Chlamydia Pneumoniae - Oxford Journals - Oxford University Press

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Attack in Children and Atypical Bacterial Infections;. Chlamydia Pneumoniae, Mycoplasma Pneumoniae and. Helicobacter Pylori by Ali Annagu¨r, S. G. Kendirli, ...
Is There Any Relationship Between Asthma and Asthma Attack in Children and Atypical Bacterial Infections; Chlamydia Pneumoniae, Mycoplasma Pneumoniae and Helicobacter Pylori _ by Ali Annagu¨r, S. G. Kendirli, M. Yilmaz, D. U. Altintas , and A. Inal Department of Pediatric Allergy and Immunology, Faculty of Medicine, University of Cukurova, Adana, Turkey

Summary Asthma is a chronic inflammatory airway disease characterized by variable airway obstruction and bronchial hyperresponsiveness. There are many factors affecting the development and severity of childhood asthma such as genetic predisposition, atopy, environmental factors, obesity, diet, socioeconomic status, and infectious triggers. In the present study we aimed to investigate the frequency of Mycoplasma pneumoniae, Chlamydia pneumoniae, and Helicobacter pylori infections in asthmatic children. We investigated also whether there is a relationship between these agents and asthma attacks. Material and methods: Seventy-nine asthmatic children (46 males, aged 5–15 years) were included in study. The study group was divided into two groups: group 1 consisted of 37 children with asthma attacks and group 2 consisted of 42 children with stable asthma. As a control group we studied 36 healthy children. Pulmonary function tests, skin prick tests for common allergens were performed; serum total IgE, phadiatop, specific IgM and IgG antibody levels (ELISA) for M. pneumoniae, C. pneumoniae and H. pylori were measured in all patients. Results: Mycoplasma IgM and Chlamidia IgM were positive in 8.1% (3 patients) and 18.9% (7 patients) of group 1 patients, respectively. There was a statistically significant difference for Mycoplasma IgM ( p ¼ 0.031) and Chlamidia IgM ( p ¼ 0.03) between group1 and other two groups. We have not found significant difference for M. pneumoniae IgG, C. pneumoniae IgG and H. pylori IgM and IgG among groups. Conclusion: M. Pneumoniae and C. Pneumoniae may play a role in development of asthma exacerbations in childhood. We could not find a relationship between H. Pylori and asthma.

Introduction The numbers of studies about risk factors for the development of asthma has increased in parallel to its increase in prevalence. The possibility of role of infectious agents in asthma development was first recognized in 1958 by Bruce Pearson, and then in 1962 by Swineford et al. [1]. The relation between infections and asthma was demonstrated in the later studies [2, 3] and its significance is still unclear. Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP) are important causes for human respiratory tract diseases [4]. Recently, these atypical

Correspondence: Dr Ali Annagu¨r, Mahfes|g˘maz mahallesi 3 sokak no 11 Sahika apt. Kat 1 daire 2 Seyhan, Adana, Turkey. Tel: 090505 790 65 54, E-mail .

microorganisms have received much attention regarding their role in bronchial asthma pathogenesis. Their potential role in asthma was divided into three aspects: asthma initiation, prolongation and exacerbation. There are some studies suggesting a link between MP or CP and exacerbation of asthma as well as initiation of the disease [2, 3, 5, 6]. It was also reported that CP infection was related with acute asthma attack and asthma severity in community. However, in two studies from our country, no significant difference in the frequency of MP infections was obtained between stable asthmatics and healthy controls or between acute exacerbation and stable asthma [7, 8]. In the present study we aimed to investigate the frequency of CP, MP and Helicobacter pylori (HP) infections in acute asthma attacks and in stable asthmatics in comparison to non-asthmatic healthy controls.

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Material—Method Seventy-nine asthmatic children between the ages of 5 and 15, who were followed up in our department between June 2003 and June 2005 were included in the study. Thirty-six non-atopic healthy children served as controls. Asthmatic patients were categorized as stable asthmatics (group 1, 42 patients) and acute exacerbation (group 2, 37 patients). All asthmatic patients fulfilled the diagnostic criteria for asthma according to Global Initiative for Asthma (GINA) guidelines [10]. Exclusion criteria were the presence of cardiovascular, immunologic or systemic diseases and having upper respiratory tract infections in last three months. The study was performed with the approval of the local ethics committee. Informed consent was obtained from all the patients. Skin prick tests Skin prick tests were performed with standardized panel of allergens including grass, tree and weed pollens, molds, Dermatophagoides pteronyssinus, D. farinae, cat’s dander, dog’s dander, cockroach, milk and egg white (Allergopharma, Germany). Histamin dihydrochloride (10 mg ml1) and glycerol diluent were used as positive and negative controls, respectively. A wheal size greater than 3 mm was used as a positive result. The patients having at least one positivity in skin prick tests were considered as atopic. Pulmonary function tests Pulmonary function tests were measured through a spirometry (ZAN 100 Spiromed, Germany). Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEF), forced expiratory flow rate at 25–75 (MEF25–75) were measured and expressed as percentages of predicted mean values. Serologic tests Blood samples were obtained from the patients with acute asthma attack both during their attack and 4 weeks later. All samples were centrifuged for 5 min at 3000 g in the first 6 h and put into polystyrene tubes after being separated from serum and closed up with paraffin and kept at—20 C until the test date. Venous blood was analysed for total IgE by (Abbott Laboratories, USA) and specific IgE (CAP-System-FEIA, Pharmacia Diagnostic, Uppsala, Sweden). Blood samples were studied with full automatic ELISA (enzyme-linked immunosorbent assay) analyzer marked as Triturus (Germany), using micro ELISA kits marked as IBL (Hamburg-Germany) to measure IgM and IgG levels of CP, MP and HP. 314

Statistical Analysis Data analysis was performed by SPSS (version 12.0 for Windows Chicago, IL) statistical program. Results were expressed as mean  SD. Oneway ANOVA test was used for the comparison of groups. Chi-square test was used for comparison of serological tests of groups. ‘McNemar’ test was used for comparison of serological results of patients during attack and after 4 weeks. A p < 0.05 was accepted as statistically significant. Results This study consisted of 42 children with stable asthma, 37 children with acute asthma exacerbation and 36 non-atopic healthy controls. Mean age of the patients was 9.7  2.2 years and there was no statistically significant difference between groups in terms of age ( p ¼ 0.09). Demographic data are shown in Table 1. Thirty-one of 37 (83.8%) patients in group 1 and 30 of 42 (71.4%) patients in group 2 were considered as atopic according to skin prick tests. No skin test positivity was detected in group 3. Skin test results of all groups are summarized in Table 2. Mean values  SD of total IgE levels are shown in Table 1. There was statistically significant difference for total IgE levels between groups ( p ¼ 0.01). Pulmonary function test results are presented in Table 1. There was significant improvement in all parameters of pulmonary function tests after 4 weeks in comparison to results obtained during attack in group 2 (p ¼ 0.01). We found no statistically significant difference between stable asthmatics and healthy controls regarding FVC, FEV1 and PEF ( p > 0.05); but, MEF25–75 values of stable asthmatics were significantly lower than those of healthy controls ( p < 0.05). Serologic test results of Group 1 during attack and 4 weeks later are illustrated in Table 3. Serologic test results of all groups are summarized in Table 4. MP IgM antibody levels of group 1 obtained after 4 weeks of attack were significantly different from antibody levels of group 2 and group 3 ( p ¼ 0.031). MP IgG antibody levels of group 1 (both during attack and 4 weeks later) were not significantly different compared to group 2 and group 3 ( p ¼ 0.517). Significant difference was observed when the results of CP IgM of group 1 were compared with group 2 and 3 ( p ¼ 0.003). There was no significant difference between group 1 results obtained 4 weeks later and other two groups regarding CP IgG levels ( p ¼ 0.071). We found no positive correlation for HP IgM and IgG in children with acute exacerbation and stable asthmatics. No significant difference about HP IgM vs. IgG positivity was present between the groups ( p ¼ 0.494, p ¼ 0.227). Journal of Tropical Pediatrics

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TABLE 1 Demographic data of the patients

Number of patients Age (years) Mean  SD Gender Female (%) Male (%) Atopy (þ) () Phadiatop (þ) () IgE levels (IU/ml) Pulmonary function tests (% of predicted) FVC FEV1 PEF MEF25–75

Children with acute asthma attack (Group 1)

Stable asthmatics (Group 2)

Healthy controls (Group 3)

37

42

36

9.3  2.20

9.4  2.48

10.4  1.88

17 (45.9%) 20 (54.1%)

16 (38.1%) 26 (61.9%)

18 (50%) 18 (50%)

31 (83.8%) 6 (16.2%)

30 (71.4%) 12 (28.6%)

0 (0%) 36 (100%)

30 (81.1%) 7 (18.9%) 587  614

30 (71.4%) 12 (28.6%) 295  286

0 (0%) 36 (100%) 44  24

67.6  6.1 70.6  5.6 67.7  8.3 67.2  6.7

88.5  6.8 99.9  10.2 106  15.4 119  18.0

95.5  7.4 103.4  7.9 112.7  12.0 129.6  15.3

Children with acute asthma attack (Group 1)

Stable asthmatics (Group 2)

Healthy controls (Group 3)

37 25/37 (67.5%) 26/37 (70.2%) 23/37 (62.1%) 28/37 (75.2%) 12/37 (32.4%) 10/37 (27.0%) 14/37 (37.8%) 5/37 (13.4%) 6/37 (16.2%)

42 20/42 (47.6%) 22/42 (52.3%) 18/42 (42.8%) 25/42 (59.5%) 15/42 (35.7%) 12/42 (28.5%) 17/42 (40.4%) 7/42 (16.6%) 8/42 (19.0%)

TABLE 2 Skin test results of all groups

Number of patients Grass Weed pollen Tree pollen Molds Cat’s dander Dog’s dander Cockroach Milk Egg white

36 0/36 0/36 0/36 0/36 0/36 0/36 0/36 0/36 0/36

(0%) (0%) (0%) (0%) (0%) (0%) (0%) (0%) (0%)

TABLE 3 Serologic test results of Group 1

M. pneumoniae IgM IgG C. pneumoniae IgM IgG H. pylori IgM IgG

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During asthma attack

4 weeks later

p

0/37 (0%) 2/35 (5.4%)

3/34 (8.1%) 2/35 ((5.4%)

0.031 1.0

3/34 (8.1%) 5/32 (13.5%)

5/32 (13.5%) 7/30 (18.9%)

0.5 0.5

10/27(27%) 2/35 (5.4%)

14/23(37.8%) 2/35 (5.4%)

0.344 0.5

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TABLE 4 Serologic test results of all groups

M. pneumoniae IgM IgG C. pneumoniae IgM IgG H. pylori IgM IgG

Children with acute asthma attack (Group 1) n ¼ 37

Stable asthmatics (Group 2) n ¼ 42

Healthy controls (Group 3) n ¼ 36

p

3 (8.1%) 2 (5.4%)

0 (0%) 2 (4.8%)

0 (0%) 4 (11.1%)

0.031 0.517

5 (13.5%) 7 (18.9%)

0 (0%) 17 (40.5%)

0 (0%) 8 (22.2%)

0.003 0.071

14 (37.8%) 12 (32.4%)

11 (26.2%) 8 (19%)

10 (27.8%) 6 (16.7%)

0.494 0.227

Discussion In the present study, we found that CP IgM and MP IgM antibody levels of asthmatic children during exacerbation were significantly higher than those of stable asthmatics and healthy controls. We did not find a statistical difference between the stable asthmatics and healthy controls regarding MP or CP infections. Results of previous studies were controversial about association of CP infections and asthma [7, 11, 12]. Although several reports about the first manifestation of asthma following acute CP infection demonstrated by serology or both serology and PCR–EIA (polymerase chain reaction with enzyme immunoassay) exist, its role in asthma initiation of previously healthy children has not been fully determined [7, 10, 13]. However, in another study including adults and children, a positive correlation between asthma severity and CP infection has been demonstrated [14–16]. Similarly, the role of CP infection in asthma exacerbation and prolongation was more clearly established. Our finding which shows that CP infections were significantly higher in children with acute asthma exacerbation is consistent with most of the previous studies. An increasing amount of evidence is implicating CP infection in the predisposition to and exacerbation of asthma, particularly chronic asthma. CP causes inhibition of ciliary function in bronchial epithelial cells and CP infection induces the release of inflammatory cytokines [17, 18]. Chronic infections may develop from infection early in life, which may either result from or induce ineffectual Th2 responses that fail to clear the infection. This results in persistent CP infection and secondary or recurring infection induces a vigorous response by adaptive immune cells that release cytokines with a Th2 profile [19]. Several in vitro and in vivo studies on intracellular infections have suggested that, in early life, Th1 and 316

cytotoxic lymphocyte (CTL) activity is poor or absent, whilst T-cell responses are biased toward a Th2 response [20, 21]. These studies suggest that the neonatal responses to Chlamydia may be highly polarized toward Th2. However, later in life, chlamydial infection induces protective Th1 responses, which may ameliorate/inhibit the Th2-driven inflammatory response that results in asthma. We found a significant association between MP infection and exacerbation of asthma. The results about association of asthma and MP are contoversial in the literature [22–25]. Actually, findings on this issue are not consistent and while CP seems more important for asthma exacerbation than MP in some studies, the role of MP was as significant as CP in other studies [2, 6]. Murine models of acute and chronic MP respiratory tract infection that show many similarities to human disease have been recently established [26, 27]. These models exhibit similar clinical features to those seen in human MP induced pneumonia including inflammatory changes, alteration in lung histology, antibody production, chronic infection of the respiratory tract but not pulmonary areas, cytokine release into BAL fluid similar to those released during asthma and persistent pulmonary airflow resistance [26, 28]. Bronchial hyperresponsiveness (BHR) and airway neutrophilia have also been demonstrated during chronic MP infection and were related to a decrease in IFNg production [29]. MP infection can also stimulate a wide variety of immune and respiratory epithelial cells, including rat mast cells and human bronchial epithelial and small airway epithelial cells that are important in asthma pathogenesis [30, 31]. Indeed, MP infection may contribute to asthma pathogenesis at different levels of the airways [31]. Most animal models, however, show that MP infection induces Th1 responses that should alleviate asthma symptoms. Recently, a potential relationship between HP and some respiratory diseases (pulmonary tuberculosis, Journal of Tropical Pediatrics

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bronchiectasia, lung cancer, bronchial asthma) has been reported in some studies [32]. The positive association between HP infection and food allergy in children was reported previously [33]. However, few studies investigated the association between asthma and HP [8, 34–36]. Tsang et al. have reported no association of HP infection with mild intermittent asthma in adults [37]. Our results are consistent with this study; we did not find a positive correlation for HP IgM and IgG antibody in children with acute exacerbation and stable asthmatics. We suggest that infections with CP and MP are related with exacerbation symptoms of asthmatic children; they should be considered as a triggering factor in all children with acute asthma attacks in order to decide antibiotic therapy targeting these pathogens.

14.

15. 16.

17. 18. 19.

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