Differential metabolic host response to pathogens associated with community-acquired pneumonia.

Background: Metabolic changes induced by the host immune response to pathogens found in patients with community-acquired pneumonia (CAP) may provide insight into its pathogenesis. In this study, we characterized differences in the host metabolic response to common CAP-associated pathogens. Method: Targeted metabolomic profiling was performed on serum samples obtained from hospitalized CAP patients (n = 119) at admission. We quantified 347 unique metabolites across multiple biochemical classes, including amines, acylcarnitines, and signaling lipids. We evaluated if unique associations between metabolite levels and specific CAP-associated pathogens could be identified. Results: Several acylcarnitines were found to be elevated in C. burnetii and herpes simplex virus and lowered in M. pneumoniae as compared to other pathogens. Phenylalanine and kynurenine were found elevated in L. pneumophila as compared to other pathogens. S-methylcysteine was elevated in patients with M. pneumoniae, and these patients also showed lowered cortisol levels in comparison to almost all other pathogens. For the herpes simplex virus, we observed a unique elevation of eicosanoids and several amines. Many lysophosphatidylcholines showed an altered profile in C. burnetii versus S. pneumoniae, L. pneumophila, and respiratory syncytial virus. Finally, phosphatidylcholines were negatively affected by the influenza virus in comparison to S. pneumoniae. Conclusions: In this exploratory analysis, metabolites from different biochemical classes were found to be altered in serum samples from patients with different CAP-associated pathogens, which may be used for hypothesis generation in studies on differences in pathogen host response and pathogenesis of CAP.

Latent class analysis-based subgroups and response to corticosteroids in hospitalised community-acquired pneumonia patients: a validation study.

In patients with community-acquired pneumonia, LCA can identify robust prognostic subgroups based on clinical and inflammatory parameters. Yet, these subgroups have not proven robust in predicting response to adjunctive dexamethasone treatment. https://bit.ly/3O5eaxz.

Community-acquired pneumonia subgroups and differential response to corticosteroids: a secondary analysis of controlled studies.

BACKGROUND: Latent class analysis (LCA) has identified subgroups with meaningful treatment implications in acute respiratory distress syndrome. We performed a secondary analysis of three studies to assess whether LCA can identify clinically distinct subgroups in community-acquired pneumonia (CAP) and whether the treatment effect of adjunctive corticosteroids differs between subgroups. METHODS: LCA was performed on baseline clinical and biomarker data from the Ovidius trial (n=304) and the Steroids in Pneumonia (STEP) trial (n=727), both randomised controlled trials investigating adjunctive corticosteroid treatment in CAP, and the observational TripleP cohort (n=201). Analyses were conducted independently in two cohorts (Ovidius-TripleP combined and the STEP trial). In both cohorts, differences in clinical outcomes and response to adjunctive corticosteroid treatment were examined between subgroups identified through LCA. RESULTS: A two-class model fitted both cohorts best. Class 2 patients had more signs of systemic inflammation compared to class 1. In both cohorts, length of stay was longer and in-hospital mortality rate was higher in class 2. In the Ovidius trial, corticosteroids reduced the median length of stay in class 2 (6.5 versus 9.5 days) but not in class 1 (p-value for interaction=0.02). In the STEP trial, there was no significant interaction for length of stay. We found no significant interaction between class assignment and adjunctive corticosteroid treatment for secondary outcomes. CONCLUSIONS: In two independent cohorts, LCA identified two classes of CAP patients with different clinical characteristics and outcomes. Given the different response to adjunctive corticosteroids in the Ovidius trial, LCA might provide a useful basis to improve patient selection for future trials.

Neutrophil count, lymphocyte count and neutrophil-to-lymphocyte ratio in relation to response to adjunctive dexamethasone treatment in community-acquired pneumonia.

BACKGROUND: It is hypothesised that community-acquired pneumonia (CAP) patients with more severe disease or inflammation might benefit more from adjunctive corticosteroid treatment. Neutrophil count, lymphocyte count and neutrophil-lymphocyte ratio (NLR) have been associated with inflammation and disease severity in CAP. We investigated the interaction between these parameters and adjunctive dexamethasone effects on clinical outcomes in CAP. METHODS: We conducted a post hoc analysis of the randomised placebo-controlled Santeon-CAP trial (n = 401), which showed a positive effect of adjunctive oral dexamethasone on length of stay (LOS) in CAP patients. White blood cell (WBC) count, neutrophil count, NLR (highest tertile vs. lowest two tertiles) and lymphocyte count (lowest tertile vs. highest two tertiles) were examined as potential effect modifiers of treatment with dexamethasone on LOS (primary outcome) and ICU-admission, 30-day mortality and hospital readmission. RESULTS: WBC differential counts were available for 354 patients. The effect of dexamethasone on LOS was more pronounced in high WBC count, high neutrophil count or high NLR subgroups (difference in median LOS of 2 days versus zero days in the reference subgroups, p for interaction < 0.05). There was no effect modification for the other outcomes. Patients with low WBC and low neutrophil counts did not benefit from dexamethasone, while hospital readmission rate was higher in those treated with dexamethasone (6% vs. 11%). CONCLUSIONS: WBC count and/or neutrophil might be easily available biomarkers to guide selection of CAP patients who are more likely to benefit from adjunctive dexamethasone treatment. Future prospective trials are needed to confirm this predictive potential.

Metabolomic profiling of microbial disease etiology in community-acquired pneumonia.

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.

Adjunctive treatment with oral dexamethasone in non-ICU patients hospitalised with community-acquired pneumonia: a randomised clinical trial.

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.

Chlorhexidine 0.5%/70% Alcohol and Iodine 1%/70% Alcohol Both Reduce Bacterial Load in Clean Foot Surgery: A Randomized, Controlled Trial.

No consensus exists regarding which cleansing technique, solution, and concentration should be used in orthopedic surgery. The aim of this randomized, controlled trial was to compare the effect of chlorhexidine 0.5%/70% alcohol with iodine 1%/70% alcohol on lowering positive cultures before elective foot surgery and to study any wound complications, infections and allergic reactions. Consecutive patients ≥18 years of age scheduled for a hallux valgus correction or arthrodesis of the first metatarsophalangeal joint were included. Swabs were taken from 2 sites before and twice after preparing the skin and were quantitatively and qualitatively analyzed. The study group consisted of 49 patients with a mean age of 52.3 ± 14.4 (range 22 to 75) years of whom 42 (86%) were female. No significant differences were observed for positive cultures between the chlorhexidine (73%, 2%, and 12%) and iodine (68%, 7%, and 9%) group at any time point. Coagulase-negative staphylococci were the most commonly isolated micro-organisms found after skin preparation. Occasionally, Bacillus spp and Corynebacterium spp were cultured. The complication rate 2 weeks postoperatively was 0% in the chlorhexidine group versus 8.7% (n = 2) in the iodine group (delayed wound healing; p = .215). The complication rate at 6 weeks postoperatively was, respectively, 3.8% (n = 1) versus 4.3% (n = 1; both showed swelling and redness; p > .999). There was no significant difference in postoperative wound problems or infection rates between the 2 skin preparation solutions. Chlorhexidine 0.5%/70% alcohol and iodine 1%/70% alcohol both decreased the amount of positive cultures in elective foot surgery.

Inter-hospital variation in the utilization of diagnostics and their proportionality in the management of adult community-acquired pneumonia.

BACKGROUND: Utilization of diagnostics and biomarkers are the second largest cost drivers in the management of patients hospitalized with community-acquired pneumonia (CAP). The present study aimed to systematically assess the inter-hospital variation in these cost drivers in relation to antibiotic use in CAP. METHODS: Detailed resource utilization data from 300 patients who participated in a multicenter placebo-controlled trial investigating dexamethasone as adjunctive treatment for community-acquired pneumonia was grouped into 3 categories: clinical chemistry testing, radiological exams, and microbiological testing. Based on the identified top 5 items per category, average costs were calculated per category and per hospital. Antibiotic de-escalation at day 3 and secondary ICU admission were assessed as outcomes for proportionality of diagnostics use. RESULTS: The mean costs for diagnostics varied between hospitals from 350 (SD 31) to 841 (SD 37) euro per patient (p < 0.001). This difference was primarily explained by variation in costs for microbiological testing (mean 195 vs. 726 euro per patient, p < 0.001). There was no difference in number of secondary ICU admissions but there was an inverse association between the costs of microbiological testing and level of antibiotic de-escalation. De-escalation occurred most frequently in the hospital with the lowest cost for microbiological testing (48% vs. 30%; p = 0.018). The latter hospital had an automated physician alert system in place to consider a timely iv-to-oral switch of antibiotics. CONCLUSIONS: Large inter-hospital variation exists in resource utilization, mainly in microbiological diagnostics in the management of adult patients with community-acquired pneumonia. A counterintuitive inverse association between the magnitude of these costs and the amount of antibiotic de-escalation was found. Future studies about the optimal cost-effective set of microbiological testing for antimicrobial stewardship in pneumonia patients should acknowledge the interaction between testing, way of communication of results and triggered physician alert systems. TRIAL REGISTRATION: ClinicalTrials.gov NCT01743755.

First human case of tick-borne encephalitis virus infection acquired in the Netherlands, July 2016.

In July 2016, the first autochthonous case of tick-borne encephalitis was diagnosed in the Netherlands, five days after a report that tick-borne encephalitis virus (TBEV) had been found in Dutch ticks. A person in their 60s without recent travel history suffered from neurological symptoms after a tick bite. TBEV serology was positive and the tick was positive in TBEV qRT-PCR. TBEV infection should be considered in patients with compatible symptoms in the Netherlands.

Dexamethasone downregulates the systemic cytokine response in patients with community-acquired pneumonia.

The influence of adjunctive corticosteroids on the cytokine response in community-acquired pneumonia (CAP) is largely unknown. In this study, we analyzed the effect of dexamethasone on the cytokine response in patients with CAP and evaluated whether this effect is dependent on the causative microorganism. We hypothesized that dexamethasone has a larger effect on the cytokine response in patients with pneumococcal pneumonia than in patients with pneumonia caused by an atypical bacterium. A total of 304 hospitalized, nonimmunocompromised patients with CAP were randomized to an adjunctive 4-day course of 5 mg dexamethasone once a day (n = 151) or a placebo (n = 153). Serum concentrations of interleukin-1 receptor antagonist (IL-1Ra), IL-6, IL-8, IL-10, IL-17, tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), macrophage inflammatory protein-1 alpha (MIP-1α), and monocyte chemotactic protein-1 (MCP-1) were measured on days 0, 1, 2, and 4 and at a control visit. Overall, the concentrations of IL-6 (P < 0.01), IL-8 (P < 0.01), MCP-1 (P < 0.01), and TNF-α (P < 0.01) were significantly lower on day 2 in the dexamethasone group than in the placebo group. In patients with pneumococcal pneumonia (n = 72), both treatment groups showed a rapid decrease of cytokine concentrations; only the concentration of TNF-α (P = 0.05) was significantly lower in the dexamethasone group on day 2. In patients with CAP caused by an atypical pathogen (Legionella pneumophila, Chlamydophila species, Coxiella burnetii, or Mycoplasma pneumoniae; n = 58), IL-1Ra (P < 0.01), IL-6 (P < 0.01), and MCP-1 (P = 0.03) decreased more rapidly in the dexamethasone group than in the placebo group. In conclusion, dexamethasone downregulates the cytokine response during CAP. This effect seems to be dependent on the causative microorganism. This study provides insight into which patients with CAP might benefit most from adjunctive dexamethasone.

Eradication of carriage with methicillin-resistant Staphylococcus aureus: determinants of treatment failure.

BACKGROUND: Using data from an observational study in which the effectiveness of a guideline for eradication of methicillin-resistant Staphylococcus aureus (MRSA) carriage was evaluated, we identified variables that were associated with treatment failure. METHODS: A multivariate logistic regression model was performed with subgroup analyses for uncomplicated and complicated MRSA carriage (the latter including MRSA infection, skin lesions, foreign-body material, mupirocin resistance and/or exclusive extranasal carriage) and for those treated according to the guideline (i.e. mupirocin nasal ointment and chlorhexidine soap solution for uncomplicated carriage, in combination with two oral antibiotics for complicated carriage). RESULTS: Six hundred and thirteen MRSA carriers were included, of whom 333 (54%) had complicated carriage; 327 of 530 patients (62%) with known complexity of carriage were treated according to the guideline with an absolute increase in treatment success of 20% (95% confidence interval 12%-28%). Among those with uncomplicated carriage, guideline adherence [adjusted odds ratio (OR(a)) 7.4 (1.7-31.7)], chronic pulmonary disease [OR(a) 44 (2.9-668)], throat carriage [OR(a) 2.9 (1.4-6.1)], perineal carriage [OR(a) 2.2 (1.1-4.4)] and carriage among household contacts [OR(a) 5.6 (1.2-26)] were associated with treatment failure. Among those with complicated carriage, guideline adherence was associated with treatment success [OR(a) 0.2 (0.1-0.3)], whereas throat carriage [OR(a) 4.4 (2.3-8.3)] and dependence in activities of daily living [OR(a) 3.6 (1.4-8.9)] were associated with failure. CONCLUSIONS: Guideline adherence, especially among those with complicated MRSA carriage, was associated with treatment success. Adding patients with extranasal carriage or dependence in daily self-care activities to the definition of complicated carriage, and treating them likewise, may further increase treatment success.

Eradication of carriage with methicillin-resistant Staphylococcus aureus: effectiveness of a national guideline.

BACKGROUND: We evaluated the effectiveness of eradication of methicillin-resistant Staphylococcus aureus (MRSA) carriage in the Netherlands after the introduction of a guideline in 2006. The guideline distinguishes complicated (defined as the presence of MRSA infection, skin lesions, foreign-body material, mupirocin resistance and/or exclusive extranasal carriage) and uncomplicated carriage (not meeting criteria for complicated carriage). Mupirocin nasal ointment and chlorhexidine soap solution are recommended for uncomplicated carriers and the same treatment in combination with two oral antibiotics for complicated carriage. METHODS: A prospective cohort study was performed in 18 Dutch centres from 1 October 2006 until 1 October 2008. RESULTS: Six hundred and thirteen MRSA carriers underwent one or more decolonization treatments during the study period, mostly after hospital discharge. Decolonization was achieved in 367 (60%) patients with one eradication attempt and ultimately 493 (80%) patients were decolonized, with a median time until decolonization of 10 days (interquartile range 7-43 days). Three hundred and twenty-seven (62%) carriers were treated according to the guideline, which was associated with an absolute increase in treatment success of 20% [from 45% (91/203) to 65% (214/327)]. CONCLUSIONS: Sixty percent of MRSA carriers were successfully decolonized after the first eradication attempt and 62% were treated according to the guideline, which was associated with an increased treatment success.

Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. METHODS: In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. FINDINGS: Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4-5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0-9·0) in the dexamethasone group compared with 7·5 days (5·3-11·5) in the placebo group (95% CI of difference in medians 0-2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). INTERPRETATION: Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. FUNDING: None.

Clinical features predicting failure of pathogen identification in patients with community acquired pneumonia.

Community acquired pneumonia (CAP) is caused by a variety of microorganisms. By identifying patients at risk for failure of pathogen identification, it is possible to make an early decision on the extent of diagnostic procedures to be performed. This is especially important in patients with severe CAP. The aim of this study was to identify these patients by using clinical and laboratory features. In 201 patients hospitalized for CAP, clinical and laboratory variables were collected. Pathogen identification was performed by culture of sputum and blood, urine antigen tests, polymerase chain reaction of sputum, serological testing and viral culture of the pharynx. In 128 patients a respiratory microorganism was identified. In both univariate and multivariate analysis, failure of pathogen identification was predicted by pre-hospital antibiotic therapy, a medical history of hypertension and a low C-reactive protein. We conclude that patients with pre-hospital antibiotic therapy, a medical history of hypertension and a relatively low C-reactive protein are at risk for failure of pathogen identification. These predictors should be confirmed in a larger population. Invasive testing in high-risk patients with CAP in the presence of these predictors should be considered at an early phase of hospitalization.

Mannose-binding lectin genotypes in susceptibility to community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is most frequently caused by Streptococcus pneumoniae, Haemophilus influenzae, atypical pathogens, and respiratory viruses. Susceptibility to CAP can be increased by single-nucleotide polymorphisms (SNPs) within the mannose-binding lectin (MBL) gene. We questioned whether MBL polymorphisms are associated with the susceptibility to and outcome of CAP and its most common pathogens. METHODS: All adult patients presenting with CAP in a 23-month period were included in this study. Frequencies of SNPs were determined for the promoter X/Y and the three coding SNPs in exon 1 (A/0). Six genotypes were constructed representing patients with sufficient and deficient serum levels of MBL. The results of the patients with CAP were compared with control subjects. RESULTS: In 199 patients and 223 control subjects, MBL genotypes were determined. There were no differences in MBL genotype frequencies between patients with CAP in general, pneumonia caused by S pneumoniae or H influenzae, and control subjects. The frequency of sufficient MBL genotypes was nonsignificantly higher in patients with pneumonia with Legionella sp and Mycoplasma pneumoniae. In Legionella spp, the sufficient YA/YA genotype was significantly more frequent than in control subjects (odds ratio [OR], 5.43; confidence interval [CI], 1.32 to 22.41; p = 0.02). The frequency of the MBL-deficient genotype was significantly higher in patients with viral (co)infections (OR, 2.36; CI, 1.06 to 5.26; p = 0.03) and nonsignificantly higher in patients with pneumococcal pneumonia and viral (co)infections. MBL genotypes had no effect on outcome. CONCLUSIONS: MBL genotypes play a limited role in pneumococcal pneumonia. Sufficient MBL genotypes were more frequently found in a small group of patients with atypical pneumonia, and MBL-deficient genotypes were more frequently found in patients with viral (co)infections.

Prior outpatient antibiotic use as predictor for microbial aetiology of community-acquired pneumonia: hospital-based study.

OBJECTIVE: The causative micro-organism in community-acquired pneumonia (CAP) is often difficult to predict. Different studies have examined chronic morbidity and clinical symptoms as predictors for microbial aetiology of pneumonia. The aim of our study was to assess whether prior outpatient antimicrobial treatment is predictive for determining the microbial aetiology of CAP. METHODS: This was a hospital-based prospective observational study including all patients admitted with CAP between 1 October 2004 and 1 August 2006. Microbial investigations included sputum, blood culture, sputum PCR, antigen testing and serology. Exposure to antimicrobial drugs prior to hospital admission was ascertained through community pharmacy dispensing records. Multivariate logistic regression analysis was conducted to assess whether prior outpatient antimicrobial treatment is a predictor of microbial aetiology. Patient demographics, co-morbidities and pneumonia severity were considered to be other potential predictors. RESULTS: Overall, 201 patients were included in the study. The microbial aetiology was determined in 64% of the patients. The five most prevalent pathogens were Streptococcus pneumoniae, Heamophilus influenzae, Legionella spp., Mycoplasma pneumoniae and Influenza virus A+B. Forty-seven of the patients (23%) had received initial antimicrobial treatment as outpatients. Multivariate analyses revealed that initial outpatient beta-lactam treatment was associated with a threefold increased chance of finding atypical pathogens and a threefold decreased probability of pneumococcal infection; the corresponding odds ratios were 3.51 (95% CI 1.25-9.99) and 0.30 (95% CI 0.10-0.90), respectively. Patients who received macrolides prior to hospitalisation had an increased probability of viral pneumonia. CONCLUSION: Prior outpatient antimicrobial therapy has a predictive value in the diagnostic workup aimed at identifying the causative pathogen and planning corresponding antimicrobial treatment in patients hospitalised for pneumonia.