Low expression of the CCL5 gene and low serum concentrations of CCL5 in severe invasive group a streptococcal disease.

PURPOSE: Our objective was to elucidate host dependent factors of disease severity in invasive group A Streptococcal disease (iGAS) using transcriptome profiling of iGAS cases of varying degrees of severity at different timepoints. To our knowledge there are no previous transcriptome studies in iGAS patients. METHODS: We recruited iGAS cases from June 2018 to July 2020. Whole blood samples for transcriptome analysis and serum for biomarker analysis were collected at three timepoints representing the acute (A), the convalescent (B) and the post-infection phase (C). Gene expression was compared against clinical traits and disease course. Serum chemokine ligand 5 (CCL5, an inflammatory cytokine) concentration was also measured. RESULTS: Forty-five patients were enrolled. After disqualifying degraded or impure RNAs we had 34, 31 and 21 subjects at timepoints A, B, and C, respectively. Low expression of the CCL5 gene correlated strongly with severity (death or need for intensive care) at timepoint A (AUC = 0.92), supported by low concentrations of CCL5 in sera. CONCLUSIONS: Low gene expression levels and low serum concentration of CCL5 in the early stages of an iGAS infection were associated with a more severe disease course. CCL5 might have potential as a predictor of disease severity. Low expression of genes of cytotoxic immunity, especially CCL5, and corresponding low serum concentrations of CCL5 associated with a severe disease course, i.e. death, or need for intensive care, in early phase of invasive group A Streptococcal disease.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Reduced plasma PCSK9 response in patients with bacteraemia is associated with mortality.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme controls blood cholesterol levels by downregulating the expression of the low-density lipoprotein receptor (LDLR). Pathogenic lipids (e.g. lipopolysaccharide) are removed from the circulation by an LDLR/PCSK9-dependent mechanism; thus, it has been suggested that PCSK9 inhibitors may be beneficial in the treatment of infections. We measured plasma PCSK9 levels in patients with culture-positive bacteraemia and explored pathogen-dependent and infection site-dependent effects as well as correlations between patient characteristics and outcome. METHODS: Proprotein convertase subtilisin/kexin type 9 in the plasma was measured with an enzyme-linked immunosorbent assay from 481 patients with blood culture-positive infection on days 0 to 4 after admission to the emergency department. Patient outcome and clinical and laboratory data were gathered retrospectively from patient records. RESULTS: The plasma PCSK9 level was elevated equally in patients with Gram-positive or Gram-negative bacterial infections; particularly high levels were seen in patients with a lower respiratory tract infection and Streptococcus pneumoniae bacteraemia. PCSK9 levels showed a significant positive correlation with C-reactive protein (CRP) level. Bacteraemia patients with liver disease or a history of alcohol abuse had significantly lower levels of plasma PCSK9. Reduced PCSK9 plasma responses in patients were significantly associated with mortality at days 7, 28 and 90. CONCLUSION: Proprotein convertase subtilisin/kexin type 9 is upregulated in blood culture-positive infections. Plasma PCSK9 resembles acute-phase proteins; its expression is induced during an infection, reduced in liver disease and correlates positively with CRP level. We have shown that PCSK9 levels are lower in patients with a fatal prognosis.

Plasma cell-free DNA and qSOFA score predict 7-day mortality in 481 emergency department bacteraemia patients.

BACKGROUND: A few studies have shown that both quick Sequential Organ Failure Assessment (qSOFA) score and cell-free DNA (cfDNA) have potential use as a prognostic marker in patients with infection. We studied these two markers alone and in combination to identify those emergency department (ED) patients with the highest risk of death. METHODS: Plasma cfDNA level was studied on days 0 to 4 after admittance to the ED from 481 culture-positive bloodstream infection cases. The qSOFA score was evaluated retrospectively according to Sepsis-3 definitions. The primary outcome was death by day 7. RESULTS: CfDNA on day 0 was significantly higher in nonsurvivors than in survivors (2.02 µg mL-1 vs. 1.35 µg mL-1 , P < 0.001). CfDNA level was high (>1.69 µg mL-1 ) in 134 (28%) of 481 cases, and the qSOFA score was ≥2 in 128 (28%) of 458 cases. High cfDNA and qSOFA score ≥2 had 70% and 77% sensitivity and 76% and 76% specificity in predicting death by day 7, respectively. High cfDNA alone had odds ratio (OR) of 7.7 (95% CI 3.9-15.3) and qSOFA score ≥2 OR of 11.6 (5.5-24.3), but their combination had OR of 20.3 (10.0-41.4) in predicting death by day 7 when compared with those with low cfDNA and qSOFA score <2. Amongst the five cases with the highest cfDNA levels, there were three patients with severe disseminated intravascular coagulation. CONCLUSION: CfDNA and qSOFA score can be used independently to identify those bacteraemia patients at high risk of death, and combining these two markers gives additional advantage.

Evidence of streptococcal origin of acute non-necrotising cellulitis: a serological study.

Bacteriological diagnosis is rarely achieved in acute cellulitis. Beta-haemolytic streptococci and Staphylococcus aureus are considered the main pathogens. The role of the latter is, however, unclear in cases of non-suppurative cellulitis. We conducted a serological study to investigate the bacterial aetiology of acute non-necrotising cellulitis. Anti-streptolysin O (ASO), anti-deoxyribonuclease B (ADN) and anti-staphylolysin (ASTA) titres were measured from acute and convalescent phase sera of 77 patients hospitalised because of acute bacterial non-necrotising cellulitis and from the serum samples of 89 control subjects matched for age and sex. Antibiotic treatment decisions were also reviewed. Streptococcal serology was positive in 53 (69%) of the 77 cases. Furthermore, ten cases without serological evidence of streptococcal infection were successfully treated with penicillin. Positive ASO and ADN titres were detected in ten (11%) and three (3%) of the 89 controls, respectively, and ASTA was elevated in three patients and 11 controls. Our findings suggest that acute non-necrotising cellulitis without pus formation is mostly of streptococcal origin and that penicillin can be used as the first-line therapy for most patients.

Healthcare workers as vectors of infectious diseases.

Nosocomial infections cause considerable morbidity and mortality. Healthcare workers (HCWs) may serve as vectors of many infectious diseases, many of which are not often primarily considered as healthcare-associated. The probability of pathogen transmission to patients depends on several factors, such as the characteristics of a pathogen, HCW and patient. Pathogens with high transmission potential from HCWs to patients include norovirus, respiratory infections, measles and influenza. In contrast, human immunodeficiency virus (HIV) and viral hepatitis are unlikely to be transferred. The prevention of HCW-associated transmission of pathogens include systematic vaccinations towards preventable diseases, continuous education, hand hygiene surveillance, active feedback and adequate staff resources.

Obesity and the risk and outcome of infection.

The interactions between obesity and infectious diseases have recently received increasing recognition as emerging data have indicated an association between obesity and poor outcome in pandemic H1N1 influenza infection. Obesity is an established risk factor for surgical-site infections, nosocomial infections, periodontitis and skin infections. Several studies indicate that acute pancreatitis is more severe in the obese. Data are controversial and limited as regards the association between obesity and the risk and outcome of community-acquired infections such as pneumonia, bacteremia and sepsis and obesity and the course of HIV infection. As the cause-effect relationship between obesity and infection remains obscure in many infectious diseases, further studies are warranted. The consequences of obesity may have substantial effects on the global burden of infectious diseases.

Recurrent cellulitis with benzathine penicillin prophylaxis is associated with diabetes and psoriasis.

Risk factors for recurrent cellulitis were assessed in a case-control study including 398 patients receiving prophylactic treatment with benzathine penicillin and 8,005 controls derived from a national population-based health survey. In the multivariate analysis, psoriasis [odds ratio (OR) 3.69], other chronic dermatoses (OR 4.14), diabetes (OR 1.65), increasing body mass index (OR 1.17), increasing age (OR 1.06) and history of previous tonsillectomy (OR 6.82) were independently associated with recurrent cellulitis. Forty percent of the patients reported a cellulitis recurrence, despite ongoing benzathine penicillin prophylaxis. The role of previous tonsillectomy in recurrent cellulitis needs further evaluation.

Distribution of emm types in invasive and non-invasive group A and G streptococci.

Our study describes the emm type distributions of invasive and non-invasive group A streptococci (GAS) and group G streptococci (GGS) strains in one of the biggest Health Districts in Finland. A total of 571 GAS or GGS were recovered from patients with invasive or non-invasive infections during a 1-year period in 2008-2009 in Pirkanmaa Health District in Finland. We describe here the emm type distributions of GAS and GGS collected from throat (n = 246), pus (n = 217), deep tissue (n = 56) and blood (n = 52). The most common emm types among GAS were emm77, emm1, emm28, emm89 and emm12. Among GGS, the most common emm types were stG480, stG643, stG6, stC6979 and stG485. Some emm types were found to associate with certain infection focus. In GAS, emm77 associated with pus isolates, whereas emm1 and emm12 were more frequent among throat isolates. In GGS, stG480 was more commonly found from throat isolates.

Streptococcus pyogenes bacteraemia, emm types and superantigen profiles.

The aim of this study was to investigate the emm types and superantigen profiles of bacteraemic group A streptococcal (GAS; Streptococcus pyogenes) isolates and to detect possible associations between the molecular characteristics of isolates and the clinical presentations of disease. In this population-based study, 87 bacteraemic GAS isolates from adult patients in Pirkanmaa Health District (HD), Finland, during the period 1995-2004 were emm typed and genotyped for superantigen (SAg) profiles. The epidemiological and clinical data of the patients were analysed with the microbiological characterisation data. Among the 87 isolates, 18 different emm types were found. emm1, emm28 and emm81 were the three most common types, covering 52% of isolates. The prevalence of specific emm types showed high variability during the 10-year study period. We could not find any association between the emm type and clinical features of bacteraemic infection, such as underlying diseases, disease manifestations or case fatality. Of nine superantigen genes examined, speA and speC were identified in 20 and 30% of the strains, respectively. No association was found between disease manifestation and the presence of single superantigen genes. The 26-valent GAS vaccine would have covered only 62% of isolates causing invasive disease in Pirkanmaa HD during the study period.

High pentraxin-3 plasma levels associate with thrombocytopenia in acute Puumala hantavirus-induced nephropathia epidemica.

Our aim was to investigate whether plasma levels of the long pentraxin-3 (PTX3) associate with the severity of Puumala hantavirus-induced nephropathia epidemica (NE). Sixty-one prospectively identified consecutively hospitalized NE patients were examined. Plasma PTX3, interleukin (IL)-6, terminal complement complex SC5b-9, complement component C3, C-reactive protein (CRP), creatinine, sodium, kynurenine, and tryptophan levels, as well as the blood cell count, were determined for up to five consecutive days after hospitalization. Receiver operating characteristic (ROC) analysis revealed that the maximum PTX3 level >101.6 ng/ml (high PTX3) showed a sensitivity of 71% and a specificity of 89% for detecting platelet level <50 × 10(9)/l, with an area under the curve (AUC) value of 0.78 (95% confidence interval [CI] 0.63-0.94). High PTX3 level was also associated with several other variables reflecting the severity of the disease: patients with high PTX3 level had higher maximum blood leukocyte (16.1 vs. 9.7 × 10(9)/l, p < 0.001), plasma IL-6 (16.9 vs. 9.0 pg/ml, p = 0.007), and creatinine (282 vs. 124 µmol/l, p = 0.007) levels than patients with low maximum PTX3 level. They also had longer hospital stays (8 vs. 5 days, p = 0.015) compared to patients with low PTX3 level. High plasma PTX3 levels are associated with thrombocytopenia and the overall severity of NE.

Smoking and the outcome of infection.

Smoking has substantial local and systemic adverse effects on the immune system, respiratory tract and skin and soft tissues. Smokers are at increased risk of invasive pneumococcal disease, pneumonia, periodontitis, surgical infections, tuberculosis, influenza and meningococcal disease. The results of several studies indicate that smokers with periodontitis or tuberculosis suffer more severe disease. Data on the impact of smoking on sepsis and pneumonia are controversial and limited, and systematic data regarding the outcome of the majority of infections in smokers are scarce. Abundant data indicate that children exposed to environmental tobacco smoke (ETS) suffer from more severe infections. However, information regarding the effects of ETS on the outcome of infections in adults is limited. Various aspects of the relation between smoking and the outcome of bacterial infection (e.g. potential dose-dependent effects and the interactions between smoking and other environmental factors that may affect the course of infectious diseases) remain to be established.

Plasma level of soluble urokinase-type plasminogen activator receptor as a predictor of disease severity and case fatality in patients with bacteraemia: a prospective cohort study.

OBJECTIVES: Urokinase-type plasminogen activator receptor (uPAR) is expressed on a variety of different immune cells and vascular endothelial cells during inflammation. Previous studies indicate that a high plasma concentration of the soluble form of the receptor (suPAR) predicts poor outcome in infectious diseases. DESIGN: A prospective cohort study. SUBJECTS AND METHODS: Plasma suPAR levels were measured in 132 patients with bacteraemia caused by Staphylococcus aureus, Streptococcus pneumoniae, ß-haemolytic streptococcae or Escherichia coli using a commercial enzyme-linked immunosorbent assay (ELISA). Values were measured on days 1-4 after a positive blood culture, on days 13-18 and on recovery. RESULTS: The maximum suPAR values on days 1-4 were markedly higher in nonsurvivors compared to survivors (15.8 vs. 7.3 ng mL(-1) , P < 0.001) and the area under the receiver operating characteristic curve (AUC(ROC) ) in the prediction of case fatality was 0.84 (95% confidence interval (CI) 0.76-0.93, P < 0.001). At a cut-off level of 11.0 ng mL(-1) , the sensitivity and specificity of suPAR for fatal disease was 83% and 76%, respectively. A high level of suPAR (≥ 11 ng mL(-1) ) was associated with hypotension (mean arterial pressure < 70 mmHg) (odds ratio (OR) 6.5; 95% CI 2.9-14.6) and high sequential organ failure assessment score (≥ 4) (OR 9.3; 95% CI 4.0-21.9). A high suPAR level remained an independent risk factor for case fatality in a logistic regression model adjusted for potential confounders. CONCLUSION: Plasma suPAR level is a sensitive and specific independent prognostic biomarker in patients with bacteraemia.

Meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia in Tampere University Hospital: a case-control study, Finland October 2002 to January 2010.

Meticillin-resistant Staphylococcus aureus (MRSA) has emerged as a frequent pathogen in blood cultures in Pirkanmaa Hospital District (HD), Finland. To study risk factors for MRSA bacteraemia and the adequacy of empirical antimicrobial treatment, we retrospectively reviewed the hospital records of 102 patients, 51 with MRSA, and 51 with meticillin-sensitive Staphylococcus aureus (MSSA) bacteraemias respectively, who had been admitted to Tampere University Hospital in Pirkanmaa HD, from October 2002 to January 2010. For each patient with MRSA bacteraemia, one consecutively detected unmatched patient with MSSA bacteraemia was chosen as control. Patients with MRSA bacteraemias were significantly older (median age: 73 years vs 59 years, p=0.001), were more likely to have been transferred directly from another healthcare facility or were already in the hospital at the onset of bacteraemia (39/51 vs 26/51, p=0.007) and had a higher McCabe class than patients with MSSA bacteraemia (p=0.005). Patients with MRSA bacteraemia more seldom received adequate empirical antimicrobial therapy when compared to those with MSSA bacteraemia (13/51 vs 43/51, p<0.001). Of previously known MRSA carriers 10 of 29 received adequate empirical antimicrobial therapy for their condition. The percentage of MRSA bacteraemias among all S. aureus bacteraemias in Pirkanmaa HD is high compared to corresponding figures for the whole of Finland.

The effect of preoperative oral antibiotic use on the risk of periprosthetic joint infection after primary knee or hip replacement: a retrospective study with a 1-year follow-up.

OBJECTIVES: Antibiotics are used for various reasons before elective joint replacement surgery. The aim of this study was to investigate patients' use of oral antibiotics before joint replacement surgery and how this affects the risk for periprosthetic joint infection (PJI). METHODS: Patients having a primary hip or knee replacement in a tertiary care hospital between September 2002 and December 2013 were identified (n = 23 171). Information on oral antibiotic courses purchased 90 days preoperatively and patients' chronic diseases was gathered. Patients with a PJI in a 1-year follow-up period were identified. The association between antibiotic use and PJI was examined using a multivariable logistic regression model and propensity score matching. RESULTS: One hundred and fifty-eight (0.68%) cases of PJI were identified. In total, 4106 (18%) joint replacement operations were preceded by at least one course of antibiotics. The incidence of PJI for patients with preoperative use of oral antibiotics was 0.29% (12/4106), whereas for patients without antibiotic use it was 0.77% (146/19 065). A preoperative antibiotic course was associated with a reduced risk for subsequent PJI in the multivariable model (OR 0.40, 95% CI 0.22-0.73). Similar results were found in the propensity score matched material (OR 0.34, 95% CI 0.18-0.65). CONCLUSIONS: The use of oral antibiotics before elective joint replacement surgery is common and has a potential effect on the subsequent risk for PJI. Nevertheless, indiscriminate use of antibiotics before elective joint replacement surgery cannot be recommended, even though treatment of active infections remains an important way to prevent surgical site infections.

Gene-environment interaction between MBL2 genotype and smoking, and the risk of gram-positive bacteraemia.

Mannose-binding lectin (MBL) insufficiency caused by point mutations in the MBL2 gene has been associated with increased susceptibility to bacteraemic infections. We here investigated the effect of MBL2 polymorphisms on the susceptibility and clinical course of bacteraemia. The study cohort comprised 145 patients with bacteraemia and 400 controls. In the case of patients with bacteraemia, laboratory findings and clinical data were registered on admission and during six consecutive days. MBL2 structural polymorphisms at codons 52 (CGT-->TGT; designated D or O), 54 (GGC-->GAC; B or O) and 57 (GGA-->GAA; C or O) in exon 1 of the MBL2 gene and promoter region polymorphisms at position -221 (G-->C, designated Y or X alleles) were determined. No difference in MBL2 genotype frequencies between the bacteraemic patients and controls was detected, and MBL2 genotype had no independent effect on mortality, nor disease severity. However, smoking proved a significant risk factor for Gram-positive (Staphylococcus aureus, Streptococcus pneumoniae or beta-haemolytic streptococci) bacteraemia in patients carrying the variant O allele (53% current smokers in Gram-positive bacteraemia patients compared with only 21% in controls, odds ratios 4.2, 95% confidence intervals 2.0-9.0; P < 0.001), while it did not have an effect in those homozygous for the A allele. The same effect was not detected in Escherichia coli bacteraemia. In conclusion, MBL2 genotypes representing MBL insufficiency were not associated with the overall risk of bacteraemia or disease severity, but smoking in carriers of the structural variant O allele may have a deleterious effect increasing the risk of Gram-positive bacteraemia.

The impact of preoperative bacteriuria on the risk of periprosthetic joint infection after primary knee or hip replacement: a retrospective study with a 1-year follow up.

OBJECTIVES: Patients who undergo elective joint replacement are traditionally screened and treated for preoperative bacteriuria to prevent periprosthetic joint infection (PJI). More recently, this practice has been questioned. The purpose of this study was to determine whether preoperative bacteriuria is associated with an increased risk of PJI. METHODS: Patients who had undergone a primary hip or knee replacement in a tertiary care hospital between September 2002 and December 2013 were identified from the hospital database (23 171 joint replacements, 10 200 hips, and 12 971 knees). The results of urine cultures taken within 90 days before the operation were obtained. Patients with subsequent PJI or superficial wound infection in a 1-year follow-up period were identified based on prospective infection surveillance. The association between bacteriuria and PJI was examined using a multivariable logistic regression model that included information on the operated joint, age, gender and the patients' chronic diseases. RESULTS: The incidence of PJI was 0.68% (n = 158). Preoperative bacteriuria was not associated with an increased risk of PJI either in the univariate (0.51% versus 0.71%, OR 0.72, 95% CI 0.34-1.54) or in the multivariable (OR 0.82, 95% CI 0.38-1.77) analysis. There were no cases where PJI was caused by a pathogen identified in the preoperative urine culture. Results were similar for superficial infections. CONCLUSIONS: There was no association between preoperative bacteriuria and postoperative surgical site infection. Based on these results, it seems that the preoperative screening and treatment of asymptomatic bacteriuria is not required.

Acute phase response in cerebral infarction.

The serum concentrations of the acute phase proteins, C-reactive protein, serum amyloid A protein, and alpha-1-antichymotrypsin were determined in 50 young and middle aged patients with cerebral infarction and in sex and age matched community controls. Of 46 case control pairs, 11 cases but only one control had raised acute phase protein concentrations simultaneously (p less than 0.01); four case control pairs were excluded because of an infectious complication following infarction and an acute phase response. Seven of the 11 patients (64%) with raised acute phase protein concentrations had a history of bacterial infection in the preceding month but of the remaining 35 patients without raised concentrations only four (11%) had such a history (p less than 0.01). In general, the acute phase response was less pronounced and occurred less often than has been reported in patients after acute myocardial infarction. The results suggest that a positive acute phase response is associated with a preceding bacterial infection or with an infectious complication after cerebral infarction. Measurement of acute phase proteins, therefore, could be used to evaluate the possible role of preceding bacterial infection in the development of cerebral infarction and also in the management of these patients as an early indicator of possible infectious complications.

Clinical course and treatment of IgA nephropathy.

Impairment of renal function, severe proteinuria and arterial hypertension are the strongest clinical predictors of an unfavorable outcome in IgA nephropathy (IgAN). Glomerulosclerosis and interstitial fibrosis are the most reliable histologic prognostic markers. Metabolic syndrome and insulin resistance probably affect the clinical course of the disease. Among the known gene polymorphism it seems that there is a link between the ACE gene D allele and the progression of IgAN. Elevated blood pressure should be actively treated. The target blood pressure is 130/80 mmHg or less and the goal should also be to reduce proteinuria. Several large-scale trials are currently testing corticosteroids and other drugs in the treatment of IgAN.

Pneumococcal bacteraemia during a recent decade.

We retrospectively reviewed 159 episodes of bacteraemic pneumococcal infection in 157 adult patients at the Helsinki University Central Hospital during two periods between 1976 and 1979 and 1986 and 1989. We looked especially at changes in underlying diseases and prognostic factors. The overall case fatality rate was 21% and there was a small diminishing trend in that rate from 28% (16/58) in the late 1970s to 17% (17/101) in the late 1980s. The patients who died in the late 1980s were younger than those who died in the earlier period. The most common underlying factors were alcohol abuse, cardiovascular diseases and chronic obstructive pulmonary diseases. Old age was neither a predisposing factor nor did it predict the outcome. No significant changes in underlying diseases or prognostic factors were noted during the two periods studied except a small decrease in connective tissue diseases as underlying conditions. The factors related to increased fatality included hepatic cirrhosis, a combination of pneumonia and meningitis, complications such as shock, respiratory insufficiency, central nervous system disorders and circulatory acidosis, and laboratory findings such as thrombocytopenia, absence of leucocytosis and increased amounts of serum creatinine, aspartate aminotransferase and alanine aminotransferase on admission to the hospital. Previous splenectomy and malignant diseases were not associated with higher mortality. The thrombocytopenia at the time of positive blood culture and the circulatory acidosis as a complication seemed to be independently the most useful predictive factors for a fatal outcome using multivariate logistical regression analysis after adjustment to classic risk factors.