Oddvar Oppegaard

Beta-haemolytic group A, C and G streptococcal infections in Western Norway: a 15-year retrospective survey

Pyogenic streptococci cause significant morbidity and mortality, and the incidence of invasive group C and G streptococcal disease appears to be increasing. In this retrospective study we describe the epidemiological characteristics of invasive group A, C and G, along with non-invasive group C and G streptococcal infections in Western Norway from 1999 to 2013. A total of 512 invasive streptococcal infections were identified, of these 297 (58%) were group A (GAS), 24 (5%) group C (GCS) and 188 (37%) group G streptococci (GGS). In the non-invasive group, 4935 GCS and GGS-infections were identified. GCS and GGS were treated as one group (GCGS) for statistical purposes. All microbial categories displayed increasing incidence with age, seasonal variation and a male predominance. The incidence of invasive GCGS infections increased significantly from 1.4/100,000 inhabitants in 1999 to 6.3/100,000 in 2013 (p <0.001). Conversely, the annual rates of invasive GAS infection exhibited marked fluctuations, ranging from 2.7/100,000 (2000) to 8.3/100,000 (1999), but no significant temporal trends were observed. The incidence of non-invasive GCGS infections decreased significantly during the study period (p <0.001). The most frequently encountered emm-types among the 209 iGAS-isolates analysed were emm1 (24%), emm3 (14%) and emm28 (14%); whereas stG643 (19%), stG485 (15%) and stG6 (13%) were most prevalent among the 122 iGCGS-isolates available for typing. The increasing burden of invasive β-haemolytic streptococcal disease in our community calls for sustained attentiveness to the clinical and molecular aspects of GAS, GCS and GGS infections.

Etiology of cellulitis and clinical prediction of streptococcal disease: A prospective study

This prospective study of cellulitis identified β-hemolytic streptococci as the dominating cause in all investigated subgroups. Group C/G streptococci were more frequently detected than group A streptococci. No single clinical feature substantially increased the probability of confirmed streptococcal etiology.

Early Response in Cellulitis: A Prospective Study of Dynamics and Predictors

In this prospective study of cellulitis, several nonpharmacological factors were associated with lack of early response. Such early nonresponse was rarely related to inappropriate therapy but strongly predictive of early treatment escalation, suggesting that broadening antibiotic treatment often may be premature.

Increased cytotoxicity and streptolysin O activity in group G streptococcal strains causing invasive tissue infections

Streptococcus dysgalactiae subsp. equisimilis (SDSE) has emerged as an important cause of severe skin and soft tissue infections, but little is known of the pathogenic mechanisms underlying tissue pathology. Patient samples and a collection of invasive and non-invasive group G SDSE strains (n = 69) were analyzed with respect to virulence factor expression and cytotoxic or inflammatory effects on human cells and 3D skin tissue models. SDSE strains efficiently infected the 3D-skin model and severe tissue pathology, inflammatory responses and altered production of host structural framework proteins associated with epithelial barrier integrity were evident already at 8 hours post-infection. Invasive strains were significantly more cytotoxic towards keratinocytes and expressed higher Streptokinase and Streptolysin O (SLO) activities, as compared to non-invasive strains. The opposite was true for Streptolysin S (SLS). Fractionation and proteomic analysis of the cytotoxic fractions implicated SLO as a factor likely contributing to the keratinocyte cytotoxicity and tissue pathology. Analyses of patient tissue biopsies revealed massive bacterial load, high expression of slo, as well as immune cell infiltration and pro-inflammatory markers. Our findings suggest the contribution of SLO to epithelial cytotoxicity and tissue pathology in SDSE tissue infections.

Sequence diversity of sicG among group C and G Streptococcus dysgalactiae subspecies equisimilis isolates associated with human infections in western Norway

Streptococcal inhibitor of complement (SIC) and distantly related to SIC (DRS) are well-characterized extracellular virulence factors produced by only a few emm types among group A streptococci. The prevalence and sequence variations of the sic-like gene (sicG) in clinical samples of group C and G Streptococcus dysgalactiae subspecies equisimilis (SDSE), however, have not been widely investigated. We constructed primers targeting sicG and screened 129 geographically matched and previously emm-typed non-invasive (n = 64) and invasive (n = 65) SDSE isolates for the presence of this gene. sicG was detected in seven non-invasive and eight invasive isolates belonging to eight different emm types. Within five of these emm types, sicG-negative isolates were also detected. All three isolates of stG2078.0 possessed sicG and were associated with severe soft tissue infections. Altogether, six sicG alleles (sicG1–6) were identified, and sequence variations were mainly caused by single nucleotide polymorphisms and deletion/insertion mutations. sicG1–6 were predicted to encode SICG proteins of varying length, composition, and homology with SIC and DRS proteins of group A streptococci. Our findings indicate an unpredictable association between sicG and emm type, a limited distribution and substantial sequence diversity of sicG, and no obvious relation between its presence and disease severity.

CD64 as a potential biomarker in septic arthritis

BackgroundTraditional inflammatory markers are generally unhelpful in discerning septic arthritis from inflammatory joint disease due to their lack of specificity. We wished to explore the discriminatory power of the novel inflammatory marker, Fc-gamma-receptor type 1, CD64, in patients presenting with acute arthritis.MethodsPatients were recruited prospectively in the time period June 2009 to December 2011. Thirty-six patients presenting with an acute flare of chronic rheumatic arthritis, 31 with crystal-induced arthritis and 23 with septic arthritis were included. Traditional inflammatory markers, CD64 and procalcitonin (PCT) were measured and their diagnostic abilities were compared.ResultsCD64 and PCT both demonstrated a specificity of 98%, but poor sensitivities of 59% and 52%, respectively. White blood cell count (WBC), and erythrocyte sedimentation rate (ESR) did not have significant discriminatory power, while C-reactive protein (CRP) proved to have the best diagnostic accuracy as measured by area under the ROC curve (AUC 0.92, 95% confidence-interval 0.87-0.98). Subgroup analysis excluding patients with septic arthritis without concurrent bacteremia, and likewise exclusion of the patients with septic arthritis caused by coagulase negative staphylococci, both improved the diagnostic accuracy of CD64 and PCT, but not of WBC and CRP.ConclusionsCD64 and PCT are highly specific for infectious disease, but they predominantly measure bacteremia. Their use in hospital practice has yet to be defined, and especially so in localized infections.

New Tricks from an Old Cow: Infective Endocarditis Caused by Streptococcus dysgalactiae subsp. dysgalactiae

ABSTRACT We present a case of infective endocarditis caused by Streptococcus dysgalactiae subsp. dysgalactiae, a major cause of bovine mastitis and previously thought to be an animal-restricted pathogen. The patient reported no direct contact with animals, and the clinical course was severe and complicated.

Association between cytokine response, the LRINEC score and outcome in patients with necrotising soft tissue infection: a multicentre, prospective study.

Early assessment of necrotising soft tissue infection (NSTI) is challenging. Analysis of inflammatory markers could provide important information about disease severity and guide decision making. For this purpose, we investigated the association between cytokine levels and the Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC)-score, disease severity and mortality in NSTI patients. In 159 patients, plasma was analysed for IL-1β, IL-6, IL-10 and TNF-α upon admission. The severity of NSTI was assessed by SAPS, SOFA score, septic shock, microbial aetiology, renal replacement therapy and amputation. We found no significant difference in cytokine levels according to a LRINEC- score above or below 6 (IL-1β: 3.0 vs. 1.3; IL-6: 607 vs. 289; IL-10: 38.4 vs. 38.8; TNF-α: 15.1 vs. 7.8 pg/mL, P > 0.05). Patients with β-haemolytic streptococcal infection had higher level of particularly IL-6. There was no difference in mortality between patients with a LRINEC-score above or below 6. In the adjusted analysis assessing 30-day mortality, the association was strongest for IL-1β (OR 3.86 [95% CI, 1.43-10.40], P = 0.008) and IL-10 (4.80 [1.67-13.78], P = 0.004). In conclusion, we found no significant association between the LRINEC-score and cytokine levels on admission. IL-6 was consistently associated with disease severity, whereas IL-1β had the strongest association with 30-day mortality.

Emergence of a Streptococcus dysgalactiae subspecies equisimilis stG62647 -lineage associated with severe clinical manifestations

Increasing incidence rates of invasive Streptococcus dysgalactiae subspecies equisimilis (SDSE) infections have been reported worldwide, but the evolutionary mechanisms underlying this development remain elusive. Through prospective surveillance of invasive SDSE infections in western Norway, we observed the emergence of a novel and virulent SDSE genotype, stG62647. This emm-type, rarely encountered as a cause of invasive disease during 1999–2012, emerged in 2013 as the predominant SDSE-genotype. The stG62647-infections were associated with an aggressive clinical course, including the occurrence of streptococcal toxic shock syndrome, necrotizing soft-tissue infections and endocarditis. All the invasive stG62647-isolates were subjected to whole genome sequencing, attempting to explore the genetic events underpinning its epidemicity. Although 10% of the genomes was unique for stG62647-genotype, notably 18 out of 19 isolates contained a disrupted streptococcal invasive locus (sil) due to the insertion of a transposase, IS1548, into the silB-gene. We postulate that the virulence of stG6267-isolates could be partly attributable to the abrogation of the attenuating control normally exerted by this regulon, although experimental verification was not performed. To the best of our knowledge, this is the first study employing large scale whole genome sequencing to illuminate the genetic landscape of epidemic lineages in SDSE.

Clinical and molecular characteristics of infective β-hemolytic streptococcal endocarditis

Streptococcus pyogenes (S. pyogenes) and Streptococcus dysgalactiae subspecies equisimilis (SDSE) cause considerable morbidity and mortality, and show similarities in disease manifestations and pathogenic mechanisms. Their involvement in infective endocarditis, however, has not been well described. Invasive S. pyogenes and SDSE infections in Health Region Bergen, Norway, in the period 1999-2013 were reviewed, and sixteen cases of endocarditis were identified. The median duration of symptoms was 2.5days, the frequency of embolic events 50%, 38% received valve replacement and the 30-day mortality was 25%. In S. pyogenes, a significant correlation was observed between the repertoire of fibronectin-binding genes, phenotypic binding ability to fibronectin and disease manifestations. Conversely, no associations between phenotypic and genotypic characteristics were detected in SDSE. S. pyogenes and SDSE endocarditis is characterized by rapid and severe clinical manifestations. The pathogenesis is multifactorial, but our results infer a potential role of fibronectin binding in the development of S. pyogenes endocarditis.