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  Clinical Abstracts






January 2008

Michael Bissell, MD, PhD

Relationship between Chlamydophila pneumoniae and asthma
Application of Bonn Risk Index to urinary stone formation
Chlamydia pneumoniae in atheromatous plaques
Combining FLCs, capillary zone electrophoresis to detect subtle M proteins
Metabolic risk factors for congestive heart failure

bullet Relationship between Chlamydophila pneumoniae and asthma

Chlamydophila pneumoniae, formerly known as Chlamydia pneumoniae, is a common intracellular respiratory pathogen that may cause acute illness in the upper and lower respiratory tracts. It has been estimated that most people have two or three C. pneumoniae infections during their lifetime. This condition has been reported as a possible etiologic agent in asthma. New adult patients with asthma often report a precipitating event, such as a severe respiratory infection, as the onset of their illness. And acute C. pneumoniae infection has been shown to exacerbate asthma. Findings in a case-control study in which bronchial biopsy and bronchoalveolar lavage of study subjects were analyzed using C. pneumoniae polymerase chain reaction support such a concept. Significant improvement in asthma symptoms and spirometry has been reported with prolonged antibiotic treatment in patients with asthma who have suspected chronic infection. However, in a randomized, controlled trial, only temporary benefit was found. Most previous studies on the connection between C. pneumoniae and asthma have been made in a cross-sectional setting or have been case series with acutely symptomatic patients or patients referred to a specific institution. No published studies have described serological findings before and after asthma diagnosis. Therefore, the authors conducted a study to establish whether there is an increased risk of asthma in subjects yielding serological findings suggestive of previous or chronic C. pneumoniae infection. They undertook a 15-year followup of a Finnish population cohort through the national register and clinically evaluated subjects who developed asthma during the followup (n=83) and matched controls (n=162). They performed serological testing by microimmunofluorescence and enzyme immunoassay from baseline and followup samples. The authors found that subjects with serologically diagnosed recent or chronic C. pneumoniae infection did not run a higher risk of new asthma. An increased risk was found in subjects with allergic rhinitis, low lung function, history of smoking, and positive family background of asthma or allergy. However, chronic C. pneumoniae infection was found to significantly accelerate loss of lung function in subjects who contracted new nonatopic asthma (median change in FEV1, 89.6 versus 55.9 mL/y; P=0.032). The authors concluded that chronic C. pneumoniae infection promotes the development of airflow limitation in adults with nonatopic asthma. However, the results indicate that, at the population level, any effect of C. pneumoniae infection on incidence of asthma is of minor significance.

Pasternack R, Huhtala H, Karjalainen J. Chlamydophila (Chlamydia) pneumoniae serology and asthma in adults: a longitudinal analysis. J Allergy Clin Immunol. 2005; 116: 1123–1128.

Reprints: Dr. Jussi Karjalainen, University of Tampere Medical School, FIN-33014, University of Tampere, Finland;

bullet Application of Bonn Risk Index to urinary stone formation

Urinary stone disease is common and its incidence may be increasing. Because of high recurrence rates, many attempts have been made to identify ways of predicting the risk of stone formation. Various urine parameters and combinations of these variables have been shown to have value for distinguishing calcium oxalate stone formers (SFs) from non-stone formers (NSFs). One such combination is the Bonn Risk Index (BRI), which is calculated from a measure of urinary calcium and an indicator of the ease of inducing calcium oxalate crystallization in that urine. Calcium oxalate is the major component in 60 percent to 80 percent of stones. BRI is expressed as the ratio of factors that might reflect different aspects of crystallization. It is the ratio of the concentration of ionized calcium and the amount of oxalate that must be added to 200 mL of urine to initiate crystallization. Higher BRI values are predictive of being a stone former, and 1.0 is the cut-off value to distinguish stone formers and controls. It is not easy to present a consistent argument based on the thermodynamics of calcium oxalate crystallization to account for the success of this index. For instance, why should two samples sharing the same BRI but with different ionized calcium and oxalate values have the same likelihood of being obtained from a stone former? Using data on 195 samples, the authors examined the distribution and interrelationships of measured variables. They were used to calculate illustrative data to examine the effects of varying the parameters and their relationships. Data simulations identified three necessary and sufficient conditions that must be met for BRI to discriminate between stone former and non-stone former urine samples. The authors concluded that the success of BRI can be explained as the natural outcome of significantly different distributions (stone formers versus non-stone formers) of the concentration of ionized calcium and the formation product minus activity product difference, as well as the correlation between these two variables.

Kavanagh JP, Laube N. Why does the Bonn Risk Index discriminate between calcium oxalate stone formers and healthy controls? J Urology. 2006;175:766–770.

Reprints: John P. Kavanagh, Dept. of Urology, Education and Research Centre, South Manchester University Hospitals Trust, Wythenshawe Hospital, Southmoor Rd., Manchester M23 9LT, United Kingdom;

bullet Chlamydia pneumoniae in atheromatous plaques

The atherosclerotic process has been thought to be a kind of inflammatory response but no one has yet proven that it results from infection of microorganisms. However, the relationship between the microorganism Chlamydia pneumoniae (Cpn) and coronary atherosclerosis has been studied extensively. An increase of inflammatory response in atherosclerotic plaque is thought to be linked to plaque instability and rupture. If increased inflammation was induced by Cpn infection in plaque, the possible role of Cpn infection in acute coronary syndrome (ACS) should be clarified. The authors conducted a study to investigate the number of Cpn or Cpn-phagocytic cells on serial sections of coronary lesion specimens obtained from ACS and non-ACS patients by directional coronary atherectomy or thrombectomy. They also assessed the association between Cpn in coronary plaques and serum antibody titers, such as IgA and IgG, against Cpn, as well as serum levels of high-sensitivity C-reactive protein (hs-CRP). And they clarified the association among Cpn infection and ACS based on the results of histology and serology. The authors divided 40 coronary plaque specimens from 40 patients who underwent thrombectomy or directional coronary atherectomy into an ACS group (n=22) and a non-ACS group (n=18). They found that Cpn immunopositive cells per square millimeter (Cpn+ cells/mm2) in the ACS group were significantly more numerous than in the non-ACS group (median, 7.44 versus 1.50; P=0.0018). Cpn IgA seropositivity rates and titers in the ACS group were significantly higher than those in the non-ACS group (86.3% versus 22.2%; P=0.0002; median titer, 1.403 versus 0.545; P=0.003). No differences in IgG antibodies were noted between the two groups. The hs-CRP values (in milligrams per liter) in the ACS group were significantly higher than in the non-ACS group (median, 2.8 versus 1.2; P=0.0019). Serum IgA titers in patients with at least 5 Cpn+ cells/mm2 in the specimens were significantly higher than in patients with fewer Cpn+ cells (median, 1.52 versus 0.86; P=0.026). No difference was found in serum hs-CRP values in patients with more Cpn+ cells, but a trend to an increase was noted. The authors concluded that immunohistology frequently detected Cpn in coronary plaques. Cpn+ cells were more prevalent in plaques associated with ACS. Furthermore, Cpn IgA titers, but not IgG titers, were increased with ACS and with high densities of Cpn+ cells within plaque.

Liu R, Yamamoto M, Moroi M, et al. Chlamydia pneumoniae immunoreactivity in coronary artery plaques of patients with acute coronary syndromes and its relation with serology. Am Heart J. 2005;150:681–688.

Reprints: Dr. Masao Moroi, Division of Cardiovascular Medicine, Ohashi Hospital, Toho University School of Medicine, 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan;

bullet Combining FLCs, capillary zone electrophoresis
     to detect subtle M proteins

Capillary zone electrophoresis is a sensitive electrophoresis technique for detecting monoclonal M proteins in serum or urine samples. As with gel-based electrophoresis, when compared with immunofixation electrophoresis, capillary zone electrophoresis (CZE) fails to detect M proteins in five percent of samples. Most often, these false-negative results occur when small M proteins are obscured by beta region proteins or, in the case of light chain myeloma, when the small free light chains (FLCs) pass readily into the urine, leaving too little in the serum to create an observable M protein deflection. A recently developed automated immunoassay for detecting FLCs in serum and urine samples can supplement CZE findings. It can detect M proteins in some samples that produce false-negative results in CZE. This method permits detection of free immunoglobulin light chains only (not bound to heavy chain). Recent studies have shown that measuring FLCs can be useful for diagnosing and monitoring patients with light chain myeloma, AL amyloidosis, and nonsecretory myeloma. Moreover, it has been reported that quantifying FLCs in serum by nephelometry correlates with changes in urinary FLC excretion. Reference ranges for kappa and lambda serum FLCs have been established, and it has been demonstrated that the serum FLC assay recognizes monoclonal light chains in some patients in whom immunofixation electrophoresis results are negative. The authors conducted a study to determine whether the serum FLC assay could serve as an adjunct to routine CZE in detecting subtle cases of monoclonal lymphoplasmacytic processes. They prospectively studied 1,003 consecutive serum samples submitted for routine protein electrophoresis or immunofixation electrophoresis, or both, by CZE and FLC. The authors excluded samples from patients previously characterized as having M proteins. Protein electrophoresis was read by a pathologist unaware of the FLC results. Sixteen cases revealed an abnormal free kappa/lambda ratio in which CZE did not demonstrate an M protein. Nine cases of B-lymphocyte or plasma cell proliferative processes were detected by an abnormal free kappa/lambda ratio in which CZE did not demonstrate an M protein. Cases with low free kappa/lambda ratios included one chronic lymphocytic leukemia (CLL), one IgM lambda with aplastic anemia, and one lambda light chain myeloma. Cases with high free kappa/lambda ratios included two CLLs, one lymphocytosis (possibly early CLL), one kappa light chain myeloma, one atypical lymphoma with neuropathy, and one nonsecretory myeloma. The authors concluded that adding the free kappa/lambda ratio to CZE increases by 56 percent the yield of lymphocyte and plasma cell proliferative processes detected.

Bakshi NA, Gulbranson R, Garstka D, et al. Serum free light chain (FLC) measurement can aid capillary zone electrophoresis in detecting subtle FLC-producing M proteins. Am J Clin Pathol. 2005;124:214–218.

Reprints: Dr. David F. Keren, Warde Medical Laboratory, 5025 Venture Drive, Ann Arbor, MI 48108

bullet Metabolic risk factors for congestive heart failure

The age-adjusted mortality for heart failure patients is four to eight times that of the general population, comparable to that for cancer diseases in the same age groups. Therefore, identifying potentially modifiable risk factors for heart failure is of great importance. The predominant causes of heart failure are hypertension and coronary heart disease. Other risk factors include left ventricular hypertrophy, valvular heart disease, diabetes mellitus, cigarette smoking, obesity, and dyslipidemia. Population-based studies have produced different results concerning the relative importance of these risk factors. In the past decade, considerable knowledge has been gained regarding the pathophysiology of heart failure in the experimental setting, small clinical samples, and larger population-based studies. New mechanisms, such as insulin resistance, inflammation, and oxidative stress, have been investigated, but the importance of many of these mechanisms has been largely unexplored in the general population. Therefore, the authors conducted a study to investigate novel metabolic risk factors for developing heart failure. The authors conducted a community-based prospective study of 2,321 middle-aged men free from heart failure and valvular disease at baseline. They compared variables reflecting glucose and lipid metabolism and variables involved in oxidative processes with established risk factors for heart failure using Cox proportional hazards analyses. During a median followup of 29 years, 259 subjects developed heart failure. In a multivariable Cox proportional hazards backward stepwise model, a 1-SD increase of fasting proinsulin (hazard ratio, 1.38; 95% confidence interval, 1.15–1.66) and apolipoprotein B/A-I-ratio (hazard ratio, 1.27; 95% confidence interval, 1.09–1.48) increased the risk of heart failure, whereas a 1-SD increase in serum ß-carotene (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94) decreased the risk. These variables remained significant when adjusting for acute myocardial infarction during followup. The authors concluded that novel variables reflecting insulin resistance and dyslipidemia, together with a low ß-carotene level, predicted heart failure independently of established risk factors. If confirmed, they believe their observations could have large clinical implications by offering new approaches to preventing heart failure.

Ingelsson E, Arnlov J, Sundstrom J, et al. Novel metabolic risk factors for heart failure. J Am Coll Cardiol. 2005;46:2054–2060.

Reprints: Dr. Erik Ingelsson, Dept. of Public Health and Caring Sciences, Section of Geriatrics, Uppsala University, Uppsala Science Park, SE-751 85 Uppsala, Sweden;

Dr. Bissell is Professor and Director of Clinical Services and Vice Chair, Department of Pathology, Ohio State University Medical Center, Columbus.