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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The worldwide increase in asthma incidences and the impact of
the disease on public health care have led to new investigations of
the cause of the disease. Besides well-defined environmental causes,
accumulating evidence suggests that respiratory tract infections
play an important role in the pathogenesis of asthma. Among
these microorganisms Chlamydia pneumoniae is an intracellular pathogen causing persistent infection. Chlamydia pneumoniae infection has been discussed as possibly inducing the development
of asthma. This study was designed to investigate the presence of
C. pneumoniae-specific IgG, IgA, and IgM antibodies in serum samples of 33 adults with a clinical history of asthma, positive methacholine test, and reduced FEV1. Patients with asthma were compared with age-, sex-, and locality-matched control subjects (n = 33). We observed no acute infection either in patients with asthma
or in control subjects, but 63% of all investigated individuals had
signs of past infection. Chlamydia pneumoniae-specific IgA was detected in 52% of the patients with asthma and in 15% of the healthy
control subjects (p < 0.01). Serological evidence of chronic infection with C. pneumoniae (high IgG [
1:512] and high IgA [ 1:40])
was more frequent in patients with asthma (18.2%) compared with
control subjects (3.0%) (p < 0.01). Our results provide further evidence that chronic infection with C. pneumoniae is linked to asthma.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Asthma is an inflammatory disease of the airways, with a worldwide unexplained increasing incidence. Marked inflammation of the bronchial mucosa is a common feature of asthma and leads to structural changes of the lung tissue. Multiple risk factors are discussed to contribute to the development of asthma in patients with underlying atopy. Chlamydia pneumoniae has been discussed as a possible cofactor causing chronic obstructive pulmonary disease (COPD) and asthma. An association of chlamydia infection with asthma was first described in the early 1990s (1) and epidemiological and clinical data support the suggestion that C. pneumoniae infection may partly explain the increased incidence of asthma.
Since the 1970s an increase in C. pneumoniae infection with a novel Chlamydia species, TWAR, recently named C. pneumoniae, was correlated with an increase in asthma in Finland (2). Over the same time period an increase in asthma prevalence was also observed in other countries (5, 6). Adult onset asthma seems to be associated with chronic C. pneumoniae infection (7, 8). In two studies patients with asthma showed a significantly higher prevalence of C. pneumoniae-specific IgA titers (8, 9). A relationship of current or recent infection with C. pneumoniae, wheezing, high IgA antibodies, and bronchial hyperresponsiveness has been postulated (9). Chlamydia pneumoniae infection was also correlated with acute exacerbation of asthma (10). In a prospective study investigating the effect of roxithromycin in patients with asthma, the severity of asthma at the start of the study was significantly correlated with high antibody titers against C. pneumoniae (11). Another study investigated the presence of bacteria in bronchoalveolar lavage fluid and bronchial mucosa samples in a group of patients with stable asthma and control subjects (12). In parallel, Chlamydia serology was performed. Patients with asthma exhibited a positive serology for C. pneumoniae significantly more frequent compared with control subjects, but C. pneumoniae could not be detected by polymerase chain reaction in bronchoalveolar lavage. In summary, there is epidemiological evidence of an association of C. pneumoniae infection with asthma.
Chlamydia is an intracellular parasite mainly infecting epithelial cells and macrophages. In contrast to most bacteria, chlamydia must invade cells for replication. Therefore, Chlamydia uses several proteins that share high homologies with host proteins (13). Both intracellular growth and the use of hostlike proteins prevent recognition of chlamydial infections by the host immune system. However, growing Chlamydia need not necessarily destroy the host cell, allowing infected cells to survive and further proliferate. By this pathway, Chlamydia can be distributed to daughter cells of the originally infected cell, persisting as a slow-spreading latent infection (13). The reasons why such a latent infection occurs or how it can be turned into an acute infection are largely unknown.
In this study we provide serological evidence that possible chronic infection with C. pneumoniae is more often present in patients with asthma than in healthy control subjects. We investigated the serology for C. pneumoniae in 33 patients with asthma and in age-, sex-, and locality-matched control subjects and we observed no differences in IgG and IgM levels, but observed significant differences for IgA (52 versus 19%, patients with asthma versus controls). We also noted high IgG levels in 6 of 33 patients with asthma (18.2%) compared with 3.3% of healthy control subjects (n = 1). Using the combination of IgG plus IgA as an indicator of chronic infection, patients with asthma showed a 6-fold increase over control subjects, 18.2 versus 3.3%.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Probands and Definition of Asthma
Patients with asthma (n = 33) included in this study had to fullfill the following criteria: all patients with asthma had a documented history of asthma, were positive for metacholine challenge test, and had no signs of acute exacerbation at the time of investigation. The cohort of nonsmoking patients with asthma included 20 males (mean age, 45.5 yr; range, 19-72 yr) and 13 females (mean age, 47.9 yr; range, 20-68 yr). Control sera (n = 33) were obtained at the blood donor center of the Kantonsspital Basel (Basel, Switzerland), from 20 males with a mean age of 44.9 yr (range, 20-71 yr) and 13 females, mean age of 48.1 yr, ranging from 20 to 69 yr. The selection of control subjects from the blood donor center included the following criteria: nonsmoking, age range 18-73 yr, living area (Basel), and the same ratio of males and females as in the asthma group. Blood samples were collected from both groups during the winter season to avoid possible differences of seasonal infection.
Serology
Serum samples from all patients with asthma and control subjects
were collected during September 1998-March 1999 at the University Hospital Basel (Basel, Switzerland). According to the local ethics committee of the University Hospital Basel, all probands gave written
consent for obtaining blood samples and serological testing. Ten milliliters of peripheral blood was collected and serum was separated by
centrifugation (600 × g, 30 min, 4° C). Serum was aliquoted and stored
at 
20° C until used for serology. Serology for C. pneumoniae antibodies was performed with a commercial microimmunofluorescence (MIF) test (Orgenium, Helsinki, Finland).
Microimmunofluorescence Test
The microimmunofluorescence (MIF) test was performed blindly for the presence of C. pneumoniae-specific IgG, IgM, and IgA antibodies. All samples had been screened at 1:32 for IgG and 1:16 for IgA and IgM according to the manufacturer instruction. In brief, the incubation time of serum samples was 30 min for IgG, and overnight for IgA and IgM. IgG-positive serum samples were retested at 1:32, 1:128, 1:256, and 1:512 dilutions. IgA- and IgM-positive serum samples were absorbed with inactivation reagent, which was provided with the kit, and retested in the MIF assay at serial dilutions of 1:20, 1:40, 1:80, and 1:160. Only an even pattern of elementary body fluorescence was regarded as positive. The absence of C. pneumoniae-specific IgA and IgM < 1:16, or serum with IgG of < 1:32, was considered negative.
The criteria to define possible chlamydial infection were as follows: (1) IgM 1:20 for current infection, (2) IgG 1:32 and 
1:256
for past infection, (3) high titer of IgG ( 1:512) with high titer of IgA
( 1:40) for possible chronic infection. The criteria used for IgA and
IgM positivity were as follows: IgA and IgM 1:20 after the treatment of serum sample with inactivation reagent. The MIF technique
has been used in earlier studies to assess Chlamydia infections (14, 15).
Statistics
The 
2 test was used to test the hypothesis of equal distribution of sex,
and serology comparing males with females and asthmatic patients
with healthy control subjects; the Student t test was used to confirm
the equal age range of control subjects compared with patients with asthma.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Serum of patients with asthma was taken either from patients
suffering from asthma for many years (n = 24), or from patients with a recent diagnosis of asthma and positive methacholine challenge (n = 9). The mean age of the 24 patients with
longstanding asthma was higher (48 ± 13 yr) compared with
patients (n = 9) with recently diagnosed asthma (37 ± 13 yr).
The mean duration of asthma in the patients with longstanding asthma was 22 ± 4 yr. Patients with recently diagnosed
asthma had symptoms from 6 to 9 mo. All patients with longstanding asthma, except one, were under therapy with inhaled
glucocorticoid and 
2-agonist therapy. None of the patients
with recently diagnosed CIC received any antiasthmatic therapy at the time of blood sampling. All patients underwent determination of their forced expiratory volume within 1 s
(FEV1). In patients with moderate asthma, the FEV1 was 72.8 ± 13.2% and was 93.6 ± 10.4% of the predicted value in the nine
cases with newly diagnosed asthma. The study comprises 33 healthy control subjects with a mean age of 46.9 ± 11 yr and
33 patients with asthma with a mean age of 46.2 ± 11 yr (Table 1).
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No proband, either asthmatic or control, expressed C. pneumoniae IgM antibodies. Therefore, none of the investigated 66 probands suffered from acute primary chlamydia infection (Table 2).
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In assessing C. pneumoniae-specific IgG antibodies, we detected 63.6% (n = 21) positive cases in the asthma group and
57.5% (n = 19) in the control group (Table 2). The IgG positivity indicates that these probands have had C. pneumoniae
infection in the past. High IgG titers of 1:512 were observed
in 18.2% (n = 6) of the patients with asthma and in 3.0% (n = 1) of the control subjects. (Table 2). The 2 test gave a statistically significant difference of both groups, with p < 0.02. No
differences were observed in IgG antibody titer comparing the
patients with longstanding asthma and those with recently diagnosed asthma.
As depicted in Table 2, the number of IgA-positive probands was significantly different by 2 test, with a p value of < 0.03 comparing both groups. Among patients with asthma
we detected 17 (51.5%), and among control subjects we observed 5 (15.15%), probands with IgA titers 1:40. Similar high IgA antibody titers were observed in patients with longstanding asthma and with recently diagnosed asthma. We observed no significant differences in comparing IgA titers of
patients' longstanding asthma with recently diagnosed asthma.
A combination of high-titer IgG ( 1:512) with high-titer
IgA ( 1:80) is regarded as an indicator of a chronic C. pneumoniae infection. In our study, we observed six patients with
asthma (18.2%) with a serological indication of chronic infection, whereas only 3% of the control subjects (n =1) revealed
this combination (Table 3). The statistical difference between
both groups compared for the combination of high IgG and
IgA by 2 test yielded a p value of < 0.02 and dropped to p < 0.03 when criteria of IgA cutoff values were lowered to > 1:40
(Table 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Serological evidence of chronic infection with C. pneumoniae is more frequently observed in patients with asthma when compared with control subjects. However, the data obtained do not indicate whether the infection with C. pneumoniae can be regarded as a causative factor for development of asthma or whether the upper airways are more sensitive to chlamydial infection in patients with asthma.
Several studies attempted to associate viral or microbial infections with the occurrence or severity of asthma; however, a clear link is controversial. In the 1990s infection with C. pneumoniae became recognized as a common etiologic agent in community-acquired pneumonia, but also in chronic inflammatory airway diseases such as chronic obstructive pulmonary disease and asthma (16).
Chronic infection with C. pneumoniae has been documented to be common in school children and the immune response to C. pneumoniae was associated with frequency of
asthma exacerbations, whereas Mycoplasma pneumoniae was
not found to be important in regard to asthma exacerbation (17).
Recent infection with C. pneumoniae has also been claimed to
be of importance for the development of asthma in previously
healthy individuals. It had been postulated that acute C. pneumoniae infection of the respiratory tract in nonasthmatic individuals could lead to development of bronchial hyperresponsiveness. Therefore patients with a new diagnosis of asthma
should be evaluated for possible C. pneumoniae infection (8,
18, 19). On the basis of C. pneumoniae specific serology we assessed the influence of chlamydial infection on asthma. By definition a current infection with C. pneumoniae is characterized as a positive IgM value 1:20. Positive IgG values 1:32
and 1:256 indicate a past chlamydial infection. Chronic infection with C. pneumoniae can be identified when a high titer
of IgG ( 1:512) is combined with an IgA titer 1:40. According to this definition none of the investigated probands,
either asthmatic or control, expressed C. pneumoniae-specific
IgM. Not only did patients with long-lasting asthma show negative IgM titers, the nine patients with a recent diagnosis of
asthma showed negative IgM titers as well.
In a Japanese study involving 186 patients with asthma and 104 age-matched control subjects, nasopharyngeal swab specimens were analyzed by isolation in cell culture and polymerase chain reaction (PCR) test for C. pneumoniae; in addition, Chlamydia serology was investigated. Chlamydia pneumoniae was detected by PCR in 5.4% of the patients with asthma and in 0.9% of the control subjects (20). The study provided serologic evidence of acute C. pneumoniae infection in 8.9% of patients with asthma and in 2.8% of control subjects. The prevalence of C. pneumoniae-specific IgG and IgA was significantly higher in patients with asthma than in control subjects, and the mean titer of IgG and IgA was also significantly greater in patients with asthma than in control subjects (20). These data are similar to our findings and may suggest that C. pneumoniae infection may trigger the development of adult asthma. We observed high titers of IgG in 18% of the asthmatic probands and in 6% of the control subjects. IgA titers were detected in half of the 33 patients with asthma.
A follow-up study for acute C. pneumoniae infection and respiratory illness was conducted with 365 patients (1). High titers for C. pneumoniae antibodies (mixture of IgG, IgA, and IgM) were significantly associated with asthmatic bronchitis after, but not before, occurrence of respiratory illness. Chlamydia pneumoniae specificity was verified in 96% of the investigated patients with asthma showing no positive serology for either Mycoplasma pneumoniae, or Chlamydia trachomatis, or respiratory viruses (1).
In a longitudinal study assessing 138 adults with asthma it was shown that respiratory virus infections are associated with exacerbations of asthma in adults. In this patient group 44% of episodes with a decreased peak in flow rate were associated with infections with either rhinoviruses, coronaviruses OC43 and 229E, influenza B, respiratory syncytial virus, parainfluenza virus, or Chlamydia (21).
In comparing C. pneumoniae-specific IgG levels in subjects with atopic versus nonatopic asthma, Von Hertzen and coworkers postulated a stronger relationship for high IgG in subjects with nonatopic asthma, with long-standing asthma, whereas a relationship between atopic asthma and elevated IgG titers was not significant. The authors concluded that asthma per se does not predispose to C. pneumoniae infection, but that asthma is significantly associated with elevated IgG antibody levels to C. pneumoniae in patients with nonatopic longstanding asthma (22). If this theory is true, one would expect higher titers of C. pneumoniae-specific IgG to be more common in patients compared with control subjects. In assessing C. pneumoniae-specific IgE in sera and histamine release from basophil leukocytes, Larsen and coworkers could not support the theory that C. pneumoniae is a cause of adult onset asthma (23). However, this study was only based on a set of 22 patients with asthma and it had never been assumed that asthma is exclusively caused by infection with C. pneumoniae.
Studies have assessed the correlation of chlamydia serology
and severity of airway obstruction (11, 24, 25). One study provided statistical evidence of a linkage of the severity of asthma
with high IgG and IgA titers in 612 adults with asthma (11).
The second investigation showed an association of chronic C. pneumoniae infection with severe chronic asthma (24). The third study investigated chlamydia serology in a cohort of
1,774 men who also underwent lung function testing. Chlamydia pneumoniae infection was not associated with development of airflow obstruction within 5 yr (25). However, in two
studies the serological criteria for chronic C. pneumoniae infection were different from those used in our study. High IgG
titer was defined as 1:64, versus 1:512 in the present
study. High IgA was defined as a titer of 1:16, versus 1:40
in this study. Transferring these criteria to the population investigated in this study (see Table 3) the number of probands
with chronic C. pneumoniae infection would change to n = 6 (18.1%) of the control subjects and to n = 16 (49%) in the
asthma group. Chlamydia pneumoniae is a common respiratory pathogen worldwide and almost everybody during their
life time may have this infection several times (14, 26). The
reported prevalence of the C. pneumoniae-specific IgG antibodies ranges between 40 and 60% in different parts of the
world. Using low antibody titers as criteria for chronic infection may cause false conclusions about the role of this microorganism in diseases such as asthma.
It is more likely that there is a link of C. pneumoniae infection and a certain type of asthma. This assumption is supported by studies investigating the effect of antichlamydial drugs in seropositive patients with asthma (29). In another study, 75% of C. pneumoniae culture-positive children with asthma demonstrated an improvement of the reactive airway disease after treatment of the chlamydial infection (30).
How might a latent infection with chlamydia affect host cell biology and therefore induce development of diseases such as asthma? Chlamydia, for example, uses cellular energy sources such as mitochondrial enzymes and oxidation-dependent phosphorylation for its own survival (13, 31, 32). It forces the host cell physiology toward enhanced synthesis of ATP and glutamate, two additional cellular energy sources (32). A central role of the interference of chlamydia and the host's energy support system seems to be mediated via the interaction of chlamydial heat shock proteins, which all share high similarity with human heat shock proteins (33, 34). Studies suggest that chlamydial heat shock proteins alter activation of transcription factors, which subsequently modulate gene expression and the differentiation status of host cells (33), and may explain the link between chlamydial infection and the development of inflammatory respiratory tract diseases including asthma.
In summary, our results support the correlation of asthma and chronic infection with Chlamydia pneumoniae.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Michael Roth, Ph.D., Institute for Respiratory Medicine, University of Sydney, P.O. Box M77, Camperdown, NSW 2050, Australia. E-mail: MichaelR{at}mail.med.usyd.edu.au
(Received in original form March 29, 2000 and in revised form September 28, 2000).
Acknowledgments:
Supported by a donation from Mr. C. Jacquet (Basel, Switzerland).
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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