and after the COVID-19 pandemic period (2009-2023) and is the first to assess whether changes in carriage rates or carried emm types contributed to the alarming post-COVID-19 upsurge in iGAS infections. We show that the 2022/2023 iGAS surge coincided with a sharp increase of emm 1, particularly the toxicogenic M1 UK variant, in invasive isolates, but not in carriage isolates. These findings suggest that increased virulence and fitness of M1 UK likely contributes to an increased dissemination between hosts. The emergence of a more virulent and fit lineage has important implications for iGAS control interventions such as antibiotic prophylaxis for close contacts of iGAS patients and calls for a reappraisal of iGAS control interventions and guidelines., Competing Interests: N.M.V.S. reports fee for service and presentations from MSD and GSK, grants from the Dutch Health Council (ZonMW; all directly paid to the institution), contract research with Argenx (unrelated to this work), a patent on vaccine development against S. pyogenes (licensee: University of California San Diego, inventors Nina van Sorge and Victor Nizet; licensed by Vaxcyte; personal revenue), and participation in the science advisory board of the ItsME foundation (no honorarium; https://itsme-foundation.com/en/) and Rapua te me ngaro ka tau, a project facilitating Strep A vaccine development for Aotearoa New Zealand (honorarium paid directly to the institution). M.A.V.H. reports grants or contracts with Pfizer (RSV prevention uptake study) and consulting fee from Pfizer on RSV vaccination (both unrelated to this work). Other authors have nothing to disclose.

Invasive group A streptococcal (iGAS) disease cases increased in the first half of 2022 in the Netherlands, with a remarkably high proportion of emm 4 isolates. Whole-genome sequence analysis of 66 emm 4 isolates, 40 isolates from the pre-coronavirus disease 2019 (COVID-19) pandemic period 2009-2019 and 26 contemporary isolates from 2022, identified a novel Streptococcus pyogenes lineage (M4 NL22 ), which accounted for 85 % of emm 4 iGAS cases in 2022. Surprisingly, we detected few isolates of the emm 4 hypervirulent clone, which has replaced nearly all other emm 4 in the USA and the UK. M4 NL22 displayed genetic differences compared to other emm 4 strains, although these were of unclear biological significance. In publicly available data, we identified a single Norwegian isolate belonging to M4 NL22 , which was sampled after the isolates from this study, possibly suggesting export of M4 NL22 to Norway. In conclusion, our study identified a novel S. pyogenes emm 4 lineage underlying an increase of iGAS disease in early 2022 in the Netherlands and the results have been promptly communicated to public health officials.

Group A streptococcal (GAS) infections are caused by the Gram-positive bacterium Streptococcus pyogenes. Infection can occur via droplet infection from the throat and via (in)direct contact with infected people. GAS can cause a wide variety of diseases, ranging from superficial skin infections, pharyngitis and scarlet fever, to serious invasive diseases such as puerperal sepsis, pneumonia, necrotising soft tissue infections (NSTI) (also known as necrotising fasciitis/myositis), meningitis and streptococcal toxic shock syndrome (STSS). In invasive GAS infections, the bacteria has penetrated into a sterile body compartment (such as the bloodstream, deep tissues, or the central nervous system). Invasive GAS infections are rare but serious, with high morbidity and mortality. Since March 2022, the National Institute for Public Health and the Environment (RIVM) reported a national increase in notifiable invasive GAS infections (NSTI, STSS and puerperal fever). Particularly NSTI has increased compared to the years before the SARS-CoV-2 pandemic. Remarkably, the proportion of children aged 0 to 5 years with invasive GAS-infections is higher in 2022 than in the previous years (12% compared to 4%). While seasonal peaks occur, the current elevation exceeds this variation. To promote early recognition and diagnosis of invasive GAS infections different clinical cases are presented.

Background: Adjunctive intravenous corticosteroid treatment has been shown to reduce length of stay (LOS) in adults hospitalised with community-acquired pneumonia (CAP). We aimed to assess the effect of oral dexamethasone on LOS and whether this effect is disease severity dependent., Methods: In this multicentre, stratified randomised, double-blind, placebo-controlled trial, immunocompetent adults with CAP were randomly assigned (1:1 ratio) to receive oral dexamethasone (6 mg once daily) or placebo for 4 days in four teaching hospitals in the Netherlands. Randomisation (blocks of four) was stratified by CAP severity (pneumonia severity index class I-III and IV-V). The primary outcome was LOS., Results: Between December 2012 and November 2018, 401 patients were randomised to receive dexamethasone (n=203) or placebo (n=198). Median LOS was shorter in the dexamethasone group (4.5 days, 95% CI 4.0-5.0 days) than in the placebo group (5.0 days, 95% CI 4.6-5.4 days; p=0.033). Within both CAP severity subgroups, differences in LOS between treatment groups were not statistically significant. The secondary ICU admission rate was lower in the dexamethasone arm (5 (3%) versus 14 (7%); p=0.030); 30-day mortality did not differ between groups. In the dexamethasone group the rate of hospital readmission tended to be higher (20 (10%) versus 9 (5%); p=0.051) and hyperglycaemia (14 (7%) versus 1 (1%); p=0.001) was more prevalent., Conclusion: Oral dexamethasone reduced LOS and ICU admission rate in adults hospitalised with CAP. It remains unclear for which patients the risk-benefit ratio is optimal., Competing Interests: Conflict of interest: E. Wittermans has nothing to disclose. Conflict of interest: S.M.T. Vestjens has nothing to disclose. Conflict of interest: S.M.C. Spoorenberg has nothing to disclose. Conflict of interest: W.L. Blok has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: R. Janssen has nothing to disclose. Conflict of interest: G.T. Rijkers has nothing to disclose. Conflict of interest: F.W.J.M. Smeenk has nothing to disclose. Conflict of interest: G.P. Voorn has nothing to disclose. Conflict of interest: E.M.W. van de Garde has nothing to disclose. Conflict of interest: W.J.W. Bos reports grants from Zilveren Kruis Insurance, outside the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Diagnosis of microbial disease etiology in community-acquired pneumonia (CAP) remains challenging. We undertook a large-scale metabolomics study of serum samples in hospitalized CAP patients to determine if host-response associated metabolites can enable diagnosis of microbial etiology, with a specific focus on discrimination between the major CAP pathogen groups S. pneumoniae, atypical bacteria, and respiratory viruses. Targeted metabolomic profiling of serum samples was performed for three groups of hospitalized CAP patients with confirmed microbial etiologies: S. pneumoniae (n = 48), atypical bacteria (n = 47), or viral infections (n = 30). A wide range of 347 metabolites was targeted, including amines, acylcarnitines, organic acids, and lipids. Single discriminating metabolites were selected using Student's T-test and their predictive performance was analyzed using logistic regression. Elastic net regression models were employed to discover metabolite signatures with predictive value for discrimination between pathogen groups. Metabolites to discriminate S. pneumoniae or viral pathogens from the other groups showed poor predictive capability, whereas discrimination of atypical pathogens from the other groups was found to be possible. Classification of atypical pathogens using elastic net regression models was associated with a predictive performance of 61% sensitivity, 86% specificity, and an AUC of 0.81. Targeted profiling of the host metabolic response revealed metabolites that can support diagnosis of microbial etiology in CAP patients with atypical bacterial pathogens compared to patients with S. pneumoniae or viral infections., Competing Interests: The authors have declared that no competing interests exist.

Background: To facilitate better discrimination between patients with active tuberculosis (TB) and latent TB infection (LTBI), whole blood transcriptomic studies have been performed to identify novel candidate host biomarkers. SERPING1, which encodes C1-inhibitor (C1-INH), the natural inhibitor of the C1-complex has emerged as candidate biomarker. Here we collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB., Methods: SERPING1 expression data were extracted from online deposited datasets. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts., Findings: SERPING1 expression was increased in patients with active TB compared to healthy controls (8/11 cohorts), LTBI (13/14 cohorts) and patients with other (non-TB) lung-diseases (7/7 cohorts). Serum levels of C1-INH were significantly increased in The Gambia and Italy in patients with active TB relative to the endemic controls but not in South Africa or Korea. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. This cohort, also showed the most abundant increase in C1-INH, and a positive correlation between C1q and C1-INH levels. Combined presence of increased levels of both C1q and C1-INH had high specificity for active TB (96 %) but only very modest sensitivity 38 % compared to the endemic controls., Interpretation: SERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: In 2006, the Netherlands introduced the 7-valent pneumococcal conjugate vaccine (PCV7) in their national immunisation programme. In 2011, PCV7 was replaced by the 10-valent vaccine (PCV10). We report on the impact of PCV on invasive pneumococcal disease (IPD) incidence, clinical syndromes and patient outcomes., Methods: Pneumococcal isolates of hospitalised IPD patients between June 2004 and May 2018 were obtained from nine sentinel laboratories, covering 25% of the Dutch population. All isolates were serotyped. IPD incidence and clinical outcome were determined before and after introduction of PCV7 and after the switch to PCV10, stratified by age and serotype., Results: Compared to before PCV7 introduction, significant declines in IPD incidence were observed in 2016-2018 in children <5 years (69%), 18-49 year olds (31%) and ≥65 year olds (19%). Compared to before PCV10 introduction, the IPD incidence in 2016-2018 declined in children <5 years (RR:0.68, 95%CI:0.42-1.11), 5-17 year olds (RR:0.58, 95%CI:0.29-1.14) and 18-49 year olds (RR:0.72, 95%CI:0.57-0.90), but not in 50-64 year olds (RR:0.94, 95%CI:0.81-1.10) and ≥65 year olds (RR:1.04, 95%CI:0.0.93-1.15). While the case fatality rate (CFR) decreased from 16.2% pre-PCV to 13.4% post-PCV10 (RR:0.83, 95%CI:0.70-0.99), the switch to PCV10 had no further impact on CFR (RR:1.14, 95%CI:0.96-1.36)., Conclusion: Twelve years of PCV in the Netherlands has resulted in a sustained reduction of IPD incidence in children and younger adults. The switch from PCV7 to PCV10 did not have additional impact on the IPD incidence in older adults and CFR due to emerging non-vaccine serotypes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The aim of this study was to explore the relationship between the extent of microbiological testing and the frequency of antibiotic alteration in adults hospitalised with community-acquired pneumonia (CAP). We retrospectively studied 283 immunocompetent patients hospitalised with CAP. Information on microbiological testing and prescribed antibiotics was obtained. Patients were grouped according to the number of different microbiological tests performed within the first 2 days of admission (0-5 tests). Alteration rates were compared between these groups. Antimicrobial alteration was defined as a switch at day 3 of hospital stay to (1) a narrower spectrum antibiotics, or (2) a different class of antibiotics, or (3) a switch from dual therapy to monotherapy (4) or discontinuation of antibiotic treatment because the indication for antibiotic treatment did no longer exist. For each additional test performed, a stepwise increase in percentage of patients with altered antibiotic regimen ranging from 0 to 59% (p = 0.001) was found. Multivariate logistic regression analyses showed that performing PCR assay for atypical pathogens was most strongly associated with any alteration of antibiotic treatment (OR 2.6 (95% CI 1.4-4.9)) and with changes in atypical coverage specifically (OR 3.1 (95% CI 1.6-6.0). The extent of microbiological testing was positively associated with antibiotic alteration in adults hospitalised with CAP. Antibiotic treatment was most likely to be altered in patients in whom PCR assay for atypical pathogens was performed.

Background: Tuberculosis (TB) remains a major threat to global health. Currently, diagnosis of active TB is hampered by the lack of specific biomarkers that discriminate active TB disease from other (lung) diseases or latent TB infection (LTBI). Integrated human gene expression results have shown that genes encoding complement components, in particular different C1q chains, were expressed at higher levels in active TB compared to LTBI. Methods: C1q protein levels were determined using ELISA in sera from patients, from geographically distinct populations, with active TB, LTBI as well as disease controls. Results: Serum levels of C1q were increased in active TB compared to LTBI in four independent cohorts with an AUC of 0.77 [0.70; 0.83]. After 6 months of TB treatment, levels of C1q were similar to those of endemic controls, indicating an association with disease rather than individual genetic predisposition. Importantly, C1q levels in sera of TB patients were significantly higher as compared to patients with sarcoidosis or pneumonia, clinically important differential diagnoses. Moreover, exposure to other mycobacteria, such as Mycobacterium leprae (leprosy patients) or BCG (vaccinees) did not result in elevated levels of serum C1q. In agreement with the human data, in non-human primates challenged with Mycobacterium tuberculosis , increased serum C1q levels were detected in animals that developed progressive disease, not in those that controlled the infection. Conclusions: In summary, C1q levels are elevated in patients with active TB compared to LTBI in four independent cohorts. Furthermore, C1q levels from patients with TB were also elevated compared to patients with sarcoidosis, leprosy and pneumonia. Additionally, also in NHP we observed increased C1q levels in animals with active progressive TB, both in serum and in broncho-alveolar lavage. Therefore, we propose that the addition of C1q to current biomarker panels may provide added value in the diagnosis of active TB.

Background and Aim: SP-D, YKL-40, CCL18 and CA 15-3 are pulmonary markers that have been extensively investigated in different chronic pulmonary diseases. However, in acute pulmonary diseases, such as community-acquired pneumonia (CAP), little is known about the course of these markers and their relationship with the aetiological agent. The aim of this study was to investigate the course of these four markers in CAP and to study influence of disease severity, aetiology and antibiotic use prior to admission on their course., Methods: We included 291 adult patients hospitalised with CAP and 20 healthy controls. Measurements were performed in serum of day 0, 2, and 4, and at least 30 days after admission., Results: Our most important results were: 1) At all time-points, including 30 days after admission, YKL-40 and CCL18 levels were higher in CAP patients compared to healthy controls; and 2) Patients with CAP caused by an intracellular, atypical bacterium had lower YKL-40 and especially CCL18 levels on and during admission in comparison with other or unknown CAP aetiology., Conclusions: Our findings suggest that these pulmonary markers could be useful to assess CAP severity and, especially YKL-40 and CCL18 by helping predict CAP caused by atypical pathogens.

Background: In 2006 a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the immunisation programme for infants in The Netherlands and replaced by PCV10 in 2011. Limited data exist about the impact of PCV on the aetiology of CAP as a whole. The aim of the present study is to describe the overall changes in microbial aetiology, pneumococcal burden (including non-bacteraemic pneumococcal pneumonia) and its serotypes in adult community-acquired pneumonia (CAP) after the introduction of these PCVs., Methods: Hospitalised adult CAP patients who participated in three consecutive trials were studied (2004-2006 (n=201), 2007-2009 (n=304) and 2012-2016 (n=300) and considered as pre-PCV7, PCV7 and PCV10 period). Extensive conventional microbiological testing was applied for all patients. In addition, patients with a serotype-specific pneumococcal antibody response were diagnosed with pneumococcal CAP. Changes in proportions of causative pathogens and distributions of pneumococcal serotypes were calculated., Results: The proportion of pneumococcal CAP decreased from 37% (n=74/201) to 26% (n=77/300) comparing the pre-PCV7 period with the PCV10 period (p=0.01). For other pathogens, including Legionella spp., Mycoplasma pneumoniae, S. aureus, H. influenzae, and respiratory viruses, no sustained shifts were observed in their relative contribution to the aetiology of CAP. Within the pneumococcal CAP patients, we observed a decrease in PCV7 and an increase in non-PCV10 serotype disease. PCV10-extra type disease did not decrease significantly comparing the PCV10 period with the pre-PCV7 and PCV7 period, respectively. Notably, PCV7 type disease decreased both in bacteraemic and non-bacteraemic patients., Conclusions: Our findings confirm that PCV introduction in infants impact the microbial aetiology of adult CAP and suggest herd effects in adults with CAP after introduction of PCVs in children., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Objective: Mortality after hospitalization with community-acquired pneumonia (CAP) is high, compared with age-matched controls. Available evidence suggests a strong link with cardiovascular disease. Our aim was to explore the prognostic value of high-sensitivity cardiac troponin T (cTnT) for mortality in patients hospitalized with CAP., Methods: CTnT level on admission was measured (assay conducted in 2015) in 295 patients hospitalized with CAP who participated in a randomized placebo-controlled double-blind trial on adjunctive dexamethasone treatment. Outcome measures were short- (30-day) and long-term (4.1-year) mortalities., Results: CTnT levels were elevated (≥14 ng/L) in 132 patients (45%). Pneumonia severity index (PSI) class was 4-5 in 137 patients (46%). Short- and long-term mortality were significantly higher in patients with elevated cTnT levels. cTnT level on admission combined with PSI classification was significantly better in predicting short-term mortality (area under the operating curve (AUC) = 0.903; 95% CI = 0.847-0.960), compared with PSI classification alone (AUC = 0.818; 95% CI = 0.717-0.919). An optimal cTnT cut-off level of 28 ng/L was independently associated with both short- and long-term mortality (OR = 21.9; 95% CI = 4.7-101.4 and 10.7; 95% CI = 5.0-22.8, respectively)., Conclusion: Elevated cTnT level on admission is a strong predictor of short- and long-term mortalities in patients hospitalized with CAP., (© 2017 Asian Pacific Society of Respirology.)