- Email: [email protected]
O273 Risk factors, including antibiotic use, at hospital level for outbreaks with Clostridium difficile PCR ribotype 027
S56 C-MRSA producing toxic shock syndrome toxin 1 (tsst1) have been isolated [Durand G et al., J Clin Microbiol 2006]. Here, we describe the first report of family transmission of C-MRSA PVL-, tsst1+, in a patient (pt) with osteomyelitis. Case report: In October 2006, a 29-year-old alcoholic man with no medical history was admitted in our department of infectious diseases for acromioclavicular osteoarthritis. He was married and had two children (6 and 8 year-old). In 2005 he had a traumatic dislocation of the right acromioclavicular joint and was operated one year later for tendons refection using homogenic graft. Two weeks after surgery, a purulent discharge from the post-operative wound was noted, and MRSA was cultured from swabs. The strain was resistant to oxacillin, kanamycin, tobramycin, and susceptible to ofloxacin, trimethoprimsulfamethoxazole, pristinamycin, clindamycin, vancomycin, and was intermediate to fusidic acid. He was given oral pristinamycin (1 g tid for 8 weeks). One week after the end of treatment, in October 2006, he was admitted for a right acromioclavicular osteoarthritis which required surgical debridement and intravenous vancomycin treatment. A C-MRSA strain PVL− tsst1+ grew from intra-operative samples. The family carriage screening (including the pt) showed that the pt’s children were colonised with the same MRSA strain according to the antibiotic susceptibility profile (PVL and tsst 1 detection still in process). The members of the pt’s family had no healthcare associated risk factors for C-MRSA. Vancomycin was switched to oral trimethoprimsulfamethoxazole and rifampicin combination for 3 months. Discussion: In 2002, a new type of MRSA producing tsst1 has been described in France and Switzerland. To the best of our knowledge, family transmission of C-MRSA PVL-, tsst1+ strain has never been reported. In the present case report, a cross contamination between the pt and his family is highly suspected. Conclusion: the present case shows that C-MRSA PVL-, tsst 1 might be associated with family transmission. O271 Legionella spp. causing community-acquired pneumonia in Germany. Data from the Competence Network for Community-Acquired Pneumonia (CAPNETZ) H. von Baum, R. Marre, S. Gonschior, T. Welte, C. L¨uck (Ulm, Hannover, Dresden, DE) Objectives: Prevalence, clinical data and outcome of Legionella pneumonia (LP) in 2503 patients from ten clinical centres with community acquired pneumonia (CAP), participating in the German multicentre study of the Competence Network for Community Acquired Pneumonia (CAPNETZ) were analysed. Methods: All demographic, clinical and diagnostic data of the patients were recorded using standardised web-based data sheets. Work up of respiratory samples included identification of bacterial microorganisms as well as PCR for C. pneumoniae, M. pneumoniae, Legionella spp. and viral pathogens. Urine was tested for the presence of S. pneumoniae and L. pneumophila antigen. Relevant results from serologic tests were considered. Results: Legionella spp. was diagnosed in 105 (4.2%) patients and thus represented after S. pneumoniae the second most frequent identified pathogen causing pneumonia. Patients with LP were predominantly older men, suffered more often from diabetes, were heavier smokers and produced more often respiratory samples, which were less often purulent. They received more often antibiotic substances with activity against atypical bacteria. Although 85% of the patients had a CRB 65 score of 0 or 1, respectively, 14 patients (13.3%) with LP expired. Conclusion: Legionella spp. is a relevant pathogen causing CAP in Germany and is associated with a serious clinical course.
17th ECCMID / 25th ICC, Oral presentations O272 Pathogenic Yersinia enterocolitica widely distributed in finishing pigs at slaughter in Switzerland M. Fredriksson-Ahomaa, A. Stolle, R. Stephan (Oberschleissheim, DE; Zurich, CH) Objectives: Yersiniosis is a common human infection, which is a reportable disease since 2001 in Germany. Y. enterocolitica 4/O:3 is the third most frequently isolated pathogen from patients with enteric disease after Campylobacter and Salmonella. The isolation rates of Yersinia enterocolitica of bioserotype 4/O:3 in German pig tonsils has shown to be high (56−67%). Only very few data are available for Switzerland. This work was conducted to study the prevalence of pathogenic Y. enterocolitica in Swiss pig tonsils. Furthermore, the isolates were characterised by pheno- and genotypic methods to get more epidemiological information to the current situation Methods: Tonsils of 212 finishing pigs were sampled from a slaughterhouse in Switzerland during February and March 2006. Seventeen to 35 samples were collected from at least two different herds at 8 different days. The culture method included direct plating on a selective CIN plate, overnight enrichment in non-selective CASO bouillon and selective enrichment in ITC bouillon. The Y. enterocolitica isolates were bio- and serotyped. The pathogenicity was confirmed with pheno-and genotypic methods. ail-Positive Y. enterocolitica was detected with real-time PCR after overnight enrichment in CASO. At least one isolate per sample was characterised with PFGE using NotI enzyme. Results: The prevalence of ail-positive Y. enterocolitica was 84% with PCR. The prevalence varied from 61% to 100% between the sampling days. The isolation rate was only 34% and varied between 18% and 82%. Bioserotype 4/O:3 was found in 96% of the culture-positive tonsils. Only 10% of the samples were biotype 2/O:9 positive. Six genotypes were obtained among bioserotype 4/O:3 isolates and 3 among bioserotype 2/O:9 isolates. Two genotypes (GT 1 and 2) of bioserotype 4/O:3 were dominant. Genotypes 1 and 2 were found on 6 and 5 out of 8 sampling days, respectively. Conclusions: The prevalence of pathogenic Y. enterocolitica in Swiss pigs was high using PCR, however, the isolation rate was clearly lower than in German pigs. Most of the Swiss pigs were infected with bioserotype 4/O:3, which is the most common type found among human Y. enterolitica gastroenteritis in German and Switzerland and is the only type isolated from German slaughter pigs. Pig was also shown to be a reservoir for bioserotype 2/O:9 in Switzerland. The genetic diversity of ail-positive Y. enterocolitica in the pig tonsils collected from one Swiss slaughterhouse was limited. O273 Risk factors, including antibiotic use, at hospital level for outbreaks with Clostridium difficile PCR ribotype 027 T. van der Kooi, M. Koningstein, D.W. Notermans, E.J. Kuijper, P.M.G. Filius, A. Lindemans, S. van den Hof (Bilthoven, Leiden, Rotterdam, NL) Objectives: After reports on outbreaks of severe Clostridium difficileassociated disease (CDAD) in Canada, the USA and the UK, epidemics of this strain (PCR ribotype 027, toxinotype III) were first reported in The Netherlands in June 2005. National surveillance and typing of strains was started. Fluoroquinolone use has been recognized in several studies as an important risk factor at patient level for CDAD due to type 027. This study aimed at identifying risk factors at hospital level for outbreaks with type 027. Methods: Data from 7 hospitals with known transmission of type 027 (group A), 5 hospitals with sporadic cases (group B) and 12 hospitals from a random selection without known type 027 (group C) were included. Quarterly data for 2004–2005 were collected on CDADincidence, inpatient antibiotic use (penicillins with extended spectrum and with b-lactamase inhibitors, cephalosporins, carbapenems, macrolides, clindamycin and fluoroquinolones) and hygienic and other preventive measures. The first 6 quarters were deemed the ‘pre-epidemic’ phase. In the last 2 quarters of 2005, the ‘epidemic’ phase, almost all
The medico-dental health interface – Paradigm shifts and advances in oral health for populations (Symposium organised by Colgate-Palmolive) 027 outbreaks took place. The association of AB use and hygiene policy with the incidence was analysed with multilevel linear regression. Results: Mean pre-epidemic incidence in affected hospitals was 3.6 per 10,000 patient days, in group B 3.2 and in group C 2.3. During the epidemic phase this was 5.4, 3.3 and 2.8, respectively. Pre-epidemically the unaffected hospitals had a significantly higher total use of the investigated AB [3776 DDD/10,000 patient days (pd)] than the A and B hospitals (3291 and 3325). In the epidemic phase, group A hospitals had significantly reduced their use of fluoroquinolones (from 615 to 416) whereas this rose in group C from 791 to 994 DDD/10,000 pd. In multivariate analysis giving special instructions to visitors of diarrhoea patients (regression coefficient [r.c.] −1.9), wearing an apron when caring for diarrhoea patients (r.c. −2.7) and being an academic hospital (r.c. 1.6) were significantly associated with the CDAD incidence. Conclusion: Hospital-wide use of most antibiotics known to be a risk factor for CDAD at patient level, such as fluoroquinolones, are not associated at institution level with higher incidences of type 027associated CDAD. Possibly, investigation at ward-level might correlate better. Wearing an apron and giving special instructions to visitors in case of diarrhoea appeared to be protective. O274 Amoebae as a second host for Vibrio cholerae G. Sandstr¨om, A. Saeed, B. Edvinsson, A. Weintraub, H. Abd (Stockholm, SE) Objectives: Acanthamoebae have been reported to represent the environmental host of several human pathogens. Vibrio cholerae requires 108 to 109 cells to cause cholera, and accordingly it needs an environmental host to enhance its growth. Our studies have shown that extracellular V. cholerae O1 and O139 have grown and survived in Acanthamoeba castellanii. The aim of this study is to examine the ability of A. castellanii to protect V. cholerae and to enhance its growth to be able to infect humans. Methods: V. cholerae producing green fluorescent protein was cocultivated with A. castellanii. An antibiotic assay used to examine ability of amoeba to protect intracellular bacteria and to differentiate between extracellular and intracellular bacteria. A. castellanii cultivated with V. cholerae for one week. After gentamicin killing and washing of extracellular V. cholerae, the number of intracellular bacteria was found to be 2×105 cells/mL. The amoebae harbouring V. cholerae were re-cultivated and growth of the microorganisms examined by viable counts during 2 weeks. Results: Gentamicin killed only the extracellular bacteria, while ciprofloxacin killed both, thus, the amoeba protected the intracellular V. cholerae from gentamicin. The antibiotic assay differentiated between extracellular bacteria that killed by gentamicin and intracellular bacteria that killed only by ciprofloxacin, which could diffuse into amoeba cells. Re-cultivation of A. castellanii harbouring intracellular V. cholerae resulted in enhanced growth of V. cholerae to 2×1011 CFU/mL and the bacteria survived for more than two weeks. Thus, amoeba acted as a biological incubator in which intracellular growth of the bacteria occurred to increase their number a million fold and maintained their overall viability. Existence of V. cholerae extracellularly as well as intracellularly in culture medium confirmed its facultative intracellular behaviour, which enhanced its growth and survival. Conclusions: The utilised antibiotic assay differentiates between extracellular and intracellular bacteria. Free-living amoeba is a possible biological factor, which protects and enhances growth of V. cholerae to exceed its infections dose and to supports the idea of amoeba as a second host to the bacterium in nature besides man. O275 Microbiology of thrombotic microangiopathies in Scotland, 2003–2006 K. Pollock, M. Locking, J. Cowden (Glasgow, UK) Without current surveillance of thrombotic microangiopathies such as HUS, neither prevalence nor outcomes are established in either adults
S57
or children. This study seeks to identify both health outcomes and existing management strategies. It comprises clinically driven enhanced surveillance of HUS and TTP and also further investigates the links between these syndromes and factors, which have been implicated in the etiology of HUS and TTP including infections, vascular procedures, chemotherapeutic agents and immuno-suppressants. Cases were ascertained prospectively by active, national surveillance during 2003 to 2006. Consultants in haematology, infectious diseases, microbiology, nephrology, paediatrics and public health medicine, were sent a monthly e-mail with case definition and asked to indicate whether they had a ‘case to report’ or ‘nil return’. Questionnaires, information sheets and consent forms were then sent to the relevant clinicians/consultants by post. All completed forms and questionnaires were returned to HPS and entered into a database for statistical analyses. From 2003 to October 2006, 145 reports of thrombotic microangiopathy were notified to HPS of which 103 were clinically designated HUS and 42 as TTP. There were 10 fatalities, 22 cases had some form of renal impairment and of those, 14 became dialysis dependent. Of 103 reports of HUS, 85 (83%) were caused by verotoxin-producing E. coli (VTEC) (82 were due to serotype O157). The non-O157 organisms were designated as serotypes O145, O177 and O-unidentifiable. Two atypical HUS cases were reported. One was preceded by parvovirus B19 infection/MMR immunisation and the other was due to infection with Streptococcus pneumoniae. The list of predisposing infections for development of TTP was more varied and included infection with coagulase-negative Staphylococcus aureus, Klebsiella pneumoniae and Clostridium difficile but development of TTP was significantly associated with severe sepsis. The study clearly demonstrates that development of HUS or TTP has serious and sometimes fatal consequences and that infection is a major predisposing factor in development of such syndromes.
The medico-dental health interface – Paradigm shifts and advances in oral health for populations (Symposium organised by Colgate-Palmolive) S279 Relationship between periodontal infections and systemic disease – the oral systemic connection G.J. Seymour (Dunedin, NZ) Common oral conditions, such as gingivitis and chronic periodontitis, are found world-wide and are among the most widely prevalent microbial diseases of mankind. A primary trigger for these conditions is the complex microbiota found as dental plaque, a complex microbial biofilm. Despite 3000 years of history demonstrating the influence of oral status on general health, recent decades have seen an accelerated effort for the prevention and management of these conditions through groundbreaking advances. One outcome of these advances is the realisation that periodontal diseases are associated with systemic conditions such as coronary heart disease and stroke; higher risk for preterm, low birth weight babies and pose threats to those with chronic disease: diabetes, respiratory diseases and osteoporosis. This presentation will highlight recent research associating periodontal disease with systemic diseases. The relationship between oral infections and systemic disease represents a paradigm shift in current research. A portion of this lecture will be devoted to examining the role of chronic infections and their association with cardiovascular diseases (CVD). These infections include Helicobacter pylori, Chlamydophila pneumoniae, Cytomegalovirus (CMV), and, more recently, periodontopathic bacteria including Porphyromonas gingivalis. Although a number of potential mechanisms have been postulated, the mechanism by which these infections are associated with CVD is still unclear. The various hypotheses concerning this relationship include common susceptibility, inflammation via increased circulating cytokines and inflammatory mediators, direct infection of the blood vessels and finally the possibility
17th ECCMID / 25th ICC, Oral presentations O272 Pathogenic Yersinia enterocolitica widely distributed in finishing pigs at slaughter in Switzerland M. Fredriksson-Ahomaa, A. Stolle, R. Stephan (Oberschleissheim, DE; Zurich, CH) Objectives: Yersiniosis is a common human infection, which is a reportable disease since 2001 in Germany. Y. enterocolitica 4/O:3 is the third most frequently isolated pathogen from patients with enteric disease after Campylobacter and Salmonella. The isolation rates of Yersinia enterocolitica of bioserotype 4/O:3 in German pig tonsils has shown to be high (56−67%). Only very few data are available for Switzerland. This work was conducted to study the prevalence of pathogenic Y. enterocolitica in Swiss pig tonsils. Furthermore, the isolates were characterised by pheno- and genotypic methods to get more epidemiological information to the current situation Methods: Tonsils of 212 finishing pigs were sampled from a slaughterhouse in Switzerland during February and March 2006. Seventeen to 35 samples were collected from at least two different herds at 8 different days. The culture method included direct plating on a selective CIN plate, overnight enrichment in non-selective CASO bouillon and selective enrichment in ITC bouillon. The Y. enterocolitica isolates were bio- and serotyped. The pathogenicity was confirmed with pheno-and genotypic methods. ail-Positive Y. enterocolitica was detected with real-time PCR after overnight enrichment in CASO. At least one isolate per sample was characterised with PFGE using NotI enzyme. Results: The prevalence of ail-positive Y. enterocolitica was 84% with PCR. The prevalence varied from 61% to 100% between the sampling days. The isolation rate was only 34% and varied between 18% and 82%. Bioserotype 4/O:3 was found in 96% of the culture-positive tonsils. Only 10% of the samples were biotype 2/O:9 positive. Six genotypes were obtained among bioserotype 4/O:3 isolates and 3 among bioserotype 2/O:9 isolates. Two genotypes (GT 1 and 2) of bioserotype 4/O:3 were dominant. Genotypes 1 and 2 were found on 6 and 5 out of 8 sampling days, respectively. Conclusions: The prevalence of pathogenic Y. enterocolitica in Swiss pigs was high using PCR, however, the isolation rate was clearly lower than in German pigs. Most of the Swiss pigs were infected with bioserotype 4/O:3, which is the most common type found among human Y. enterolitica gastroenteritis in German and Switzerland and is the only type isolated from German slaughter pigs. Pig was also shown to be a reservoir for bioserotype 2/O:9 in Switzerland. The genetic diversity of ail-positive Y. enterocolitica in the pig tonsils collected from one Swiss slaughterhouse was limited. O273 Risk factors, including antibiotic use, at hospital level for outbreaks with Clostridium difficile PCR ribotype 027 T. van der Kooi, M. Koningstein, D.W. Notermans, E.J. Kuijper, P.M.G. Filius, A. Lindemans, S. van den Hof (Bilthoven, Leiden, Rotterdam, NL) Objectives: After reports on outbreaks of severe Clostridium difficileassociated disease (CDAD) in Canada, the USA and the UK, epidemics of this strain (PCR ribotype 027, toxinotype III) were first reported in The Netherlands in June 2005. National surveillance and typing of strains was started. Fluoroquinolone use has been recognized in several studies as an important risk factor at patient level for CDAD due to type 027. This study aimed at identifying risk factors at hospital level for outbreaks with type 027. Methods: Data from 7 hospitals with known transmission of type 027 (group A), 5 hospitals with sporadic cases (group B) and 12 hospitals from a random selection without known type 027 (group C) were included. Quarterly data for 2004–2005 were collected on CDADincidence, inpatient antibiotic use (penicillins with extended spectrum and with b-lactamase inhibitors, cephalosporins, carbapenems, macrolides, clindamycin and fluoroquinolones) and hygienic and other preventive measures. The first 6 quarters were deemed the ‘pre-epidemic’ phase. In the last 2 quarters of 2005, the ‘epidemic’ phase, almost all
The medico-dental health interface – Paradigm shifts and advances in oral health for populations (Symposium organised by Colgate-Palmolive) 027 outbreaks took place. The association of AB use and hygiene policy with the incidence was analysed with multilevel linear regression. Results: Mean pre-epidemic incidence in affected hospitals was 3.6 per 10,000 patient days, in group B 3.2 and in group C 2.3. During the epidemic phase this was 5.4, 3.3 and 2.8, respectively. Pre-epidemically the unaffected hospitals had a significantly higher total use of the investigated AB [3776 DDD/10,000 patient days (pd)] than the A and B hospitals (3291 and 3325). In the epidemic phase, group A hospitals had significantly reduced their use of fluoroquinolones (from 615 to 416) whereas this rose in group C from 791 to 994 DDD/10,000 pd. In multivariate analysis giving special instructions to visitors of diarrhoea patients (regression coefficient [r.c.] −1.9), wearing an apron when caring for diarrhoea patients (r.c. −2.7) and being an academic hospital (r.c. 1.6) were significantly associated with the CDAD incidence. Conclusion: Hospital-wide use of most antibiotics known to be a risk factor for CDAD at patient level, such as fluoroquinolones, are not associated at institution level with higher incidences of type 027associated CDAD. Possibly, investigation at ward-level might correlate better. Wearing an apron and giving special instructions to visitors in case of diarrhoea appeared to be protective. O274 Amoebae as a second host for Vibrio cholerae G. Sandstr¨om, A. Saeed, B. Edvinsson, A. Weintraub, H. Abd (Stockholm, SE) Objectives: Acanthamoebae have been reported to represent the environmental host of several human pathogens. Vibrio cholerae requires 108 to 109 cells to cause cholera, and accordingly it needs an environmental host to enhance its growth. Our studies have shown that extracellular V. cholerae O1 and O139 have grown and survived in Acanthamoeba castellanii. The aim of this study is to examine the ability of A. castellanii to protect V. cholerae and to enhance its growth to be able to infect humans. Methods: V. cholerae producing green fluorescent protein was cocultivated with A. castellanii. An antibiotic assay used to examine ability of amoeba to protect intracellular bacteria and to differentiate between extracellular and intracellular bacteria. A. castellanii cultivated with V. cholerae for one week. After gentamicin killing and washing of extracellular V. cholerae, the number of intracellular bacteria was found to be 2×105 cells/mL. The amoebae harbouring V. cholerae were re-cultivated and growth of the microorganisms examined by viable counts during 2 weeks. Results: Gentamicin killed only the extracellular bacteria, while ciprofloxacin killed both, thus, the amoeba protected the intracellular V. cholerae from gentamicin. The antibiotic assay differentiated between extracellular bacteria that killed by gentamicin and intracellular bacteria that killed only by ciprofloxacin, which could diffuse into amoeba cells. Re-cultivation of A. castellanii harbouring intracellular V. cholerae resulted in enhanced growth of V. cholerae to 2×1011 CFU/mL and the bacteria survived for more than two weeks. Thus, amoeba acted as a biological incubator in which intracellular growth of the bacteria occurred to increase their number a million fold and maintained their overall viability. Existence of V. cholerae extracellularly as well as intracellularly in culture medium confirmed its facultative intracellular behaviour, which enhanced its growth and survival. Conclusions: The utilised antibiotic assay differentiates between extracellular and intracellular bacteria. Free-living amoeba is a possible biological factor, which protects and enhances growth of V. cholerae to exceed its infections dose and to supports the idea of amoeba as a second host to the bacterium in nature besides man. O275 Microbiology of thrombotic microangiopathies in Scotland, 2003–2006 K. Pollock, M. Locking, J. Cowden (Glasgow, UK) Without current surveillance of thrombotic microangiopathies such as HUS, neither prevalence nor outcomes are established in either adults
S57
or children. This study seeks to identify both health outcomes and existing management strategies. It comprises clinically driven enhanced surveillance of HUS and TTP and also further investigates the links between these syndromes and factors, which have been implicated in the etiology of HUS and TTP including infections, vascular procedures, chemotherapeutic agents and immuno-suppressants. Cases were ascertained prospectively by active, national surveillance during 2003 to 2006. Consultants in haematology, infectious diseases, microbiology, nephrology, paediatrics and public health medicine, were sent a monthly e-mail with case definition and asked to indicate whether they had a ‘case to report’ or ‘nil return’. Questionnaires, information sheets and consent forms were then sent to the relevant clinicians/consultants by post. All completed forms and questionnaires were returned to HPS and entered into a database for statistical analyses. From 2003 to October 2006, 145 reports of thrombotic microangiopathy were notified to HPS of which 103 were clinically designated HUS and 42 as TTP. There were 10 fatalities, 22 cases had some form of renal impairment and of those, 14 became dialysis dependent. Of 103 reports of HUS, 85 (83%) were caused by verotoxin-producing E. coli (VTEC) (82 were due to serotype O157). The non-O157 organisms were designated as serotypes O145, O177 and O-unidentifiable. Two atypical HUS cases were reported. One was preceded by parvovirus B19 infection/MMR immunisation and the other was due to infection with Streptococcus pneumoniae. The list of predisposing infections for development of TTP was more varied and included infection with coagulase-negative Staphylococcus aureus, Klebsiella pneumoniae and Clostridium difficile but development of TTP was significantly associated with severe sepsis. The study clearly demonstrates that development of HUS or TTP has serious and sometimes fatal consequences and that infection is a major predisposing factor in development of such syndromes.
The medico-dental health interface – Paradigm shifts and advances in oral health for populations (Symposium organised by Colgate-Palmolive) S279 Relationship between periodontal infections and systemic disease – the oral systemic connection G.J. Seymour (Dunedin, NZ) Common oral conditions, such as gingivitis and chronic periodontitis, are found world-wide and are among the most widely prevalent microbial diseases of mankind. A primary trigger for these conditions is the complex microbiota found as dental plaque, a complex microbial biofilm. Despite 3000 years of history demonstrating the influence of oral status on general health, recent decades have seen an accelerated effort for the prevention and management of these conditions through groundbreaking advances. One outcome of these advances is the realisation that periodontal diseases are associated with systemic conditions such as coronary heart disease and stroke; higher risk for preterm, low birth weight babies and pose threats to those with chronic disease: diabetes, respiratory diseases and osteoporosis. This presentation will highlight recent research associating periodontal disease with systemic diseases. The relationship between oral infections and systemic disease represents a paradigm shift in current research. A portion of this lecture will be devoted to examining the role of chronic infections and their association with cardiovascular diseases (CVD). These infections include Helicobacter pylori, Chlamydophila pneumoniae, Cytomegalovirus (CMV), and, more recently, periodontopathic bacteria including Porphyromonas gingivalis. Although a number of potential mechanisms have been postulated, the mechanism by which these infections are associated with CVD is still unclear. The various hypotheses concerning this relationship include common susceptibility, inflammation via increased circulating cytokines and inflammatory mediators, direct infection of the blood vessels and finally the possibility