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The Role of Chlamydophila Pneumoniae in the Inflammatory Response and Expansion of Abdominal Aortic Aneurysms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Abdominal aortic aneurysm (AAA) is a common disease that develops gradually over several years and is characterised by weakening and dilatation of the aortic wall. AAAs also demonstrates a marked inflammatory infiltrate throughout the aortic wall. Chlamydophila pneumoniae (C. pneumoniae), is a common bacterium. About 50% of the population has been infected in adolescence. Thirteen studies report the presence of either C. pneumoniae or its antigens in 35-100% of AAA specimens.

The overall aim of this thesis was to evaluate the possible role of C. pneumoniae in inflammatory response and expansion of AAA from a clinical point of view.

In paper I, viable C. pneumoniae was detected in a majority of 26 patients with AAA having open surgery. Patients operated for AAA had higher C. pneumoniae antibodies titers than controls. In paper II, 247 patients were randomised in a double-blind trial, to evaluate the effect of azithromycin on the expansion of small AAAs. No such effect was seen and there was no correlation between C. pneumoniae antibody titers and AAA expansion. In paper III, 42 patients with AAA were compared to 100 age- and sex matched controls with normal aortas. C. pneumoniae antibodies were analysed in plasma samples obtained at screening, and in samples from a study conducted 5-15 (mean 12) years previously on the same population. There was no significant difference between the groups. In paper IV, were 211 patients were analysed, we could not find an association between levels in plasma of three markers of inflammation (IL-6, MMP-9 and CRP) and AAA expansion. A significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins.

In conclusion, viable C. pneumoniae is found at the scene of the crime, but we were unable to reverse or halt expansion of AAA with antibiotic treatment. C. pneumoniae antibody titers cannot be used, to detect small AAA, or to evaluate AAA expansion. From a clinical point of view, based on the methods and analyses used in this thesis, the role of C. pneumoniae in the inflammatory response and expansion of abdominal aortic aneurysms is limited.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2009. , p. 85
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 485
Keywords [en]
Abdominal aortic aneurysm, Chlamydophila pneumoniae, inflammation, aspirin, statin, expansion, randomised clinical trial
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-108867ISBN: 978-91-554-7617-5 (print)OAI: oai:DiVA.org:uu-108867DiVA, id: diva2:241190
Public defence
2009-11-06, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2009-10-16 Created: 2009-10-01 Last updated: 2009-10-16Bibliographically approved
List of papers
1. Detection of viable Chlamydia pneumoniae in abdominal aortic aneurysms.
Open this publication in new window or tab >>Detection of viable Chlamydia pneumoniae in abdominal aortic aneurysms.
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2000 (English)In: Eur J Vasc Endovasc Surg, Vol. 19, p. 630-Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-54540 (URN)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2011-01-14
2. The effect of azithromycin and Chlamydophila pneumoniae infection on expansion of small abdominal aortic aneurysms: a prospective randomised double-blind trial
Open this publication in new window or tab >>The effect of azithromycin and Chlamydophila pneumoniae infection on expansion of small abdominal aortic aneurysms: a prospective randomised double-blind trial
Show others...
2009 (English)In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 50, no 1, p. 23-29Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Abdominal aortic aneurysm, Chlamydophila pneumoniae, inflammation, statin, expansion, randomised clinical trial, MMP-9, IL-6, CRP, azithromycin
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-108598 (URN)10.1016/j.jvs.2008.12.048 (DOI)000267498500004 ()19563951 (PubMedID)
Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2017-12-13Bibliographically approved
3. The association between serological markers for chlamydophila pneumoniae and the development of abdominal aortic aneurysm
Open this publication in new window or tab >>The association between serological markers for chlamydophila pneumoniae and the development of abdominal aortic aneurysm
2011 (English)In: Annals of Vascular Surgery, ISSN 0890-5096, E-ISSN 1615-5947, Vol. 25, no 3, p. 322-326Article in journal (Refereed) Published
Abstract [en]

Background: To investigate the association between serological markers for Chlamydophila pneumoniae (Cpn) and the development of abdominal aortic aneurysm (AAA) in a population-based case-control study. Methods: A screening for AAA among 65-75-year-old men and women was performed in a population with high prevalence of disease. Most of the subjects had undergone previous testing at the age of 60, including blood sampling. A total of 42 patients with AAA were compared with 100 age- and gender-matched controls with normal aortas. Cpn immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies present in plasma samples obtained at the time of screening (current) and in the past 5-15 (mean, 12) years (historical) were analyzed. Cpn antibody titers (<1/64, 1/64, 1/264, and 1/1024) were analyzed using the microimmunofluorescence technique. Results: No differences in current Cpn immunoglobulin A and IgG antibodies titers (p = 0.111 and 0.659), historical titers (p = 0.449 and 0.228), or titer change (delta) (p = 0.794 and 0.172) were observed between patients with AAA and controls. In all, 82% of the patients with AAA had a current Cpn IgG titer of 1/1024 as compared with the 70% of the control group. All 11 patients who had an aortic diameter of >40 mm reported having high current Cpn IgG titers. The fact that such a large proportion of the healthy population demonstrated an immune response against Cpn made it difficult to demonstrate possible effects of Cpn infection on AAA formation in a case-control study. Conclusion: No significant associations were found between AAA detected by screening and Cpn antibody titer levels at the time of screening or during past screening at the age of 60.

Keywords
Abdominal aortic aneurysm, Chlamydophila pneumoniae, inflammation, statin, expansion, randomised clinical trial, MMP-9, IL-6, CRP, azithromycin.
National Category
Surgery Medical and Health Sciences
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-108601 (URN)10.1016/j.avsg.2010.09.001 (DOI)000288196600004 ()21126854 (PubMedID)
Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2017-12-13Bibliographically approved
4. Expansion of small-diameter abdominal aortic aneurysms is not reflected by the release of inflammatory mediators IL-6, MMP-9 and CRP in plasma
Open this publication in new window or tab >>Expansion of small-diameter abdominal aortic aneurysms is not reflected by the release of inflammatory mediators IL-6, MMP-9 and CRP in plasma
2009 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 37, no 4, p. 420-424Article in journal (Refereed) Published
Abstract [en]

Abdominal aortic aneurysm (AAA) is a common disease that develops gradually over several years and is characterised by weakening and dilatation of the aortic wall. AAAs also demonstrates a marked inflammatory infiltrate throughout the aortic wall. Chlamydophila pneumoniae (C. pneumoniae), is a common bacterium. About 50% of the population has been infected in adolescence. Thirteen studies report the presence of either C. pneumoniae or its antigens in 35-100% of AAA specimens.

The overall aim of this thesis was to evaluate the possible role of C. pneumoniae in inflammatory response and expansion of AAA from a clinical point of view.

In paper I, viable C. pneumoniae was detected in a majority of 26 patients with AAA having open surgery. Patients operated for AAA had higher C. pneumoniae antibodies titers than controls. In paper II, 247 patients were randomised in a double-blind trial, to evaluate the effect of azithromycin on the expansion of small AAAs. No such effect was seen and there was no correlation between C. pneumoniae antibody titers and AAA expansion. In paper III, 42 patients with AAA were compared to 100 age- and sex matched controls with normal aortas. C. pneumoniae antibodies were analysed in plasma samples obtained at screening, and in samples from a study conducted 5-15 (mean 12) years previously on the same population. There was no significant difference between the groups. In paper IV, were 211 patients were analysed, we could not find an association between levels in plasma of three markers of inflammation (IL-6, MMP-9 and CRP) and AAA expansion. A significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins.

In conclusion, viable C. pneumoniae is found at the scene of the crime, but we were unable to reverse or halt expansion of AAA with antibiotic treatment. C. pneumoniae antibody titers cannot be used, to detect small AAA, or to evaluate AAA expansion. From a clinical point of view, based on the methods and analyses used in this thesis, the role of C. pneumoniae in the inflammatory response and expansion of abdominal aortic aneurysms is limited.

Abstract [en]

OBJECTIVES: The aim of this study was to evaluate a possible correlation between plasma levels of interleukin-6 (IL-6), metalloproteinase-9 (MMP-9) and C-reactive protein (CRP) and the expansion of small abdominal aortic aneurysms (AAAs). DESIGN: Patients were selected from a prospective randomised clinical trial and categorised in two groups, in which one group received active treatment (azithromycin) and the other received placebo. No statistical difference in the expansion rate of AAAs between the groups was found and the two groups were considered as one cohort in the present study. MATERIAL AND METHODS: In this study, 213 patients with AAAs between 35 and 49 mm were followed-up with ultrasound examination every 6th month. Blood samples were taken on two occasions (6 months apart). IL-6 and MMP-9 were analysed on one occasion using Quantikine analysing kits (R&D Systems, Inc., USA). CRP was analysed using sensitive-CRP method. RESULTS: Levels of IL-6, MMP-9 and CRP did not correlate with AAA expansion. Neither was there any correlation between statin medication and changes in MMP-9 levels over the 6-month period. Patients on statins had a lower expansion rate than those not taking statins: 0.16 versus 0.25 cm per year. CONCLUSION: No correlation was found between levels of circulating IL-6, MMP-9, CRP and the expansion of small-diameter AAAs, indicating no clinical use of these markers in AAA surveillance.

Keywords
Abdominal aortic aneurysm, Chlamydophila pneumoniae, inflammation, statin, expansion, randomised clinical trial, MMP-9, IL-6, CRP, azithromycin.
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:uu:diva-108599 (URN)10.1016/j.ejvs.2008.11.027 (DOI)000265199400008 ()19119028 (PubMedID)
Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2017-12-13Bibliographically approved

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