The effect of azithromycin and Chlamydophilia pneumonia infection on expansion of small abdominal aortic aneurysms--a prospective randomized double-blind trial.

OBJECTIVE: The aim of the study was to evaluate the effect of azithromycin on the expansion rate of small abdominal aortic aneurysms (AAAs), and to determine whether or not a correlation exists between serological markers for Chlamydophilia pneumonia (Cpn) infection and AAA expansion. METHODS: Nine vascular centers were included and 259 patients were invited to participate. Ten patients declined and 2 patients had chronic kidney failure, leaving a total of 247 patients. Inclusion criteria were: AAA 35-49 mm and age <80 years. Patients were randomized to receive either azithromycin (Azithromax, Pfizer Inc, New York, NY) 600 mg once daily for 3 days and then 600 mg once weekly for 15 weeks, or placebo in identical tablets. The ultrasound scans were performed in a standardized way within a month before inclusion and every 6 months for a minimum follow-up time of 18 months. Cpn serology was analyzed in blood samples taken at inclusion and 6 months later. Serum was analyzed for Cpn IgA and IgG antibodies by microimmunofluorescence (MIF). Computed tomography (CT) scans were done in 66 patients at inclusion and at 1 year for volume calculations. RESULTS: Thirty-four patients were excluded, ie, could not be followed for 18 months, 20 in the placebo group and 16 in the active treatment group. A total of 211 patients had at least two measurements and all were analyzed in an intention-to-treat analysis. Detectable IgA against Cpn was found in 115 patients and detectable IgG against Cpn in 160 patients. No statistically significant differences were found between the groups regarding median expansion rate measured by ultrasound scan (0.22 cm/year, interquartile range [IQR]: 0.09 to 0.34 in the placebo group vs 0.22, IQR: 0.12 to 0.36 in the treatment group, P = .85). Volume calculation did not change that outcome (10.4 cm(3)/year in the placebo group vs 15.9 cm(3)/year in the treatment group, P = .61). No correlation was found between serological markers for Cpn infection and the expansion rate. Patients taking statins in combination with acetylsalicylic acid (ASA) had significantly reduced expansion rate compared to patients who did not take statins or ASA, 0.14 cm/year vs 0.27 cm/year, P < .001. CONCLUSION: Azithromycin did not have any effect on AAA expansion. No correlation was found between serological markers for Cpn and AAA expansion, indicating no clinical relevance for Cpn testing in AAA surveillance. However, a significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins.

No prognostic significance of chronic infection with Chlamydia pneumoniae in acute coronary syndromes: insights from the Global Utilization of Strategies to Open Occluded Arteries IV Acute Coronary Syndromes trial.

BACKGROUND: Although relationships between chronic Chlamydia pneumoniae (Cpn) infection and the risk of coronary events in stable coronary artery disease patients have been reported, a similar link in acute coronary syndrome (ACS) patients has not been consistently observed. METHODS: In a nested case-control substudy of the Global Utilization of Strategies to Open Occluded Arteries IV Acute Coronary Syndromes trial, 295 cases (30-day death/myocardial infarction [MI]) were matched by age, sex, baseline creatine kinase-myocardial kinase, and smoking status with 295 control subjects. To test the hypothesis on 1-year mortality, another subset (n = 276) was drawn from the 590-patient cohort; 138 patients who died at 1 year plus the matching controls who survived at 1 year. We measured Cpn IgG and IgA antibody titers in baseline serum with microimmunofluorescence. Conditional logistic regression was used to quantify the prognostic relevance seropositivity (IgG > or = 1:32; IgA > or = 1:16) and elevated titer levels. RESULTS: The prevalence of Cpn IgG and IgA was similar between cases and controls (30-day death/MI: IgG, 80% vs 85%, P = .126; IgA, 45% vs 37%, P = .079), and were not statistically significant predictors of 30-day death/MI after baseline adjustment. Likewise, the 1-year death cohort had comparable proportions of Cpn IgG and IgA among cases and controls (86% vs 91% [P = .265] and 49% vs 43% [P = .334], respectively), and did not add prognostic value. CONCLUSIONS: These findings are in concert with study results suggesting that chronic Cpn infection is not associated with 30-day death/MI or 1-year mortality in non-ST elevation ACS.

Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study.

BACKGROUND: Limited prospective epidemiological data are available on the relation between exposure to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and hepatitis A virus (HAV), individually or as a total pathogen score, and human cardiovascular (CV) disease. METHODS AND RESULTS: We analyzed enrollment sera from 3168 Canadian patients in the Heart Outcomes Prevention Evaluation (HOPE) study for antibodies to C pneumoniae, H pylori, CMV, and HAV and measured the relation between serostatus and 494 adjudicated trial outcomes of myocardial infarction, stroke, or CV death over 4.5 years of follow-up. CV events were associated with CMV serostatus (covariate-adjusted hazard ratio [HR], 1.24; 95% CI, 1.01, 1.53). Neither C pneumoniae IgG (adjusted HR, 0.87; 95% CI, 0.68, 1.10), C pneumonia IgA (adjusted HR, 1.10; 95% CI, 0.90, 1.34), H pylori IgG (HR, 0.99; 95% CI, 0.82, 1.19), nor HAV IgG (HR, 1.01; 95% CI, 0.83, 1.24) predicted CV events. Total pathogen score was associated with CV events (adjusted HR for 4 versus 1 or 0=1.41; 95% CI, 1.02, 1.96). CONCLUSIONS: Exposure to CMV but not to C pneumoniae, H pylori, or HAV was associated with a slight excess risk of subsequent myocardial infarction, stroke, or CV death in HOPE study patients, and total pathogen score based on these infections predicted a small increased hazard of CV events.

Relationship of anti-60 kDa heat shock protein and anti-cholesterol antibodies to cardiovascular events.

BACKGROUND: Several recent studies have indicated an association between key inflammatory mediators and atherosclerotic diseases. We evaluated whether high levels of antibodies against heat shock proteins and cholesterol (ACHA) predicted cardiovascular (CV) events. METHODS AND RESULTS: We used blood samples from the Heart Outcomes Prevention Evaluation (HOPE) study to conduct a nested case-control study of 386 cases with CV events and 386 age- and sex-matched HOPE study controls without events. We explored the relationship between anti-hsp antibodies, ACHA, and subsequent outcomes (incident myocardial infarction, stroke, or CV death) during a mean follow-up of 4.5 years using conditional logistic regression. High levels of anti-hsp65 antibodies (> or =90th percentile) predicted CV events (OR, 2.1; 95% CI, 1.2 to 3.9, P=0.01). Anti-hsp60 antibodies did not predict any event type, whereas incident stroke developed significantly less frequently in patients with high ACHA levels. Anti-hsp antibodies and ACHA did not correlate with inflammatory (fibrinogen, C-reactive protein, interleukin-6, intracellular adhesion molecule-1) or infectious markers (C pneumoniae or cytomegalovirus antibodies). Anti-hsp65 antibodies (> or =90th percentile) and fibrinogen (highest tertile) had a strong joint effect: patients with high concentrations of both had more CV events (OR, 5.5; 95% CI, 1.8 to 17.5, P=0.004) than patients with low levels of both. A similar joint effect (OR, 2.7; 95% CI, 1.3 to 5.7, P=0.01) was found for high levels of anti-hsp65 and presence of cytomegalovirus antibodies. CONCLUSIONS: Serum antibodies to hsp65 were associated with subsequent CV events in this study of high-risk patients, independent of conventional cardiovascular risk factors and other inflammatory markers.

Chronic Chlamydia pneumoniae infection is a risk factor for the development of COPD.

Smoking is the major risk factor for the development of Chronic Obstructive Pulmonary Disease (COPD), but epidemiological data suggest that other etiological factors may also be involved. Chlamydia pneumoniae (Cpn) is an established cause of acute and chronic upper and lower respiratory tract infections. Data obtained from in vitro and in vivo studies indicate that Cpn infection can be involved in the development of both small airways disease and emphysema, the two major components of COPD. The aim of this study was to investigate the possible association between chronic Cpn infection and COPD. The study population was comprised of 199 consecutive patients who underwent bronchoscopy due to longstanding airway symptoms and for whom spirometry and serum samples for serology were available. Acute and convalescent sera were analysed for specific IgG and IgA Cpn antibodies using microimmunofluorescence. Chronic Cpn infection, defined as persistent elevated titres of IgA > or = 1/64, was present in 85 patients. Chronic infection was associated with smoking and higher age, but no gender difference was observed. Thirty patients had COPD, defined as FEV1/FVC < 70% without any features of asthma. Patients with COPD were older than those without, and there was no association with gender in this group. A statistically significant association, remaining after correction for smoking, was observed between chronic Cpn infection and COPD, and there was a trend for decreasing lung function with increasing antibody titres. The results suggest that chronic Cpn infection may be an independent risk factor for the development of COPD.

Does chronic Chlamydia pneumoniae infection increase the risk of myocardial injury? Insights from patients with non-ST-elevation acute coronary syndromes.

BACKGROUND: Cumulative evidence suggests a positive association between Chlamydia pneumoniae (Cpn) infection and risk of future coronary events among patients with stable coronary artery disease. However, its prognostic role in unstable coronary syndromes is less well defined. Because Cpn immunoglobulin A (IgA) may be a more reliable indicator of chronic infection than immunoglobulin G (IgG), we speculated that in patients with non-ST-elevation acute coronary syndromes (ACS), this marker might serve as a more useful prognostic tool. Accordingly, we evaluated plasma samples acquired at presentation in 178 patients with ACS for a possible association between Cpn IgA titer and biochemical evidence of myocardial injury. METHODS: Cpn IgG (positive if > or =1:32), and IgA titers (positive if > or =1:16) were measured by use of the microimmunofluorescence technique in 70 patients with ACS in whom myocardial injury developed associated with their presenting events (elevated CK-MB and/or troponin I); and in 108 patients with ACS without such injury. The odds ratios (ORs) for myocardial injury associated with consecutive antibody titers were determined for each of Cpn IgG and IgA. Multiple logistic regression was applied to adjust for key baseline characteristics. RESULTS: Median age of subjects was 64 years; 63% were male and 33% were smokers. The median antibody titers among those with and without myocardial injury respectively were as follows: IgG (1:128 vs 1:128), IgA (1:32 vs <1:16, P =.2). The adjusted ORs for myocardial injury associated with consecutive IgA titers were as follows: IgA > or =1:16, adjusted OR 1.49 (P =.22); > or =1:32, OR 1.95 (P =.04); > or =1:64, OR 1.37 (P =.38); > or =1:128, OR 0.77 (P =.55). No significant trend was found for any IgG titer. CONCLUSIONS: Among patients with non-ST-elevation ACS, a Cpn IgA > or =1:32 at presentation was associated with a significantly higher risk of myocardial injury complicating the presenting event.

Comparison of individuals with and without specific IgA antibodies to Chlamydia pneumoniae: respiratory morbidity and the metabolic syndrome.

STUDY OBJECTIVES: To determine whether a correlation exists between markers for persistent Chlamydia pneumoniae infection, respiratory morbidity, and the metabolic syndrome. DESIGN: Case-control study. A group of individuals with serologic markers (specific IgA > or = 1/128) suggestive of persistent C pneumoniae infection were compared with a group of control subjects without IgA antibodies (< 1/32). SETTING: Apoteksgårdens Health Care Center, Kopparberg, Sweden. PARTICIPANTS: One hundred case subjects (61 men and 39 women) and 100 control subjects matched for age and gender (mean age, 55 years). MEASUREMENTS AND RESULTS: Individuals completed a questionnaire on respiratory symptoms and smoking habits. Body mass index (BMI) was calculated, BP, and peak expiratory flow (PEF) were determined. Blood specimens were drawn for determination of high-sensitivity C-reactive protein (hsCRP), blood glucose level, serum lipids, and Chlamydia antibodies. No significant difference was found between case subjects and control subjects regarding myocardial infarctions, stroke, diabetes type II, BP, BMI, hsCRP, blood glucose levels, and serum lipids. Symptoms of both asthma and chronic bronchitis were more common in case subjects, as were symptoms of chronic upper respiratory tract infections (p < 0.005). Case subjects with asthma or chronic bronchitis had more chronic upper respiratory tract disorders (p < 0.05). Symptoms of chronic respiratory tract diseases increased parallel to increasing specific C pneumoniae IgA antibody titers (p < 0.0005). PEF percentage of the predictive value was inversely correlated (p < 0.0005) to IgA antibody titers. CONCLUSION: The data show that persistent increased levels of C pneumoniae IgA antibodies were associated with pronounced respiratory dysfunction. These data provide additional evidence suggesting that IgA antibodies may be a marker for persistent C pneumoniae infection.

A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease.

OBJECTIVES: To assess whether doxycycline and rifampin have a therapeutic role in patients with Alzheimer's disease (AD). DESIGN: Randomized, triple-blind, controlled trial. SETTING: Three tertiary care and two community geriatric clinics in Canada. PARTICIPANTS: One hundred one patients with probable AD and mild to moderate dementia. INTERVENTION: Oral daily doses of doxycycline 200 mg and rifampin 300 mg for 3 months. MEASUREMENTS: The primary outcome was a change in Standardized Alzheimer's Disease Assessment Scale cognitive subscale (SADAScog) at 6 months. Secondary outcomes were changes in the SADAScog at 12 months and tests of dysfunctional behavior, depression, and functional status. RESULTS: There was significantly less decline in the SADAScog score at 6 months in the antibiotic group than in the placebo group, (-2.75 points, 95% confidence interval (CI)=-5.28 to -0.22, P=.034). At 12 months, the difference between groups in the SADAScog was -4.31 points (95% CI=-9.17-0.56, P=.079). The antibiotic group showed significantly less dysfunctional behavior at 3 months. There was no significant difference in adverse events between groups (P=.34). There were no differences in Chlamydia pneumoniae detection using polymerase chain reaction or antibodies (immunoglobulin (Ig)G or IgA) between groups. CONCLUSION: Therapy with doxycycline and rifampin may have a therapeutic role in patients with mild to moderate AD. The mechanism is unlikely to be due to their effect on C. pneumoniae. More research is needed to investigate these agents.

Lack of association between vascular dementia and Chlamydia pneumoniae infection: a case-control study.

BACKGROUND: Chronic inflammation appears to play a role in the pathogenesis of vascular dementia. Given the association between Chlamydia pneumoniae and stroke, the possibility exists that previous exposure to C. pneumoniae may play a role in vascular dementia. The objective of this study was to determine if there was an association between serological evidence of C. pneumoniae infection or inflammatory markers with vascular dementia. METHODS: 28 case-patients with vascular dementia at a geriatric clinic and 24 caregiver-controls were tested for C. pneumoniae IgG and IgA antibodies. The association between vascular dementia and C. pneumoniae titres as well as inflammatory markers was estimated by using both conditional logistic regression and stratified logistic regression. RESULTS: When matched cases were compared to controls, there was no significant difference in elevated C. pneumoniae specific IgG antibodies (titre >or= 1:32), odds ratio [OR] 1.3 (95% confidence intervals [CI] 0.3 to 6.0), p = 0.71, or in elevated C. pneumoniae specific IgA antibodies (titre >or= 1:16), OR 2.0 (95%CI 0.5 to 8.0), p = 0.33 indicative of past or persistent C. pneumoniae infection. Similarly, no difference in high IgG or IgA antibody levels (IgG titre >or= 1:512 or IgA titre >or= 1:64) between the two groups, indicative of recent C. pneumoniae infection, was found, OR 0.4 (95%CI 0.1 to 2.1), p = 0.27. For C-reactive protein (CRP), the mean difference between 18 matched pairs (case - control) was - 3.33 mg/L. There was no significant difference between cases and controls when comparing log transformed values, OR 0.03 (95%CI 0.00 to 2.89), p = 0.13 or comparing CRP values above or below the median, OR 0.8 (95%CI 0.2 to 3.4), p = 0.71. For fibrinogen, the mean difference between pairs (case - control) was -0.07 g/L. There was no statistical difference between cases and controls when comparing log transformed values, OR 0.6 (95%CI 0.0 to 31.2), p = 0.79 or between fibrinogen values above and below the median, OR = 0.5 (95%CI 0.1 to 2.0), p = 0.50. CONCLUSION: We found no evidence for a significant association between C. pneumoniae infection, inflammatory markers such as CRP and fibrinogen, and vascular dementia.

A family with abdominal aortic aneurysms.

This investigation focused on 7 siblings to 2 brothers with abdominal aortic aneurysm (AAA), with respect to AAA, Chlamydia pneumoniae (CP) serology, serum cholesterol, and smoking habits. Five male and 4 female siblings were included. All siblings underwent ultrasonography, and surgical specimens from the aorta were prepared for immunohistochemical (IHC) analysis. Blood was obtained from all living siblings and serum cholesterol level was analyzed. Serologic analysis was done by microimmunofluorescence (MIF). Smoking habits were recorded. In addition to the 2 known siblings with AAA, 2 other brothers with AAA were found. Four of 8 siblings had IgG 1/512 or greater and 7 of 8 had IgA 1/64 or greater. Two of 3 were positive for CP in IHC obtained from aortic specimens. Two of 8 had hypercholesterolemia; 7 of 9 were smokers. C. pneumoniae as well as smoking seems to be important in the pathogenesis of AAA in this small cohort; however, larger patient cohorts are needed.

Detection of Chlamydia pneumoniae on cytospin preparations from bronchoalveolar lavage in COPD patients and in lung tissue from advanced emphysema.

Chronic obstructive pulmonary disease (COPD) is associated with smoking but other etiological factors contribute. Chlamydia pneumoniae is an obligate intracellular bacterium causing both acute and chronic respiratory tract infections. Studies have revealed an association between chronic C. pneumoniae infection and COPD, asthma and lung cancer but there have been difficulties detecting C. pneumoniae in the bronchial tree. Cytospin slides prepared from bronchoalveolar lavage (BAL) fluid from 14 patients with COPD, 10 healthy smokers (S) and 7 non smokers (NS) were analyzed with a fluorescein isothiocyanate labeled monoclonal antibody to C. pneumoniae. Lung tissue from 24 patients with advanced emphysema who had undergone lung volume reduction surgery (LVRS) was examined with immunohistochemistry for C. pneumoniae. Archived serum samples for detection of specific C. pneumoniae antibodies by microimmunofluorescence were available for 30 of the BAL subjects and 11 of LVRS patients. C. pneumoniae elementary body like structures were found in 29% of cytospin specimens from COPD patients, 14% of NS and 10% of HS. C. pneumoniae was detected in lung tissue in 8%. COPD patients had higher titres of IgG and IgA than NS and S. There was no association between occurrence of C. pneumoniae in BAL fluid and antibody titres. In conclusion, the assays used for detection of C. pneumoniae in lung tissue are feasible, and could be adapted in adequately powered studies to further confirm an association between C. pneumoniae infection and COPD.

Chlamydia pneumoniae infection predicts a reduced risk for subsequent atopic disease.

AIM: To investigate long-term effects on children previously infected with Chlamydia pneumoniae. METHODS: A follow-up questionnaire was sent to all participants from a former population-based study in order to investigate health status during the 4 y that had elapsed between the two studies. In the original study, the prevalence of C. pneumoniae infection was 23% as determined by PCR analyses on throat swab specimens. These PCR results were found to have no detectable correlation for clinical disease. The main outcome measures in this follow-up study were the reported prevalence of respiratory tract infections, asthma and allergy. RESULTS: Approximately 83% completed the follow-up questionnaire. No increase in respiratory tract infections was reported by children previously found to have C. pneumoniae infection. A diagnosis of allergy was more common in the former PCR-negative population (13.4% vs 4.7%, p<0.03). The differences were most apparent in the population with atopic heredity. In a logistic regression model with different suggested risk factors for allergy, earlier infection with C. pneumoniae reduced the risk for allergy (OR=0.13; 95% CI: 0.02-0.99). This was not found for asthma. CONCLUSION: A positive PCR test for C. pneumoniae in young children was associated with a lower risk of developing allergic airway disease in this study population, and did not predict an increase in respiratory tract infections.

Azithromycin therapy in patients with chronic Chlamydia pneumoniae infection and coronary heart disease: immediate and long-term effects on inflammation, coagulation, and lipid status in a double-blind, placebo-controlled study.

Background: An association between Chlamydia pneumoniae (Cp) infection and coronary heart disease (CHD) has already been reported. We investigated the relationship between Cp infection and other risk factors in CHD patients, as well as the effects of azithromycin treatment. Methods: We studied 38 patients with Cp infection (Cp-pos) and 15 without (Cp-neg). Cp-pos patients had, both at inclusion and 2 years prior to inclusion, elevated Cp-specific IgA-antibodies, with or without the presence of pharyngeal Cp by polymerase chain reaction (PCR) detection. Blood was analyzed for Cp-antibodies, interleukin-6, interleukin-1 receptor antagonist (IL-1ra), CRP, orosomucoid, fibrinogen, leukocytes, PAI-1, tPA, von Willebrand factor (vWf), platelet count and aggregation, and lipids. Cp-pos patients were randomized to placebo or oral azithromycin, 500 mg on day 1 and then 250 mg/day for 4 days, with repeated therapy after 3 weeks. Blood was taken immediately, as well as 3 months and 2 years after therapy. Results: CRP and IL-1ra levels were higher in Cp-pos than in Cp-neg patients: median, interquartile range 8.5 (3.0-20) vs. 2.0 (1.0-3.8) mg/l, and 316 (165-404) vs. 178 (118-195) ng/l, p=0.0006 and p=0.002, and platelet aggregation was lower: 4.8 (2.9-6.4) vs. 8.1 (4.7-11.4) Omega, p<0.05. tPA levels increased in azithromycin-treated patients between entry and 3-month follow-up: mean+/-S.D. 3.7+/-4.2 vs. 1.0+/-2.1 microg/l, p<0.05. Other variables did not differ. Conclusions: Cp infection was associated with increased inflammatory activity and lower platelet aggregability, suggesting that inflammation may be of greater pathophysiological importance than platelet activity in these patients. Although an effect on Cp infection was not shown, azithromycin may have a positive effect on fibrinolysis, as increased levels of tPA were observed in the treatment group.

Intermittent azithromycin treatment for respiratory symptoms in patients with chronic Chlamydia pneumoniae infection.

Chlamydia pneumoniae (Cpn) is a common respiratory pathogen with a biphasic replicative cycle and has a tendency to cause chronic infections. Azithromycin is commonly used for the treatment of Cpn infections, but little is known about the optimal dose and duration of therapy. In this prospective double-blind, randomized study the effects of azithromycin and placebo were compared regarding longstanding airway and/or pharyngeal symptoms in patients with chronic Cpn infection. Further, effects on antibody titres and lung function were assessed. 103 patients were treated with either azithromycin 500 mg daily for 5 d, repeated 3 times with a 23-d interval, or placebo. Patients were examined 4 months and 1 y after completed treatment. Evaluation of symptoms showed general improvement and less hawking in patients treated with azithromycin compared to placebo after 4 months, but there was no sustained difference 1 y after completed treatment. The antibody titres remained stable, and there was no influence on lung function. Adverse events, primarily gastrointestinal, were more frequently reported with azithromycin than placebo. In conclusion, azithromycin was effective for reduction of respiratory symptoms in patients with chronic Cpn infection, but prolonged intermittent treatment with high doses did not eradicate the chronic infection.