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We are convinced that Chlamydia pneumoniae research has been unfavorably affected by the negative results of antibiotic treatment trials for the secondary prevention of late-stage coronary heart disease (CHD) (O'Connor et al. , 2003; Cannon et al. , 2005; Grayston et al. , 2005). There is a widespread belief that the clinical trials showed that C. pneumoniae has no role in atherosclerotic disease. This flawed causal inference from these trials has contributed to slowing much-needed research on C. pneumoniae. It has also resulted in a nearly complete loss of momentum for research on the infection-based response to injury hypothesis as a key factor in the initiation and progression of CHD. ### Box 1 Chlamydia pneumoniae had been considered a possible cause of atherosclerosis. That antibiotics failed to prevent secondary coronary events in patients with established coronary artery disease has been erroneously interpreted as ruling out a causative role for C. pneumoniae . This misinterpretation has had a chilling effect on C. pneumoniae research. Our concern has been confirmed by the sharp drop in published reports (PubMed citations) on C. pneumoniae since 2005. From 1999 to 2005, approximately 375 papers were published each year. There has been a 62% drop from that number with 143 being listed for 2013. The antibiotic treatment trials were not etiologic studies. No inference regarding the role of C. pneumoniae in the cause of atherosclerosis can properly be made from the trials. A prior publication stated that the study design for these trials precluded proving or disproving a role for C. pneumoniae in the initiation or progression of atherosclerosis, and predicted an overreaction to either negative or positive results (Grayston 2000). All subjects of these trials had established coronary artery disease with mostly advanced disease. Most had had a myocardial infarction (MI). The trials studied whether antibiotics could prevent …

background Chlamydia pneumoniae has been found within atherosclerotic plaques, and elevated titers of antibody to this organism have been linked to a higher risk of coronary events. Pilot studies have suggested that antibiotic treatment may reduce the risk of cardiovascular events. methods We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and evaluated the efficacy of long-term treatment with gatifloxacin, a bactericidal antibiotic known to be effective against C. pneumoniae, in a double-blind, randomized, placebo-controlled trial. Subjects received 400 mg of gatifloxacin daily during an initial 2-week course of therapy that began 2 weeks after randomization, followed by a 10-day course every month for the duration of the trial (mean duration, 2 years), or placebo. The primary end point was a composite of death from all causes, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. results A Kaplan–Meier analysis revealed that the rates of primary-end-point events at two years were 23.7 percent in the gatifloxacin group and 25.1 percent in the placebo group (hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.08; P=0.41). No benefit was seen in any of the prespecified secondary end points or in any of the prespecified subgroups, including patients with elevated titers to C. pneumoniae or C-reactive protein. conclusions Despite long-term treatment with a bactericidal antibiotic effective against C. pneumoniae, no reduction in the rate of cardiovascular events was observed.

While seroepidemiologic studies first suggested a possible association of prior infection with Chlamydia pneumoniae and atherosclerotic risk, the contribution of seroepidemiologic studies of C. pneumoniae and atherosclerotic risk remains a source of controversy, in part because the reported findings appear inconsistent. In general, cross-sectional studies of C. pneumoniae and atherosclerotic risk suggest an association, but recent reports from several prospective studies failed to demonstrate associations between the presence of IgG antibodies to C. pneumoniae and incident myocardial infarction. Evidence from other paradigms-pathologic, animal experimental, and molecular studies-supports a possible etiologic role for C. pneumoniae in atherothrombotic disease, raising questions about the contribution of seroepidemiologic studies. This review summarizes the major findings from seroepidemiologic studies in the context of other research paradigms, explores alternative explanations for the inconsistent findings, and suggests a further role for seroepidemiologic studies of C. pneumoniae and atherothrombotic risk.

Seventy-five consecutive patients undergoing directional coronary atherectomy were evaluated by measuring anti-Chlamydia immunoglobulin G and anticytomegalovirus immunoglobulin G antibodies, and serum levels of C-reactive proteins (before atherectomy). The results showed that although both Chlamydia infection and elevated C-reactive protein levels are associated with coronary artery disease and coronary artery disease events, neither of these appears to play a role in the development of restenosis.

Background — Chlamydia pneumoniae has been identified in coronary atheroma, but concomitant serum antibody titers have been inconsistently positive and unavailable before the detection of early or advanced atherosclerotic lesions. Methods and Results —This retrospective investigation was performed on premortem serum specimens and autopsy tissue from 60 indigenous Alaska Natives at low risk for coronary heart disease, selected by the potential availability of their stored specimens. Serum specimens were drawn a mean of 8.8 years (range, 0.7 to 26.2 years) before death, which occurred at a mean age of 34.1 years (range, 15 to 57 years), primarily from noncardiovascular causes (97%). Coronary artery tissues were independently examined histologically and, for C pneumoniae organism and DNA, by immunocytochemistry (ICC) and polymerase chain reaction (PCR) with species-specific monoclonal antibody and primers. Microimmunofluorescence detected species-specific IgG, IgA, and IgM antibody in stored serum. C pneumoniae , frequently within macrophage foam cells, was identified in coronary fibrolipid atheroma (raised lesions, Stary types II through V) in 15 subjects (25%) and early flat lesions in 7 (11%) either by PCR (14, 23%) or ICC (20, 33%). The OR for C pneumoniae in raised atheroma after a level of IgG antibody ≥1:256 >8 years earlier was 6.1 (95% CI, 1.1 to 36.6) and for all coronary tissues after adjustment for multiple potential confounding variables, including tobacco exposure, was 9.4 (95% CI, 2.6 to 33.8). Conclusions —Serological evidence for C pneumoniae infection frequently precedes both the earliest and more advanced lesions of coronary atherosclerosis that harbor this intracellular pathogen, suggesting a chronic infection and developmental role in coronary heart disease.

This paper will concentrate on Chlamydia pneumoniae, whch is the most common non-viral intracellular pathogen and has been a major focus of this Symposium. It has now been 10 years since we first obtained serologic evidence suggesting that the untypeable Chlamydia isolate obtained from the eye of a child in Taiwan in 1965 was associated with respiratory tract infection [l], and then isolated a s d a r strain from acute respiratory hsease 121. While much circumstantial evidence has accumulated that the TwAR organism causes acute respiratory disease, there have been very few appropriately controlled investigations directed at proving an etiologic role for the organism in acute respiratory disease (ARD) [3].

It is just 17 years since Chlamydia pneumoniae was first described and 14 years since the first observational evidence of a possible association of the organism with coronary heart disease (CHD). For 5 years there was little interest in this association, but it has subsequently attracted an increasing number of investigators. The question of an association was settled by the frequent demonstration of C. pneumoniae in atherosclerotic lesions. However, understanding the pathogenic significance of the organism in the lesions has remained elusive. See p 1253 Efforts to determine the pathogenic role of C. pneumoniae have included animal model studies, mechanistic studies, and clinical trials of antibiotic treatment. In rabbits and mice, C. pneumoniae pulmonary inoculation causes acceleration of atherosclerosis in the presence of elevated lipids. This effect of C. pneumoniae can be prevented by antibiotic treatment shortly after inoculation but not after the organism becomes established in the arteries. There are now a variety of studies of basic mechanisms that have shown ways that C. pneumoniae could play a role in the pathogenesis of atherosclerosis. With the publication in this issue of Circulation of a clinical trial of antibiotic treatment of patients after acute myocardial infarctions,1 there are now 12 published clinical trials of antibiotic treatment for secondary prevention of atherosclerotic cardiovascular disease.1–12 Two additional trials, not yet published, were presented at the 2002 Annual Scientific Sessions of the American College of Cardiology. They are Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders (WIZARD) and AZithromycin in Acute Coronary Syndromes (AZACS). Nine of the 14 trials studied prevention of events of CHD. Five studied changes in arteries. Table 1 lists information on 8 small trials involving CHD. Small trials include those with an inadequate number of …

To determine whether pelvic damage is associated with positive Chlamydia trachomatis serology in women with tubal ectopic pregnancy.Cross-sectional retrospective study.A prepaid health maintenance organization.Two-hundred eighty-one women admitted with confirmed tubal ectopic pregnancy were interviewed for history of sexually transmitted diseases. Chlamydia serology was obtained for 135 subjects, and operative findings were available for 121 of these.None.Pelvic damage, as determined by review of operative findings of the pelvis at the time of ectopic surgery.Pelvic damage was associated with positive chlamydia serology with an adjusted odds ratio of 4.2 (95% confidence interval: 1.8 to 9.7). Moderate and severe pelvic damage were more strongly associated with positive serology than mild damage.Women with ectopic pregnancies and antibodies to C. trachomatis are more likely to have damaged pelves than women with ectopic pregnancies without such antibodies. Prevention or early treatment of C. trachomatis infection may reduce pelvic damage and, therefore, reduce incidence of ectopic pregnancy.

purpose: To determine whether past infection by Chlamydia pneumoniae strain TWAR is associated with asymptomatic atherosclerosis. Previous studies have linked this organism with symptomatic coronary heart disease. subjects and methods: Between 1986 and 1989, 15,800 men and women aged 45 to 64 years were examined as part of the Atherosclerosis Risk in Communities Study, a prospective cohort study of atherosclerosis being conducted in 4 United States communities. The examination included B-mode ultrasonography of the carotid arteries and an assessment of cardiovascular disease risk factors. Carotid wall thickening (blood-intima to medial-adventitial interface) in the absence of clinical cardiovascular disease was considered evidence of asymptomatic atherosclerosis. In 1991, IgG antibody titers to TWAR were assayed by microimmunofluorescence in stored sera from 326 case-control pairs matched by age group, race, sex, examination period, and field center. A titer of 1:8 or higher was considered a positive TWAR antibody response. results: Seventy-three percent of atherosclerosis cases had serologic evidence of past TWAR infection versus 63% of controls (matched odds ratio 1.76; 95% confidence interval, 1.21 to 2.57). After adjustment for age, hypertension, diabetes, cigarette smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and education, the odds ratio for atherosclerosis was essentially unchanged at 2.00 (95% confidence interval, 1.19 to 3.35). The association was stronger for individuals aged 45 to 54 years than for those aged 55 to 64 years. conclusion: There was a significant cross-sectional association between past TWAR infection and asymptomatic atherosclerosis. This organism may be a contributor to the pathogenesis of atherosclerosis.

Chlamydia pneumoniae strain TWAR, the new third species of Chlamydia, is a common cause of pneumonia and other acute respiratory tract infections. About 10% of hospitalized and outpatient pneumonia cases have been associated with TWAR infection. TWAR is among the four or five most commonly identified causes of all pneumonia. Most TWAR infections are mild or asymptomatic, but occasionally severe pneumonia with death has been observed. Laboratory diagnosis is not generally available. Vigorous treatment with tetracycline or erythromycin is recommended. Both epidemic and endemic infections have been described in North America and the Nordic Countries. Population prevalence antibody studies suggest that TWAR infection is wide-spread throughout the world, that nearly everyone is infected and reinfected during their life-time, and that infection is common in all ages except those less than 5 years in temperate zone countries. The infection is transmitted from person to person, apparently with a long incubation period.

used, different antibody titers were considered to indicate positive results, and different types of adjustments for cardiac risk factors were made. The problem with C. pneumoniae seroepidemiologic studies that involve adults is the frequency of antibody in the population. We showed that 75% of children in a Seattle, Washington, study were infected with C. pneumoniae between the ages of 5 and 14 years. Despite loss of antibody after infection, population prevalence antibody rates reached 50% by 20 years of age. The prevalence rate is low in persons !5 years of age. After increasing to 50% by 20 years of age, the prevalence continues to increase throughout adulthood, reaching 80% in older adults [4]. It is thought that the increasing prevalence of antibody is associated with reinfection. These antibody patterns suggest that everyone is infected and reinfected with C. pneumoniae during his or her lifetime. Atherosclerosis begins in childhood and

BACKGROUND Epidemiologic, laboratory, animal, and clinical studies suggest that there is an association between Chlamydia pneumoniae infection and atherogenesis. We evaluated the efficacy of one year of azithromycin treatment for the secondary prevention of coronary events. METHODS In this randomized, prospective trial, we assigned 4012 patients with documented stable coronary artery disease to receive either 600 mg of azithromycin or placebo weekly for one year. The participants were followed for a mean of 3.9 years at 28 clinical centers throughout the United States. RESULTS The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, -13 to 13 percent]). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or C. pneumoniae serologic status at baseline. CONCLUSIONS A one-year course of weekly azithromycin did not alter the risk of cardiac events among patients with stable coronary artery disease.

Abnormalities of vascular function occur in patients with risk factors for atherosclerosis before the development of obstructive disease. Our pilot data suggest that elevated serum markers of infection and/or inflammation are associated with functional abnormalities of the vasculature in subjects at otherwise low risk for atherosclerosis.

TWAR, the only known serovar of Chlamydia pneumoniae, is a newly described bacterium that has been identified as a cause of both epidemics and endemic cases of pneumonia. The role of TWAR infection in patients with chronic obstructive pulmonary disease (COPD) is not known. We conducted a prospective study to establish whether TWAR infection is a common cause of acute exacerbations of COPD. We studied two groups of patients: 44 patients admitted to the hospital with acute exacerbations of COPD, and 65 stable clinic patients with COPD. We found that evidence of acute TWAR infection was infrequent in patients with exacerbations (5%). In contrast, the majority of patients from both groups had serologic evidence of previous TWAR infection (77%). This was not significantly greater than the prevalence found in a small group of patients of similar age and sex without lung disease from the same institution (73%). TWAR was not isolated from the oropharyngeal specimens obtained from 97 subjects, suggesting that it does not colonize the respiratory tract of patients with COPD. This study shows that at the time of low incidence in the community, acute TWAR infection is uncommon in patients with acute exacerbations of COPD. The majority of patients with COPD have, however, been infected with TWAR in the past. The clinical manifestations of these infections are not known and should be the focus of further studies.

A pilot study of azithromycin treatment following percutaneous coronary revascularization procedures was performed to assess safety and the effect of azithromycin treatment on anti-Chlamydia pneumoniae antibody titres. Patients were randomized to a 1 month course of azithromycin (total dose of 8.0 g) or placebo. Safety and compliance were assessed at 2 and 4 weeks and serological testing was performed on samples obtained at enrolment and at 6 months post-enrolment. Azithromycin was well tolerated at this dose. No effect of treatment on antibody titres was demonstrated. These results support further clinical trials to assess the effect of azithromycin treatment on cardiovascular disease outcomes.

Accumulating evidence supports an association between Chlamydia pneumoniae infection and atherosclerosis. To determine whether there is a causal relationship, the effects of chronic infection with C. pneumoniae on the development of atherosclerosis in apolipoprotein E (apoE)-deficient mice were evaluated. Eight-week-old male apoE-deficient mice were inoculated intranasally with C. pneumoniae three times, at 8, 9, and 10 weeks of age. The combined area of atherosclerotic lesions in the lesser curvature of the aortic arch was measured en face by computer-assisted morphometry. The lesion area was 2.4-fold greater (P = .05) at 16 weeks of age and 1.6-fold greater (P = .05) at 20 weeks of age in infected mice than in control mice. There were no differences in total plasma cholesterol levels between groups. This study demonstrates that C. pneumoniae infection accelerates the progression of atherosclerosis in the aortic arch of apoE-deficient mice.

Since the publication of two preliminary antibiotic treatment trials for secondary prevention of cardiovascular events in persons with coronary artery disease (CAD),1 2 there has been increased interest in the possibility that the association between Chlamydia pneumoniae and atherosclerosis is causal and that antibiotic treatment can have a favorable effect on the complications and outcome of the disease. The impetus for these trials was the repeated demonstration by many investigators of an association of C pneumoniae and atherosclerosis by both seroepidemiology and demonstration of the organism in atherosclerotic lesions. A number of antibiotic treatment trials to evaluate reduction in cardiac events are being planned or initiated in many different countries. Adequately sized and properly designed trials are both desirable and justified. Two of the difficult questions in planning such trials are the inclusion criteria for subjects and the appropriate length of treatment. In choosing the subjects, one consideration is the expected rate of end-point events: cardiovascular death, myocardial infarction (MI), and defined episodes of unstable angina. A trial with a higher event rate will require fewer subjects and a shorter observation period. The results will be applicable only to the higher-risk patient. This is exemplified by the trial in Buenos Aires2 in which hospitalized patients with unstable angina and non–Q-wave MI were studied. Although this is an important study that could aid many patients, evaluation of antibiotic treatment of patients with stable CAD will have even wider applicability. A surprising finding in the …

Summary Chlamydia are among the most common bacteria to infect humans. The three species are genetically distinct and vary in the magnitude of their importance as human pathogens and in the clinical syndromes resulting from infection. Chlamydia trachomatis is of major worldwide importance, causing trachoma, the leading cause of preventable blindness in the world, as well as sexually transmitted genital infections which are important causes of infertility and ectopic pregnancy. C. psittaci is common in birds but is an uncommon cause of human infection. C. pneumoniae infects the majority of individuals by adulthood, is a leading cause of pneumonia, and has a worldwide distribution. Recent evidence suggests that C. pneumoniae may also be associated with atherosclerosis, an important cause of morbidity and mortality in adults.

Chlamydia pneumoniae has been associated with atherosclerotic cardiovascular disease by both seroepidemiologic studies and direct detection of the organism in atherosclerotic plaque by electron microscopy (EM), immunocytochemistry (ICC), and polymerase chain reaction (PCR). Despite the frequent detection of the organism in atheromatous cardiovascular specimens by these methods, only 1 cardiovascular isolate of C. pneumoniae, obtained from a coronary artery, has been previously reported. This study reports the isolation of C. pneumoniae from a prospectively obtained carotid endarterectomy specimen. The organism appears to be identical to other C. pneumoniae isolates by EM morphology, reactivity to species-specific monoclonal antibodies, and Southern hybridization analysis of chromosomal digests using C. pneumoniae-specific DNA probes. C. pneumoniae was detected by PCR or ICC (or both) in 11 (69%) of 16 other endarterectomy specimens tested by both of these methods. These results provide further evidence for an association of C. pneumoniae and atherosclerosis by confirming the presence of viable bacteria within atherosclerotic plaque.

Chlamydia pneumoniae have been demonstrated in atherosclerotic lesions but not in normal arteries. An animal model of both C. pneumoniae and atherosclerosis is needed to investigate the role of the organism in atherosclerosis. Apolipoprotein (apo) E-deficient transgenic mice, which spontaneously develop atherosclerosis, and C57BL/6J mice, which only develop atherosclerosis on an atherogenic diet, were evaluated. Following single and multiple intranasal inoculations of apoE-deficient transgenic mice, C. pneumoniae were detected in lung, aorta, and spleen for 20 weeks after inoculation in 25%-100% of mice. In the aorta, C. pneumoniae were detected within the atherosclerotic lesion. In C57BL/6J mice on a nonatherogenic diet, C. pneumoniae were detected in the aorta only 2 weeks after a single intranasal inoculation in 8% of mice. The persistence of C. pneumoniae in atheromas suggests a tropism of C. pneumoniae to the lesion. These mouse models should be useful for studying the pathogenic role of C. pneumoniae in atherosclerosis.

OBJECTIVE To determine the prevalence of acute Chlamydia pneumoniae infection in ED patients presenting with a persistent cough. METHODS This was a case series consisting of a convenience sample of 65 patients > or = 18 years of age who presented with a chief complaint of a cough lasting > or = 2 weeks. Patients were treated in the ED of an urban university hospital. Patients with immunosuppression, lung disease, pneumonia, or a cough lasting > or = 3 months were excluded. Acute and convalescent sera were assayed for antibody to C. pneumoniae. Subjects with C. pneumoniae antibody titers showing a fourfold rise in either immunoglobin M (IgM) or immunoglobin G (IgG) antibody, an IgM titer of > or = 16, or an IgG titer of > or = 512 were considered to have evidence of acute C. pneumoniae infection. RESULTS Thirteen (20%; 95% CI, 11% to 32%) of the 65 subjects had serologic evidence of acute C. pneumoniae infection. Except for an increased rate of fever, clinical signs and symptoms and laboratory studies did not differentiate those who had C. pneumoniae from those who did not have the disease. Patients diagnosed as having Bordetella pertussis or Mycoplasma pneumoniae infection did not have serologic evidence of concurrent C. pneumoniae infection. CONCLUSIONS C. pneumoniae infection appears to be associated with a persistent cough in ED patients. Clinicians should consider this organism when evaluating these patients. It is unclear whether antibiotic therapy is indicated for these patients. If antibiotics are used, a tetracycline or macrolide antibiotic would be most appropriate.

used, different antibody titers were considered to indicate positive results, and different types of adjustments for cardiac risk factors were made. The problem with C. pneumoniae seroepidemiologic studies that involve adults is the frequency of antibody in the population. We showed that 75% of children in a Seattle, Washington, study were infected with C. pneumoniae between the ages of 5 and 14 years. Despite loss of antibody after infection, population prevalence antibody rates reached 50% by 20 years of age. The prevalence rate is low in persons !5 years of age. After increasing to 50% by 20 years of age, the prevalence continues to increase throughout adulthood, reaching 80% in older adults [4]. It is thought that the increasing prevalence of antibody is associated with reinfection. These antibody patterns suggest that everyone is infected and reinfected with C. pneumoniae during his or her lifetime. Atherosclerosis begins in childhood and

Background Chlamydia pneumoniae has been demonstrated in atherosclerotic lesions of coronary arteries and aorta. A seroepidemiological study found C pneumoniae –specific antibody more frequently in persons with significant carotid artery wall thickening than in matched control subjects. Methods and Results Fresh-frozen or formalin-fixed tissue obtained at carotid endarterectomy was examined by immunocytochemistry (ICC) and the polymerase chain reaction (PCR) for the presence of C pneumoniae. Five of five fresh-frozen and formalin-fixed carotid endarterectomy specimens were positive for C pneumoniae by ICC (three of five by PCR). A total of 56 archival formalin-fixed, paraffin-embedded carotid endarterectomy tissues from three hospitals were examined by ICC. Thirty-two were positive. Thirteen normal carotid artery tissue sections from six patients were negative for C pneumoniae . Conclusions C pneumoniae organisms are frequently found in the advanced carotid atherosclerotic lesions of persons undergoing endarterectomy. Although these findings do not establish causality for C pneumoniae in carotid artery atherosclerosis, they should stimulate investigation of a possible causal or pathogenic role for the organism in the disease.

Studies using monoclonal antibodies have demonstrated species-specific reactivities with Chlamydia pneumoniae. In this study, further characterization of C. pneumoniae specific monoclonal antibodies TT-205 and RR-402 and description of C. pneumoniae specific antibodies prepared against other isolates are presented. TT-205 and RR-402 were shown to neutralize infectivity. Neutralization in cell culture was specific and enhanced by complement. Attempts to characterize the reactive antigen by immunoblotting, immunoaffinity chromatography and radioimmunoprecipitation were unsuccessful, probably due to difficulties in solubilizing the immunoreactive epitope without denaturing it. Recognition of the determinant by the monoclonal antibodies is labile to physical and chemical treatments suggesting that the reactive epitope is conformational.

We compared the transmission rate of Chlamydia trachomatis infection from infected women to their infants after various modes of delivery. After vaginal birth, Chlamydia trachomatis was isolated from 58 of 125 infants with a cephalic presentation, and serological evidence of chlamydial infection was found in another eight. C. trachomatis was isolated from the only infant with a frank breech presentation. After Caesarean birth, C. trachomatis was isolated from two of 10 infants born after rupture of the membranes and from one of six without prior rupture of the membranes. No serological evidence of infection was found in any of the culture-negative infants born by Caesarean section. By survival analysis, rates of transmission were significantly lower after Caesarean section with rupture of the membranes before delivery than after vaginal delivery. Infants born to infected women are at risk of C. trachomatis infection regardless of route of delivery.

We assessed risk of tubal pregnancy associated with past use of an intrauterine device (IUD). Cases were 256 members of Group Health Cooperative of Puget Sound who experienced a tubal pregnancy between 1981 and 1986. Controls were 666 female members of the Cooperative at risk of ectopic pregnancy who were similar to cases with respect to age and county of residence, but otherwise selected at random. The presence of antibody to Chlamydia trachomatis was assessed in a sample of 134 cases and 182 controls. Women who had previously used an IUD for 3 or more years were more than twice as likely as women who had never used an IUD to have a tubal pregnancy (adjusted relative risk = 2.5, 95% confidence interval = 1.5-4.3). Among these long-term users of an IUD, risk of tubal pregnancy remained elevated for many years after the device was removed. Also, among long-term users, women known to have more than one IUD insertion were no more likely than women with one known insertion to develop a tubal pregnancy. When we restricted our analyses to women who used only copper-containing devices, the results were nearly identical. We conclude that extended past use of an IUD, including use of a copper device, increases the risk of tubal pregnancy.In King County, Washington, health workers interviewed 256 members of the Group Health Cooperative of Puget Sound who had had an ectopic pregnancy between October 1981 and September 1986 and 666 randomly selected, age and country matched controls who were at risk of ectopic pregnancy. Researchers wanted to examine the risk of ectopic pregnancy associated with past use of an IUD, particularly a copper releasing IUD They tested for Chlamydia trachomatis antibody in 134 cases and 182 controls. Cases were more likely to have a positive titer for C. trachomatis than controls (42.5% vs. 18.1%). The risk of ectopic pregnancy rose with increasing duration of past IUD use (e.g., odds ratio for past IUD use of 36 or more months was 2.5). The risk was the same when the researchers only considered past use of copper releasing IUDs. Further, the risk remained elevated for at least 7 years after stopping IUD use, including copper IUDs. Women with no evidence of chlamydial infection experienced an elevated risk of ectopic pregnancy with increasing duration of past IUD use (adjusted relative risk at 36 or more months was 3.4 for all IUD users and 5.5 for copper IUD users), suggesting that events other than chlamydial salpingitis damage tubes in IUD users. Among women who used IUDs for at least 36 months in the past, women who continuously used the same IUD were just likely to have an ectopic pregnancy as were those with more than one IUD insertion. These results indicate that longterm, past use of an IUD, including a copper IUD, elevates the risk of ectopic pregnancy.

Summary of a Discussion There is no expectation that one experiment, no matter how innovative, will definitively prove or disprove the hypothesis of an etiologic role for Chlamydia pneumoniae in atherosclerosis. Rather a gradual accumulation of data from many investigators will lead to acceptance or rejection of the hypothesis. Proof will not be absolute but an overwhelming consensus of knowledgeable scientists. Koch’s postulates cannot be expected to be fulfilled. Sir Branford Hill’s criteria will be helpful. They look at the possible etiologic association in terms of strength, consistency, specificity, temporality, plausibility, coherence, analogy, and experimental evidence. There are three stages of atherosclerosis—any or all of which could be potentially caused by C. pneumoniae (table 1): initiation of the disease process, acceleration of the process, and complications of the disease (e.g., myocardial infarction). If C. pneumoniae is involved in initiation of the disease, it would be a cause of atherosclerosis. If it plays a role in the acceleration of the disease that has already been initiated, then it could be considered a risk factor. It is clear that the experiments of greatest interest and significance to cardiologists (a most important constituency) are the large-scale, secondary prevention, antibiotic treatment trials. If the clinical trials clearly show a positive effect of antibiotic treatment of coronary artery disease (CAD), and animal model studies also show a favorable effect of specific treatment of C. pneumoniae, it is likely that the hypothesis will be accepted as true. If the clinical trials fail to show an effect, there will be a significant loss of interest in the basic hypothesis. The reaction to the results of the clinical trials, either positive or negative, will probably be in excess of what is justified. If positive, the results will prove little about the cause of atherosclerosis and much about C. pneumoniae being involved in the cascade of events leading to acute complications of atherosclerosis (table 2). The unlikely possibility will exist that the antibiotic effect is due to inhibition of an unidentified organism other than C. pneumoniae. If the results are negative they will say little about C. pneumoniae in the initiation of atherosclerosis

Chlamydia pneumoniae is commonly detected in atherosclerotic plaque but the frequency of detection in non-cardiovascular (CV) tissues has not been well determined. In this study, archival autopsy tissue specimens from both CV and non-CV sites from 38 patients were tested by polymerase chain reaction and immunocytochemistry to detect C. pneumoniae. In addition, 33 surgical granuloma biopsy specimens were also tested. C. pneumoniae was detected most frequently in coronary artery tissue (34%) but was also detected in specimens from lung (13%), liver (10%), spleen (5%), bone marrow (10%), and lymph node (8%). The organism was detected in 3 of 33 granuloma specimens. These findings suggest that C. pneumoniae demonstrates a tropism for CV tissues and is either not widely distributed to non-CV tissues or does not persist chronically in those tissues after initial infection.

To explore the possible association between vaginal douching and tubal pregnancy, we interviewed 273 women who were diagnosed with tubal pregnancy at Group Health Cooperative between September 31, 1981 and October 1, 1986. Their responses were compared with responses of a random sample of 722 female members of Group Health Cooperative who were assumed to be at risk of becoming pregnant at the time the cases conceived. After adjusting for differences between cases and controls with regard to other measured risk factors, we found a modest increase in risk associated with having douched more than two times per year in the past (RR = 1.3, 95% CI: 0.9-1.8). Among women who had more than one sexual partner during their lifetime, however, the risk for those who had douched more than twice per year was somewhat higher (RR = 1.6, 95% CI: 1.1-2.3). There was an indication that women who had been exposed to Chlamydia trachomatis, as indicated by elevated antibody titers, may further increase their risk for tubal pregnancy by douching (RR = 2.4, 95% CI: 0.8-7.3). The associations found in other studies between douching and pelvic inflammatory disease, and between pelvic inflammatory disease and subsequent tubal pregnancy, argue that a relation between douching and tubal pregnancy might be anticipated. Our results offer further support for this hypothesis.

purpose: Limited data suggest that tetracycline or erythromycin is the antibiotic of choice for treating Chlamydia pneumoniae infection, but they are not always effective or well tolerated. Because the fluoroquinolone ofloxacin is effective for Chlamydia trachomatis infections, we investigated its role in treating C. pneumoniae infections. patients and methods: Eighty-seven patients were enrolled in a randomized trial of antibiotic therapy for acute lower respiratory tract infections. The patients were randomly assigned to oral treatment with either ofloxacin (400 mg twice a day) or erythromycin (400 mg four times a day) for 10 days. Frozen acute and convalescent serologic specimens were tested for TWAR antibody by microimmunofluorescence. Susceptibility testing of C. pneumoniae to ofloxacin was also performed. results: Four patients who received ofloxacin were retrospectively identified as having C. pneumoniae pneumonia (two) or bronchitis (two). Within 2 weeks of starting ofloxacin therapy, all were cured or markedly improved. The minimum inhibitory concentrations of ofloxacin for three previously isolated clinical strains of C. pneumoniae were determined to be 1.0 to 2.0 μg/mL, well within the achievable serum levels (3 to 5 μg/mL) with ofloxacin therapy. conclusion: Ofloxacin may be an effective alternative antibiotic treatment for C. pneumoniae respiratory infections.

Three hundred fifty-nine consecutive patients with community-acquired pneumonia admitted to university, community, and VA hospitals underwent a standardized evaluation, including specialized tests for Legionella spp. and Chlamydia pneumoniae (TWAR). The most common underlying illnesses were immunosuppression (36.3%), chronic obstructive pulmonary disease (32.4%), and malignancy (28.4%). The most frequent etiologic agents were Streptococcus pneumoniae (15.3%) and Hemophilus influenzae (10.9%). Surprisingly, Legionella spp. and C. pneumoniae were the third and fourth most frequent etiologies at 6.7% and 6.1%, respectively. Aerobic gram-negative pneumonias were relatively uncommon causes of pneumonia despite the fact that empiric broad-spectrum combination antibiotic therapy is so often directed at this subgroup. In 32.9%, the etiology was undetermined. Antibiotic administration before admission was significantly associated with undetermined etiology (p = 0.0003). There were no distinctive clinical features found to be diagnostic for any etiologic agent, although high fever occurred more frequently in Legionnaires' disease. Clinical manifestations for C. pneumoniae were generally mild, although 38% of patients had mental status changes. Mortality was highest for Staphylococcus aureus (50%) and lowest for C. pneumoniae (4.5%) and Mycoplasma pneumoniae (0%). We document that specialized laboratory testing for C. pneumoniae and Legionella spp. should be more widely used rather than reserved for cases not responding to standard therapy. Furthermore, realization that C. pneumoniae and Legionella spp. are common etiologies for community-acquired pneumonia should affect empiric antibiotic prescription.

Objective: To compare the efficacy and safety of azithromycin dihydrate monotherapy with those of a combination of cefuroxime axetil plus erythromycin as empirical therapy for community-acquired pneumonia in hospitalized patients. Methods: Patients were enrolled in a prospective, randomized, multicenter study. The standard therapy of cefuroxime plus erythromycin was consistent with the American Thoracic Society, Canadian Community-Acquired Pneumonia Consensus Group, and Infectious Disease Society of America consensus guidelines. The doses were intravenous azithromycin (500 mg once daily) followed by oral azithromycin (500 mg once daily), intravenous cefuroxime (750 mg every 8 hours), followed by oral cefuroxime axetil (500 mg twice daily), and erythromycin (500-1000 mg) intravenously or orally every 6 hours. Randomization was stratified by severity of illness and age. Patients who were immunosuppressed or residing in nursing homes were excluded. Results: Data from 145 patients (67 received azithromycin and 78 received cefuroxime plus erythromycin) were evaluable. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 19% (28/145) and 13% (19/145), respectively. The atypical pathogens accounted for 33% (48/145) of the etiologic diagnoses; Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae were identified in 14% (20/ 145), 10% (15/145), and 9% (13/145), respectively. Clinical cure was achieved in 91% (61/67) of the patients in the azithromycin group and 91% (71/78) in the cefuroxime plus erythromycin group. Adverse events (intravenous catheter site reactions, gastrointestinal tract disturbances) were significantly more common in patients who received cefuroxime plus erythromycin (49% [30/78]) than in patients who received azithromycin (12% [8/67]) (P

The Frequency of Serologic Evidence of Bordetella Infections and Mixed Infections with Other Respiratory Pathogens in University Students with Cough Illnesses

Objective. —To study the natural history of Chlamydia trachomatis infections in infants. Design. —Bacteriologic and serologic study of an inception cohort. Setting. —University of Washington Medical Center, Seattle. Participants. —Twenty-two infants with C trachomatis infections either not treated early in life or recurring after antimicrobial treatment. Main Outcome Measures. —Persistence of infection in various anatomic sites, antibody responses to specific serovars (serologic variants) of C trachomatis , and serovars of isolates from mothers and infants. Results. —The cumulative proportion of infants still infected at the age of 1 year was 35%. Infection persisted in the conjunctiva, nasopharynx, and oropharynx in one child for as long as 866 days (28.5 months), when she was cured by treatment. In none of the infants did serologic tests suggest acquisition of infection other than at birth. Isolates of C trachomatis from mothers and their respective infants were always of the same serovar. Conclusions. —Many infants infected with C trachomatis at birth remain infected for months or years in the absence of specific antimicrobial therapy. Such infections may be confused with those acquired by sexual abuse. ( JAMA . 1992;267:400-402)

Guinea pigs sensitized via the footpad with inactivated trachoma organisms in complete Freund's adjuvant developed delayed hypersensitivity to trachoma at the 9th day as demonstrated by skin tests and in vitro blastogenic transformation of lymphocytes obtained from the regional lymph nodes. The supernatant of lymph node lymphocytes cultured in the presence of trachoma antigen for 24 hr and concentrated 10-fold induced erythema in the normal guinea pig skin. Similar supernatant cultured for 5 days was shown to inhibit the growth of the mouse L cell at a 1:4 dilution.

The trachoma and LGV organisms, the human pathogens of the species C. trachomatis, cause oculogenital infections and disease syndromes of the eye and genital tract. The incidence of the most prominent disease, endemic trachoma with eye-to-eye transmission, is decreasing all over the world. At the same time there is increasing recognition of high-frequency venereal infections with trachoma organisms and of the genital disease and occasional ocular disease that they cause. Laboratory techniques for diagnosis and investigation are improving, but work with these interesting intermediate agents remains more difficult than that with many other microorganisms. Proper recognition of the diseases is important because specific therapy is available.

We studied 23 patients with pelvic inflammatory disease associated with symptoms of pleuritic up'per abdominal pain, characteristic of Fitz-Hugh-Curtis syndrome (FHC). A fourfold or greater change in antibody titer to Chlamydia trachomatis was demonstrated by microimmunofluorescence in 14; an IgG antibody titer greater than or equal to 1:1,024 was seen in 13; and IgM antibody was demonstrated in 11. Twenty (87%) of the 23 FHC patients, including all of the 12 with paired sera obtained at least 6 weeks apart, had serologic evidence of acute C. trachomatis infection. Neisseria gonorrhoeae was isolated from seven (30%) of the 23 FHC cases, and C. trachomatis was isolated from three of 10. Two groups of matched controls were studied; one group with PID but without FHC, and the other without PID. A larger proportion of patients with FHC had serologic evidence of acute C. trachomatis infection than either of the two control groups (p less than 0.05 for each comparison). Among those with antibody to C. trachomatis, the geometric mean antibody titer for the FHC group (1:724) was significantly higher than that for the PID group (1:138) or for the non-PID group (1:103). Thus, FHC is not solely attributable to infection with N. gonorrhoeae; most cases are associated with acute C. trachomatis infection.

A new immunotype J is proposed for a group of Chlamydia trachomatis strains which are related to trachoma type C in the microimmunofluorescence typing test. Ten immunologically identical strains have been identified from four separate areas of the world. The strains were either isolated from the genital tract or from eye infection originating from the genital tract. They grow readily in HeLa 229 cell culture but poorly in egg culture. Whereas two-way cross-reactions were found between types C and J, tests with mouse antisera cross-absorbed with heterologous antigens showed that type J is completely separable from type C. The J strain caused typical follicular conjunctivitis in monkey eyes. Both humans and monkeys infected with J strains developed type-specific micro IF antibody patterns similar to immunized mouse antisera. C antisera showed broader and higher titer heterologous reactions than J antisera. Two immunologically identical strains, UW-61/Cx and 469/OC, related to both C and J, remain unclassified. They immunologically bridge the two types but are more closely related to type C immunologically and at the same time resemble type J epidemiologically and biologically.