Role of infections in atherosclerosis.

A growing amount of epidemiologic, experimental, and clinical evidence has linked infection as a risk factor to variousatherosclerotic diseases including acute myocardial infarction and cerebral infarction. Bacteremic infections with and without endocarditis carry a high risk for both stroke and acute myocardial infarction. During the last decade, chronic bacterial infections such as Chlamydia pneumoniae and dental infections have been associated as risk factors for various atherosclerotic diseases. These chronic bacterial infections are risk factors for acute cardiovascular events, but they may also have some role in the etiopathogenesis of atherosclerotic process itself. There are many known mechanisms that might explain the observed association of infection and atherosclerotic diseases, but it is probable that these mechanisms are complex and multifactorial and probably differ from infection to infection and from patient to patient. Infection theory is by no means against classic risk factor theory in the etiopathogenesis of atherosclerosis. Infection may also act as a synergistic risk factor together with classic risk factors in the development of various atherosclerotic diseases.

Ceftriaxone versus vancomycin prophylaxis in cardiovascular surgery.

The efficacy of antibiotic prophylaxis in cardiac surgery was compared between 97 patients receiving a single 2 g dosage of ceftriaxone and 103 receiving 500 mg of vancomycin i.v. every 6 h for 48 h. The overall infection rate was 13.4% in the ceftriaxone and 10.7% in the vancomycin group. Four (4%) wound infections, including one mediastinitis, occurred in the ceftriaxone group and five (5%) in the vancomycin group, with no statistically significant difference. The findings of this study support the adequacy of a simple single dose of ceftriaxone prophylaxis in cardiac surgery, at least in hospitals with low incidence of vancomycin-resistant staphylococcal infections.

Factors associated with improved outcome of Pseudomonas aeruginosa bacteremia in a Finnish university hospital.

All 134 episodes of bacteremia caused solely by Pseudomonas aeruginosa in a university hospital in the periods 1976-1982 and 1992-1996 were reviewed retrospectively to determine the clinical manifestations, outcome and prognostic factors. The mortality for the 30-day interval after drawing the first positive blood culture was 41%, but dropped from 53% in the first period to 29% in the second period (P=0.006). Mortality was highest in patients treated with an aminoglycoside only, as against those treated with other appropriate antibiotics (55% versus 25%, P=0.001). Over the two decades studied, use of an aminoglycoside only decreased, use of paracetamol (=acetaminophen) increased, and removal of both urinary and blood vessel catheters became more common. The mortality was 18% in patients with catheter removal (46% in the other patients, P=0.017) and 27% in patients who received paracetamol around the time of drawing the first positive blood culture (50% for the other patients, P=0.010). Logistic regression analysis showed that shock, central nervous system involvement, preceding thromboembolism and rapidly fatal underlying disease were associated with a fatal outcome, whereas catheter removal, appropriate antibiotic therapy and paracetamol therapy were associated with survival. The improved prognosis of Pseudomonas aeruginosa bacteremia over the two decades is thus due mainly to three changes in management of the infection: the more frequent use of new anti-pseudomonal beta-lactams and ciprofloxacin instead of aminoglycosides as monotherapy; the more frequent practice of removing catheters; and the increased use of paracetamol around the time of drawing the first positive blood sample.

Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study.

BACKGROUND & AIMS: Although bacterial bowel flora may be one of the contributing factors in the pathogenesis of chronic mucosal inflammation, antibiotic treatment has no established role in ulcerative colitis. The aim of the study was to evaluate the role of ciprofloxacin in the induction and maintenance of remission in ulcerative colitis in patients responding poorly to conventional therapy with steroids and mesalamine. METHODS: Ciprofloxacin (n = 38; 500-750 mg twice a day) or placebo (n = 45) was administered for 6 months in a double-blind, randomized study with a high but decreasing dose of prednisone and maintenance treatment with mesalamine including follow-up for the next 6 months. Clinical assessment and colonoscopic evaluation were performed at 0, 3, 6, and 12 months. Treatment failure, the primary end point, was defined as both symptomatic and endoscopic failure to respond. RESULTS: During the first 6 months, the treatment-failure rate was 21% in the ciprofloxacin-treated group and 44% in the placebo group (P = 0.02). Endoscopic and histological findings were used as secondary end points and showed better results in the ciprofloxacin group at 3 months but not at 6 months. CONCLUSIONS: Addition of a 6-month ciprofloxacin treatment for ulcerative colitis improved the results of conventional therapy with mesalamine and prednisone.

Occurrence of HLA-B27 tissue antigen in patients with purulent arthritis caused by Staphylococcus aureus or beta-haemolytic streptococci.

The HLA-B27 tissue antigen is associated with reactive arthritis caused by different bacterial infections but its occurrence in purulent arthritis has not been studied earlier. We analysed the frequency of HLA-B27 in patients with culture proven purulent arthritis caused by Staphylococcus aureus or beta-haemolytic streptococci. The study included 41 patients treated during the years 1979-96 (15 female and 26 male) with a mean age of 52 years (range 16-80 years). HLA-B27 was found in 24% (9/37) of the tested patients compared with 14% in the healthy Finnish population, but the difference was not statistically significant (P < 0.50). No statistical difference in disease activity according to febrile days or duration of the disease could be found between HLA-B27 positive and negative patients. We conclude that HLA-B27 is not a risk factor for purulent arthritis, and when present it has no significant modifying effect on the clinical picture of purulent arthritis.

Comparison of risk factors and outcome in patients with Enterococcus faecalis vs Enterococcus faecium bacteraemia.

The purpose of our study was to determine retrospectively the risk factors for the acquisition of Enterococcus faecalis vs E. faecium bacteraemia, as well as the clinical outcomes of these patients. 62 patients with Enterococcus faecalis bacteraemia were compared to 31 patients with E. faecium bacteraemia. Haematologic malignancies, neutropenia, high-risk source and previous use of aminoglycosides, carbapenems, cephalosporins and clindamycin were significantly associated with E. faecium bacteraemia. Instead, urinary catheterization was found to be related to Enterococcus faecalis bacteraemia. The mortality rates within 7 d and 30 d were 13% and 27%, respectively, in patients with E. faecalis bacteraemia and 6% and 29%, respectively, in patients with E. faecium bacteraemia. There was no difference in mortality between E. faecalis and E. faecium bacteraemia, nor was there a difference in seriousness of disease at the time of bacteraemia. In the subgroups of patients with monomicrobial or clinically significant E. faecalis vs E. faecium bacteraemia, the mortality rates were similar to the results of all subjects. Our results do not support the theory that E. faecium would be a more virulent organism than E. faecalis.

Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke.

An increasing body of evidence has linked infections to atherosclerosis and thrombosis. Herpesviruses cause atherosclerosis in experimental animals. Herpesviruses can also be detected in atherosclerotic lesions in humans. Cytomegalovirus may play a role in arteriosclerosis in transplanted hearts, and this virus, together with tumor suppressor protein p53, can be found in restenosis lesions following angioplasty. Chlamydia pneumoniae and dental infections are associated with coronary heart disease in cross-sectional and longitudinal studies, and preceding respiratory infections are associated with ischemic stroke. Infections may favor formation of atherosclerosis and thrombosis by elevation of blood levels of fibrinogen, leukocytes, clotting factor, and cytokines and by alteration of the metabolism and functions of endothelial cells and monocyte macrophages. Low-grade infections may also be one of the causes of the inflammatory reaction observed in atherosclerotic lesions and acute ischemic symptoms, reflected in elevated levels of C-reactive protein. These observations warrant further studies in this field.

Prognostic factors associated with improved outcome of Escherichia coli bacteremia in a Finnish university hospital.

All cases of bacteremia caused solely by Escherichia coli in 1977-1979, 1987-1989, and 1993-1994 in a Finnish university hospital were reviewed retrospectively to determine the clinical manifestations, the outcome, and the prognostic factors. In 332 episodes, mortality during the month after the first positive blood culture was 17%. This figure diminished during the study period from 23% in the 1970s to 9% in the 1990s (p = 0.028). Mortality was lowest among patients treated with a combination of antibiotics, 7% versus 18% among those treated otherwise (p = 0.034). The use of acetaminophen increased during the study period from 18 to 55%. Mortality among patients who received acetaminophen within a period < 24 h to 48 h of the first positive blood culture was 10% versus 22% among others (p = 0.002). Logistic regression analysis showed six factors predictive of a fatal outcome: pneumonia, no known focus, shock, CNS disorder, thromboembolism, and rapidly fatal underlying disease. Appropriate antibiotic therapy predicted survival. In the analysis, replacement of appropriate antibiotic therapy by acetaminophen revealed that this drug was significantly associated with survival.

Serological findings in patients with acute syndromes fulfilling the proposed criteria of adult onset Still's disease.

In order to analyse possible triggering or contributing infections and HLA-B27 frequency in patients with acute febrile joint syndrome fulfilling the proposed criteria of adult Still's disease (AOSD), we studied prospectively the serological findings of 25 patients. They were aged 15-62 years and diagnosed between 1978-1992. We then compared results with a control group consisting of 119 healthy persons. Positive viral or bacterial serology was found in 12 patients (48%) in the AOSD group compared with 13 cases (11%) in the control group (p < 0.001). Fourfold or higher viral antibody rise was found in two patients and bacterial antibody rise in three patients. High stable viral antibody titre was observed in one patient and high stable bacterial antibody titre in six patients. HLA-B27 was not overrepresented in the study group (12%) compared with a healthy Finnish population (14%). We conclude that many different bacterial and viral infections may trigger or contribute to AOSD.

Association between high antistaphylolysin and teichoic acid antibody titres with rheumatic syndromes.

To analyse which rheumatic syndromes are associated with serological evidence of recent Staphylococcus aureus infection, we studied retrospectively 44 adult patients, gathered between 1979-1990, having an acute arthritis syndrome or an exacerbation in their chronic rheumatic disease and simultaneously a high antistaphylolysin (ASTA > 4,0) and/or high teichoic acid antibody titre (TAA > 8). Patients with septic arthritis or endoprosthetic infections were not included. 25 patients had arthritis/arthralgia associated with a known rheumatic disease, 9 patients had reactive arthritis and 8 patients had arthralgia. The frequency of HLA-B27 in tested patients was significantly higher in the whole patient group than in the healthy Finnish population (43% v 14%, p < 0.001). It is concluded that high ASTA and/or TAA titres are associated with various acute rheumatic syndromes including reactive arthritis.

Overgrowth of Enterococcus faecium in the feces of patients with hematologic malignancies.

The objective of this study was to characterize the overgrowth and susceptibility of Enterococcus faecium, compared with that of other enterococci, in the feces of patients with hematologic malignancy. During a 52-week period, surveillance samples of feces were cultured weekly. Three hundred thirty-three samples were obtained from 92 patients. E. faecium outnumbered other enterococci in 170 (44%) of the samples, while the opposite was true in 119 (31%) of the samples. Fecal overgrowth of E. faecium (> or = 9.0 log10 cfu/g) was found in 62 samples (16%), while overgrowth of other enterococci was documented in 20 samples (5%) (P < .001). Treatment with third-generation cephalosporins preceded the overgrowth of E. faecium in 93% of the patients. Resistance of E. faecium isolates to ampicillin, high-level gentamicin, and vancomycin was detected in 41%, 4%, and 2% of the patients, respectively. There were 6 patients with enterococcal bacteremia (due to E. faecium in 5 and Enterococcus faecalis in 1) during the study period. The high prevalence of resistance to ampicillin and imipenem rendered few (if any) intravenous antibiotics able to prevent fecal overgrowth of E. faecium.

Nontuberculous mycobacterial infection in HIV-negative patients receiving immunosuppressive therapy.

The clinical significance of nontuberculous mycobacterial isolates and presentation of mycobacteriosis was compared in HIV-negative patients with or without preceding immunosuppression. Patients with nontuberculous mycobacterial isolates (n = 139), mainly from the respiratory system, were divided into three groups: those who had had previous immunosuppressive treatment (24%), those with other underlying diseases (54%) and those without predisposing factors (22%). The distribution of mycobacterial species among the various patient groups was similar. The immunosuppressed patients fulfilled the criteria of the American Thoracic Society for clinical mycobacteriosis less frequently (18%) than those with other underlying diseases (32%) or without predisposing factors (45%), p = 0.07, the difference being more striking for patients with Mycobacterium avium complex isolates. This was partly due to the difficulty in distinguishing the relevant symptoms from those caused by the underlying disease. The proportion of patients receiving antimycobacterial therapy differed similarly (18%, 21%, 45%, respectively). Among the immunosuppressed patients, positive acid-fast smears were significantly less common and polymicrobial infections, initial lymphocytopenia, fever and fatal outcome significantly more common. About half of the immunosuppressed patients died within one year. In order to better define patients requiring treatment, the criteria for localized mycobacteriosis among immunosuppressed patients should be reevaluated.

Dental infection and the risk of new coronary events: prospective study of patients with documented coronary artery disease.

Several recent studies have suggested that dental infections are associated with coronary artery disease. To further elucidate this association, we conducted a prospective 7-year follow-up study of 214 individuals (182 males and 32 females; mean age, 49 years) with proven coronary artery disease who had undergone a dental examination and evaluation for the classic coronary risk factors at entry. The main outcome measures were the incidence of fatal and nonfatal coronary events and overall mortality. Fifty-two patients met the endpoint criteria during follow-up. Dental health was a significant predictor of coronary events when controlled for the following factors: age, sex, socioeconomic status, smoking, hypertension, the number of previous myocardial infarctions, diabetes, body mass index, and serum lipids. Other significant predictors were the presence of diabetes, the number of previous myocardial infarctions, and the body mass index. Our results give further support to the hypothesis that dental infections are a risk factor for coronary events.

Dental infections and coronary atherosclerosis.

An association between dental and other bacterial infections and coronary heart disease has recently been observed in both cross-sectional and longitudinal studies. To elucidate this topic, the severity of dental infections and coronary atheromatosis was assessed, together with measurements of the conventional coronary risk factors, in 100 individuals (88 men, 12 women, mean age 48, range 28-68 years) referred for diagnostic coronary angiography. Pantomography X-rays and coronary angiograms of the participants were scored blindly by single observers, a dentist and a radiologist respectively. The median pantomography score was 3.0 in male individuals belonging to the highest tertile of coronary atheromatosis score, as compared with 0.0 among the rest of the male participants (P = 0.003). The association between dental infections and severe coronary atheromatosis in males remained significant after adjusting for the effect of age, blood lipids, body mass index, hypertension, smoking and social class. No association between dental infections and coronary atheromatosis was observed in the small number of females studied. This observation supports the proposal that bacterial infections play a role in the pathogenesis of coronary atherosclerosis.

Various rheumatic syndromes in adult patients associated with high antistreptolysin O titres and their differential diagnosis with rheumatic fever.

OBJECTIVES: The purpose of this study was to analyse retrospectively adult patients with acute joint or muscle symptoms and a high antistreptolysin O (ASO) titre to find out which syndromes of clinical arthritis are associated with serological evidence of streptococcal infection. METHODS: Seventy six adult patients with an acute arthritis syndrome or an exacerbation in their chronic rheumatic disease and simultaneously a high ASO titre (> or = 500 Todd units) were examined in two time periods in the 1980s. RESULTS: Twenty six patients had arthritis associated with a known rheumatic disease, 25 had non-specific arthralgia/myalgia, 20 had reactive arthritis, and five had septic arthritis. No case of classic rheumatic fever classified by two major criteria was found. Six patients fulfilled one major and at least two minor criteria. The frequency of HLA-B27 was significantly higher in the whole patient group than in the healthy Finnish population (30 v 14%). CONCLUSIONS: It is concluded that classic rheumatic fever is now rare, even in patients with arthritis with a high ASO titre. These results support the suggestion that beta haemolytic streptococci may trigger reactive arthritis as well as rheumatic fever.

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.

Infection as a risk factor for infarction and atherosclerosis.

A growing amount of clinical and experimental evidence suggests a link between infection and atherosclerotic diseases including both myocardial and cerebral infarction. A prime example is a greatly increased risk of stroke in septicaemic patients with and without endocarditis. Controlled clinical studies have recently shown, however, that certain other milder bacterial infections are also a risk factor for infarction. A preceding febrile respiratory infection was a major risk factor for stroke in young and middle aged patients. In patients with acute myocardial infarction Chlamydia pneumoniae and dental infections seem to be risk factors according to one controlled clinical study. Several possible mechanisms could explain the observed association of infection and infarction. For instance, infection causes a hypercoagulable state which increases the risk of thrombosis. In addition, infection has profound and harmful effects on prostaglandin and lipid metabolism. Infection may also have some role in the atherosclerotic process itself by inducing damage and inflammation in vascular endothelium in the presence of hypercholesterolemia. So far, however, little clinical evidence is available to suggest that by controlling infection the risk of infarction or development of atherosclerotic lesions might be reduced except in patients with endocarditis, where the risk of thromboembolic complications rapidly diminished when the infection is controlled with antimicrobial therapy.

Lipoproteins and acute phase response during acute infection. Interrelationships between C-reactive protein and serum amyloid-A protein and lipoproteins.

To study the interrelations between the changes of acute phase proteins and those of serum lipoproteins in acute infections we measured the concentrations of different lipoproteins, serum amyloid-A protein and C-reactive protein and activities of lipoprotein lipase and hepatic lipase during acute and convalescence phase and after complete recovery in 64 patients with infectious diseases (30 with viral infection and 34 with bacterial infection). The maximal decrements of both low density lipoprotein and high density lipoprotein cholesterol correlated significantly with the acute phase levels of C-reactive protein and serum amyloid-A protein. The acute phase concentration of very low density lipoprotein triglyceride correlated inversely to C-reactive protein level (r = -0.31, P less than 0.05) but not to serum amyloid-A protein level. Regression analysis showed that the concentration of C-reactive protein was a significant predictor of very low density lipoprotein triglyceride level in the acute phase of infection but not during convalescence. These results and the previous findings that C-reactive protein binds to low and very low density lipoproteins and that serum amyloid-A protein is associated with high density lipoprotein give credence to the view that C-reactive protein and serum amyloid-A protein interfere with the metabolism of serum lipoproteins during acute phase of infection.

Association between dental health and acute myocardial infarction.

Known risk factors for coronary heart disease do not explain all of the clinical and epidemiological features of the disease. To examine the role of chronic bacterial infections as risk factors for the disease the association between poor dental health and acute myocardial infarction was investigated in two separate case-control studies of a total of 100 patients with acute myocardial infarction and 102 controls selected from the community at random. Dental health was graded by using two indexes, one of which was assessed blind. Based on these indexes dental health was significantly worse in patients with acute myocardial infarction than in controls. The association remained valid after adjustment for age, social class, smoking, serum lipid concentrations, and the presence of diabetes. Further prospective studies are required in different populations to confirm the association and to elucidate its nature.

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.