Alexander, Russell

Davidson, Michael

Ewald, Paul

Hughes, James

Leinonen, Maija

Meier, Cristopher

Nieto, Javier

O'Connor, Siobhan

Puolakkainen, Mirja

Siscovick, David

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S430Collaborative Multidisciplinary Workshop Report: The Role of EpidemiologyStudies in Determining a Possible Relationship between Chlamydia pneumoniaeInfection and Atherothrombotic DiseasesDavid Siscovick,1,a Russell Alexander,2,aMichael Davidson,3 Maija Leinonen,7Siobhan O’Connor,4 Paul Ewald,5 Cristopher Meier,9Mirja Puolakkainen,8 James Hughes,4 and Javier Nieto61Cardiovascular Health Research Unit, and 2Departmentof Epidemiology, University of Washington; 3MedStar ResearchInstitute, Washington, DC; 4National Center for Infectious Diseases,Centers for Disease Control and Prevention, Atlanta, Georgia;5Department of Biology, Amherst College, Amherst, Massachusetts;6Department of Epidemiology, Johns Hopkins University Schoolof Hygiene, Baltimore, Maryland; 7National Public Health Institute,Oulu, and 8Department of Virology, University of Helsinki, Finland;9Pharmacoepidemiologie, Abt. Klinische Pharmakologie, DepartmentInnere Medizin, Kantonsspital, Basel, SwitzerlandThe Workshop Group on Epidemiology was asked to identifyweaknesses of current seroepidemiology studies that examinethe association of Chlamydiae pneumoniae with atherothrom-botic diseases and to identify the potential for multidisciplinarycollaborative research at various levels. The group structuredthis report according to the following categories: overall con-cept, questions, measurement needs, informative populations,trials, other proposals, and recommendations.Overall ConceptWe began by taking a broad view of the relationship betweenC. pneumoniae infection and atherothrombotic diseases. Amodel was used to express various components, such as deter-minants and characteristics of infection, possible effect modi-fiers, and various outcomes, both clinical and subclinical (figure1). The model was designed to indicate significant gaps in ourknowledge.As detailed in figure 1, the first stage of the model is “prein-fection,” which may be influenced by host factors, environ-mental factors, and other determinants of infection. The secondstage, “infection,” may be an incident, a reinfection, or per-sistent (i.e., chronic active) infection. It also was noted thatthere might be “other factors” that influence infection, includ-ing genetic or noninfectious factors and other infections.Another component of the model is “outcome.” The initialoutcome is subclinical atherosclerosis, which may or may notprogress to clinical events, such as myocardial infarction, coro-nary heart disease death, and peripheral vascular disease. Un-fortunately, most epidemiology studies have looked at the rela-tionship of C. pneumoniae infection and late clinical athero-a D.S. was the workshop leader, and R.A. was rapporteur.Correspondence: Dr. Russell Alexander, 5661 Beach Dr. S.W., Seattle,WA 98136 (russa@u.washington.edu).The Journal of Infectious Diseases 2000;181(Suppl 3):S430–1q 2000 by the Infectious Diseases Society of America. All rights reserved.0022-1899/2000/18106S-0009$02.00thrombotic diseases, leaving a dearth of studies looking at theprimary prevention of atherosclerosis, potential interactions ofC. pneumoniae with other risk factors, and additional high-riskpopulations.QuestionsThe workshop group began with a statement of critical epi-demiologic questions that remain to be answered regarding theassociation between C. pneumoniae infection and atherosclerosis:1. What are the determinants of incident infection with C.pneumoniae?2. How do genetic factors relate to the response to infectionwith C. pneumoniae?3. Is progression of atherosclerosis associated with persistenceof infection or reinfection with C. pneumoniae?4. Are there persons for whom it can be predicted that C.pneumoniae infection is harmful and others in whom it is not?5. How does the natural history of C. pneumoniae infectionrelate to the natural history of atherosclerosis?Measurement NeedsGroup members generally agreed that there are a number ofdeficiencies in serologic and other measurements that impedefurther seroepidemiology studies:1. The organisms being studied and the serologic and antigen-detection methods used need to be standardized.2. A means is needed for differentiating incident, reactivated,and chronic infections.3. Methods for the timing and collection of serial blood spec-imens must be standardized, and more quantitative serology isneeded.4. Methods for collecting peripheral blood monocytes to as-sess chlamydial antigens must be standardized.Other measurements that should be included in future epi-JID 2000;181 (Suppl 3) C. pneumoniae and Atherothrombotic Diseases S431Figure 1.demiology studies examining the association between infectionwith C. pneumoniae and atherothrombotic diseases include thefollowing:1. Noninvasive measurements of atherosclerosis in differentvascular beds (e.g., coronary arteries, carotid arteries, adhesionfactors).2. Intermediate or surrogate markers of inflammation andadhesion molecules (e.g., inflammatory markers, acute-phasereactants, cytokines, adhesion factors).3. Other factors potentially related to both infection andatherothrombotic diseases, such as lipids, dietary fat, and quan-titative smoking measures (including measurements of earlyexposure to passive smoking).Informative PopulationsThere was a concern that population subsets of particularinterest have not been dealt with in past and current epide-miology studies. In particular, it was felt that the followingpopulation subsets should be considered in future studies:1. Women.2. Persons with high and low lipid levels.3. Young adults (e.g., the Coronary Artery Risk Developmentin Young Adults Study) and army recruits.4. Children and adolescents (e.g., the ongoing cohort studyof childhood respiratory infections in Arizona).5. Different ethnic groups (e.g., the Multi-Ethnic Study ofAtherosclerosis).6. Immunosuppressed persons.7. Persons with prior chronic lung disease.TrialsThe workshop group noted that the large ongoing secondaryprevention trials are excellent but do not deal comprehensivelywith all at-risk persons and are restricted to late stages of ath-erosclerosis. In particular, it was felt that there have been adeficient number of studies regarding the primary preventionof atherosclerosis, the selection of high-risk populations (asclassified on the basis of evidence of chronic persistent infec-tion), and potential interactions with other risk factors. Forexample, most trials are being conducted among middle-agedand older adults, while studies of younger men and women areneeded to examine the effect of antibiotic treatment on the earlystages of atherosclerosis.It was also felt that both epidemiology studies and preventiontrials should begin to define cohorts that would be suitable forvaccine trials in the event that a C. pneumoniae vaccine isdeveloped.Other ProposalsThere was general agreement that epidemiology studies havenot sufficiently dealt with analysis of multiple factors (i.e., effectmodification). The problem here is that studies to date havenot had large enough sample sizes to do this. The solutionwould be to pool data from databases from prior studies.There was also discussion of the paradox that although mostinternational studies showed a remarkable uniformity of pastinfection with C. pneumoniae, there did not seem to be an anal-ogous uniformity in the prevalence of atherosclerosis in thecountries under study. Some panel members felt that furtherinternational comparative studies are needed.Recommendations1. Further epidemiology studies regarding the associationbetween C. pneumoniae and atherothrombotic diseases wouldbenefit from a standardization of the means of measuring an-tibodies and antigens (see Measurement Needs section).2. Most epidemiology studies have been done with middle-aged and older populations and in relation to clinical diseaseend points of atherosclerosis, such as myocardial infarction andcoronary heart disease death. It is advised that epidemiologystudies be extended to additional populations (see InformativePopulation section)3. In regard to trials, the same concerns apply. The trials thatare being conducted are primarily using middle-aged and olderadults and are in relation to advanced stages of atherosclerosis,which is a logical place to start. However, future studies shouldextend to other populations, particularly women and youngermen and women in early stages of atherosclerosis (see Trialssection).

Collaborative Multidisciplinary Workshop Report: The Role of Epidemiology Studies in Determining a Possible Relationship between Chlamydia pneumoniae Infection and Atherothrombotic Diseases

Collaborative Multidisciplinary Workshop Report: The Role of Epidemiology Studies in Determining a Possible Relationship between Chlamydia pneumoniae Infection and Atherothrombotic Diseases

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