Infectious Diseases, 2015; Early Online: 1–7
ORIGINAL ARTICLE
Association of Helicobacter pylori infection with chronic obstructive pulmonary disease and chronic bronchitis: a meta-analysis of 16 studies
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Feng Wang1, Juan Liu2, Yun Zhang1 & ping Lei1 From the 1Department of Gerontology, General Hospital of Tianjin Medical University, Tianjin, PR China, and 2Department of Internal Medicine, Tianjin Union Medicine Center & Tianjin People’s Hospital, Tianjin, PR China
Abstract Background: Chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB) are common respiratory diseases globally. The aim of this meta-analysis was to quantify the risk of these two diseases being associated with Helicobacter pylori infection. Methods: A literature search was performed to identify studies published before 5 June 2014 for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for COPD and CB. Results: Sixteen observational studies involving 1390 patients with COPD, 734 with CB and more than 13 000 controls were included. Helicobacter pylori infection was associated with an increased risk of COPD and CB [odds ratio (OR) 2.07, 95% confidence interval (CI) 1.81–2.36, p for heterogeneity 0.05; and OR 1.57, 95% CI 1.33–1.86, p for heterogeneity 0.08]. We discovered a significant association between CagA-positive strains and risk for COPD (OR 3.46, 95% CI 2.29–5.25, p for heterogeneity 0.20). Conclusions: Our meta-analysis suggested a potential relationship between H. pylori infection and the development of COPD and CB.
Keywords: Chronic bronchitis, chronic obstructive pulmonary disease, Helicobacter pylori, meta-analysis
Introduction Helicobacter pylori (HP) is a microaerophilic spiralshaped Gram-negative bacterium, which colonizes the human gastric mucosa. The prevalence of infection reaches 70% in many areas [1]. More than half of the world’s population are infected [2], typically before the age of 5 years [3]. Over the past few decades, compelling data have emerged suggesting that HP infection could cause peptic ulcer disease and gastric malignancies [4,5]. Recent studies suggested an increased HP prevalence in patients with various extraintestinal disorders, including cardiovascular diseases and diabetes mellitus [6,7]. Many studies have investigated the role of HP in the pathogenesis of respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB), and obtained conflicting results [8–11]. Because of insufficient evidence for the role of HP infection
in COPD and CB, we conducted a meta-analysis to examine this relationship. Materials and methods Literature search Studies were selected on the basis of a structured literature search in Medline and Embase. Search parameters were ‘Helicobacter pylori [MeSH Terms]’, ‘Helicobacter pylori [Text Word]’, ‘H. pylori [Text Word]’, ‘Campylobacter pylori [Text Word]’, ‘C. pylori [Text Word]’, ‘Lung Diseases, Obstructive [MeSH Terms]’, ‘COPD [Text Word]’, ‘Chronic obstructive pulmonary diseases [Text Word]’, ‘Pulmonary Emphysema [MeSH Terms]’, ‘Emphysema [MeSH Terms]’, ‘Emphysema [Text Word]’, ‘Bronchitis, Chronic [MeSH Terms]’, ‘Chronic bronchitis [Text Word]’ and their combinations. References in
Correspondence: Professor Ping Lei, Department of Gerontology, General Hospital of Tianjin Medical University, Tianjin 300052, PR China. E-mail: [email protected] (Received 28 June 2014; accepted 13 November 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.989539
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articles were checked and suitable studies were selected. The date of the most recent search was 5 June 2014.
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Study selection We performed all selections in duplicate. The final inclusion of studies was determined by consensus, and when this failed, a third author adjudicated. The following inclusion criteria were used: studies that compared the prevalence of HP infection in patients with and without COPD, and studies that compared the prevalence of HP infection in patients with and without CB. Studies that did not meet these inclusion criteria were excluded. Non-English-language articles were excluded.
was dichotomous variables, expected data (events/ total) of each study were obtained. If the data type was continuous variables, expected data (mean, standard deviation and total) were used. We compiled all data into RevMan 5.2. Pooling was performed using both the fixed effects and the random effects method. If results were homogeneous (p for heterogeneity 0.05), the fixed effects model was reported. If not, the random effects model was reported. The effect measures estimated were odds ratio (OR) for dichotomous data and standard mean difference (SMD) for continuous data reported with 95% confidence intervals (95% CIs). An OR was considered statistically significant if the 95% CI did not include the value 1 and an SMD was considered statistically significant if the 95% CI did not include the value 0.
Data extraction Two trained research personnel independently extracted the following data according to a prespecified protocol: first author, year of publication, country, ethnicity, age, gender, smoking history, socioeconomic status of participants, study size, case type, control type, detection method for HP and results of pulmonary function tests. All data were double entered.
Data analysis Our meta-analysis was performed according to recommendations from the Cochrane Collaboration, Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines [12,13] and was conducted using Review Manager Version 5.2 (RevMan 5.2; The Cochrane Collaboration, Software Update, Oxford, UK). If the data type
Bias and heterogeneity assessment First, graphical exploration with funnel plots was used to evaluate publication bias [14,15]. Secondly, a sensitivity analysis was performed. Each study was sequentially removed from the analysis to determine its contribution to the overall effect size. Thirdly, all studies were scored using the Newcastle-Ottawa Scale with some modifications to match the needs of this study [16]. This scoring system was a self-composed and empirical system, which evaluated studies based on participant selection, comparability and outcome assessment (Table I). Therefore, we did not define the concept of ‘high-quality studies’, but high score studies were separately analyzed. Fourthly, we assessed heterogeneity among meta-analyses using the chisquared test for heterogeneity with a 5% level of statistical significance.
Table I. Self-composed scoring system for quality assessment in the meta-analysis.a. Checklist Participant selection 1. Definition of the case 2. Exclusion criteria of the case 3. Representativeness of the case 4. Definition of the control 5. Representativeness of the control Comparability 6. Matched variables Outcome assessment 7. Detection of Helicobacter pylori 8. Data collection 9. Non-response rate
Description Use generally accepted diagnostic criteria Remove cases with other diseases or conditions Select cases randomly from community or select consecutive cases from hospital Use healthy controls or controls without related diseases Select controls randomly from community or select controls from the same unit where cases are selected Controls are matched to cases by potential confounding factors Use generally accepted method to detect the bacteria Select data from medical record or structured interview where blind to case/control status Declare same rate for both groups
aScoring criteria: if yes, one point; if no or not described, zero.
COPD and Helicobacter pylori
Definition and diagnosis COPD was diagnosed by a post-bronchodilator forced expiratory volume in one second (FEV1)/ forced vital capacity (FVC) ratio of less than 70% and the severity of COPD was classified by spirometric data [17]. CB was diagnosed as the presence of chronic productive cough for 3 months in each of successive years, in a patient in whom other causes of chronic cough have been excluded [18]. Results Infect Dis Downloaded from informahealthcare.com by SUNY Health Sciences Center on 03/29/15 For personal use only.
Eligible studies Of the 107 studies found with the search parameters described above, 13 studies were eligible. Searching the listed references by hand revealed three more studies. The major reasons why 94 studies did not meet the inclusion criteria were that they were reviews, comments, news or case reports with no original data (46), other topic studies (35) or articles not in English (13). The characteristics and quality scores of 16 included studies [8–11,19–30] are presented in Table II. Three included studies [19,23,27] selected control subjects from patients with pulmonary diseases other than COPD and CB. Four included studies [8,11,20,26] selected control subjects from
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healthy people. The other nine studies did not clearly mention the source of control subjects, and were designated ‘normal subjects’. Helicobacter pylori versus chronic obstructive pulmonary disease We found 10 studies reporting on the relationship between HP infection and COPD risk. The random effect pooled OR was 2.31 (95% CI 1.74–3.07, p for heterogeneity 0.003). After excluding one study [10] which received four scores, another meta-analysis showed that the fixed effect pooled OR was 2.07 (95% CI 1.81–2.36, p for heterogeneity 0.05) (Figure 1). Several subgroup meta-analyses were conducted, and the results are shown in Table III. Two studies evaluated infection with a CagA-positive strain and COPD risk. The fixed effect pooled OR was 3.46 (95% CI 2.29–5.25, p for heterogeneity 0.20). However, no significant relationship between HP infection and one major pulmonary function index level was found in COPD patients. Helicobacter pylori versus chronic bronchitis We found six included studies focusing on the relationship between HP infection and risk for CB. The
Table II. Characteristics of studies included in the meta-analysis. First author Helicobacter pylori [8] Pawar [9] Siva [10] Minov [11] Tabaru [19] Hashemi [20] Gencer [21] Sørhaug [22] Behrendt [23] Roussos [24] Prónai Helicobacter pylori [25] Fullerton [26] Jun [27] Kanbay [28] Roussos [29] Rosenstock [30] Caselli
Year
Country
Study sizea
Case type
versus chronic obstructive pulmonary disease 2014 India 27/42 Hospital subjects 2013 UK 64/17 Hospital subjects 2012 Macedonia 84/84 Hospital subjects 2012 Turkey 50/20 Hospital subjects 2011 Iran 90/90 Hospital subjects 2007 Turkey 49/50 Hospital subjects 2006 Norway 354/499 Community subjects 2005 USA 495/7031 Community subjects 2005 Greece 126/126 Hospital subjects 2004 Hungary 135/200 Hospital subjects versus chronic bronchitis 2009 UK 315/2060 Community subjects 2006 China 46/48 Hospital subjects 2005 Turkey 68/95 Hospital subjects 2002 Greece 144/120 Hospital subjects 2000 Denmark 245/2668 Community subjects 1999 Italy 60/69 Hospital subjects
Control typeb
Bacteria detection
Matched variablesc
Quality score
Healthy subjects Normal subjects Normal subjects Healthy subjects Patients Healthy subjects Normal subjects Normal subjects Patients Normal subjects
HP seropositivity HP seropositivity HP seropositivity [14C]Urea breath test HP seropositivity HP seropositivity HP seropositivity HP seropositivity HP seropositivity [14C]Urea breath test
1, 2, 4 1, 3, 4 1 3 1, 2 1, 2, 3 – – 1, 2, 4 1
6 5 4 6 5 6 5 5 5 6
Normal subjects Healthy subjects Patients Normal subjects Normal subjects Normal subjects
HP HP HP HP HP HP
– 1, 2 1, 2, 4 1, 2, 4 – 1, 4
6 6 5 4 5 5
seropositivity seropositivity seropositivity seropositivity seropositivity seropositivity
HP, Helicobacter pylori. aNumber of participants with chronic obstructive pulmonary disease (COPD) or chronic bronchitis (CB)/Number of participants without these diseases. bPatients patients with pulmonary diseases other than COPD and CB; normal subjects healthy subjects or patients with pulmonary diseases other than COPD and CB. c1, age; 2, gender; 3, smoking history; 4, socioeconomic status; -, no matched variables; all matched variables were only used to calculate quality scores.
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Figure 1. Fixed effects meta-analysis of studies evaluating Helicobacter pylori infection and chronic obstructive pulmonary disease risk. The squares indicate point estimates of pathogenic effect, with the size of the square representing the weight attributed to each study, and 95% confidence intervals (CIs) are indicated by horizontal bars. The diamond represents the summary odds ratio (OR) from the pooled studies with 95% CIs. ‘Case favour’ represents ‘in favour of an association between H. pylori and COPD’. ‘Control favour’ represents ‘in favour of no association between H. pylori and COPD’.
random effect pooled OR was 2.04 (95% CI 1.45– 2.85, p for heterogeneity 0.01). Another metaanalysis excluding one study [28] that received low
scores (four scores) was conducted, and the fixed effect pooled OR was 1.57 (95% CI 1.33–1.86, p for heterogeneity 0.08) (Figure 2).
Table III. Results of the meta-analysis in the chronic obstructive pulmonary disease (COPD) subgroup. Subgroup Disease severity Mild Moderate Severe Case type Hospital subjects Community subjects Control type Normal subjects Healthy subjects Patients Ethnicity Caucasian Oriental Economic level Developed countries Developing countries Bacteria detection Detect antibodies by ELISA [14C]Urea breath test Strains CagA-positive virulent strains Pulmonary function tests FEV1/FVC
No. of studies (study size)
OR/SMD (95% CI)c
pf
4 (108/211)a 4 (107/211)a 3 (73/191)a
2.76 (1.68 to 4.54)d 2.44 (0.99 to 5.97)d 4.48 (2.30 to 8.70)d
0.64 0.04 0.38
8 (625/629)a 2 (849/7530)a
2.36 (1.52 to 3.67)d 2.25 (1.50 to 3.38)d
0.009 0.02
5 (1132/7831)a 3 (126/112)a 2 (216/216)a
2.57 (1.75 to 3.76)d 2.27 (1.23 to 4.17)d 1.81 (0.70 to 4.64)d
0.002 0.39 0.02
9 (1447/8117)a 1 (27/42)a
2.34 (1.74 to 3.15)d 1.60 (0.38 to 6.81)d
0.002 -
4 (1039/7673)a 6 (435/486)a
2.20 (1.90 to 2.55)d 2.14 (1.20 to 3.79)d
0.05 0.005
8 (1289/7939)a 2 (185/220)a
2.54 (1.81 to 3.55)d 1.60 (1.05 to 2.43)d
0.002 0.78
2 (216/216)a
3.46 (2.29 to 5.25)d
0.20
4 (236/73)b
0.19 (0.46 to 0.07)e
0.75
ELISA, enzyme-linked immunosorbent assay; FVC, forced vital capacity; FEV1, forced expiratory volume in one second. aNumber of participants with COPD/Number of participants without COPD. bNumber of COPD patients with Helicobacter pylori infection/Number of COPD patients without H. pylori infection. cIf p for heterogeneity 0.05, the fixed effects model was reported; if not, the random effects model was reported. dOdds ratio (95% confidence interval). eStandard mean difference (95% confidence interval). fp value for heterogeneity.
COPD and Helicobacter pylori
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Figure 2. Fixed effects meta-analysis of studies evaluating Helicobacter pylori infection and chronic bronchitis risk. The squares indicate point estimates of pathogenic effect, with the size of the square representing the weight attributed to each study, and 95% confidence intervals (CIs) are indicated by horizontal bars. The diamond represents the summary odds ratio (OR) from the pooled studies with 95% CIs. ‘Case favour’ represents ‘in favour of an association between H. pylori and chronic bronchitis’. ‘Control favour’ represents ‘in favour of no association between H. pylori and chronic bronchitis’.
Discussion A previous systematic review published in 2014 investigating the same topic reported that no definite evidence of a causal relationship between HP infection and respiratory diseases was found, but it did not give enough original data and pooled results [31]. Therefore, the role of HP infection in the pathogenesis of CB and COPD remains controversial. According to the results of our meta-analysis, there was an approximately 60–100% increased risk for CB and a more than 100% increased risk for COPD in patients with HP infection. CagA-positive strains showed stronger pathogenicity in other HP-related diseases [32]. The metaanalysis suggested that a more than 200% increased risk of COPD may occur with CagA-positive strains. This is consistent with previous studies. However, there was not enough evidence to prove the relationship between HP infection and the severity of COPD, although our subgroup analysis suggested that the prevalence of infection may be higher in severe than in mild COPD. In addition, our meta-analysis did not reveal a relationship between HP infection and the level of one major lung function index. More studies on the relationship should be conducted in the future. In the subgroup analysis, the controls of two included studies [19,23] were patients with other chronic respiratory diseases, and gave adverse results. However, previous studies reported that the prevalence of HP may be increased in other respiratory diseases, such as lung cancer [33]. Thus, the differences in prevalence between cases and controls should be smaller in these two included studies than in other studies. This fact may underestimate the relationship between the bacteria and the COPD/ CB. Therefore, we did not believe that this could affect our conclusion. The two methods used to detect HP infection were the anti-HP immunoglobulin G (IgG) test and
the [14C]urea breath test (C14UBT). The anti-HP IgG test does not prove current infection. Positive serology indicates a present or a previous infection. Seronegative individuals may have been infected previously, and become seronegative after treatment. This could introduce bias in our meta-analysis. However, C14UBT is a reliable method with high sensitivity and specificity. Two subgroup meta-analyses separately using the anti-HP IgG test and C14UBT yielded the same results and, thus, confirmed our conclusion. In the meta-analysis, the included studies showed high quality and good homogeneity. Most of the studies had satisfactory quality assessment scores, except for two [10,28]. After excluding these two studies, all results were calculated by the fixed effects model. Sensitivity analysis was conducted, and did not demonstrate that any single study would lead to a statistically significant effect size in the metaanalysis. During the graphical exploration with funnel plots, a symmetrical inverted funnel shape was obtained (Figure 3) and no evidence of significant publication bias was found. All included studies in our meta-analysis were observational studies, with a case-control design. This potential limitation may cause ‘reverse causality’, and a causal relationship between the infection and the risk for pulmonary disease could not be confirmed. Recall bias was another limitation in the meta-analysis. However, two objective tests were used to detect HP infection, and all studies established COPD diagnosis by pulmonary function tests. All study data were obtained from medical records. These factors reduced the effects of recall bias on the conclusion. Age and socioeconomic status, which were related with both HP infection and COPD risk, should be considered as potential confounders in our metaanalysis. But most included studies were matched for age and several studies were also matched for
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Figure 3. Funnel plots of studies evaluating publication bias in the meta-analysis.
socioeconomic status. In the subgroup analysis, the studies from developed countries and developing countries gave the same results. Therefore, we believe that age and socioeconomic status were equally distributed between case and control groups. Smoking history, which was a major risk factor for COPD and CB, could be another confounding factor and certainly introduced recall bias. Data on the relationship between HP infection and smoking history are controversial. The prevalence of the infection in smokers has been variously reported as low, normal and high [34–36]. The relationship between smoking history and HP infection is unclear and most included studies did not match cases and controls for smoking history. Therefore, smoking history could be a potential limitation of the study, and deserves attention in future studies. One study from Asia [8] showed no significant relationship between HP infection and risk for COPD, in contrast to studies from nine Caucasian countries. However, based on a previous study, a greater proportion of the strains possessed CagA in Asia [37]. The likelihood of Asian patients carrying an aggressive strain should be higher and the association between the bacteria and the lung diseases should be even stronger. According to our judgment, the small sample size may be one reason why a contradictory result was obtained in this Asian study. More studies should be conducted in Asia. There are two hypothetical explanations for the relationship between HP infection and risk for CB and COPD. First, the bacteria were recovered from lung tissue and bronchoalveolar lavage fluid in previous studies [38], which implied that the bacteria may directly affect the lung tissue and lead to COPD. But HP would only survive in an acidic environment and it seems unlikely that it would stay long enough in the lungs to cause tissue damage. Secondly, several inflammatory factors, such as interleukin-1, interleukin-8 and tumor necrosis factors, were
related to the pathogenesis of CB and COPD [39]. These factors could be stimulated by HP infection, and eradication of the bacteria could lead to normalization of serum factor levels [40]. Therefore, the infection may trigger CB and COPD by inflammatory processes. However, more studies should be conducted to explore the mechanisms involved. In conclusion, our meta-analysis suggested a possible relationship between HP infection and the risk of COPD and CB. Declaration of interest: The authors have no interests to declare. References [1] Brown LM. Helicobacter pylori: epidemiology and routes of transmission. Epidemiol Rev 2000;22:283–97. [2] Bener A, Uduman SA, Ameen A, Alwash R, Pasha MA, Usmani MA, et al. Prevalence of Helicobacter pylori infection among low socio-economic workers. J Commun Dis 2002;34:179–84. [3] Rowland M, Daly L, Vaughan M, Higgins A, Bourke B, Drumm B. Age-specific incidence of Helicobacter pylori. Gastroenterology 2006;130:65–72. [4] Cohen H. Peptic ulcer and Helicobacter pylori. Gastroenterol Clin North Am 2000;29:775–89. [5] Xue FB, Xu YY, Wan Y, Pan BR, Ren J, Fan DM. Association of H. pylori infection with gastric carcinoma: a meta analysis. World J Gastroenterol 2001;7:801–4. [6] Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, et al. Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J 1994;71:437–9. [7] Jeon CY, Haan MN, Cheng C, Clayton ER, Mayeda ER, Miller JW, et al. Helicobacter pylori infection is associated with an increased rate of diabetes. Diabetes Care 2012; 35:520–5. [8] Pawar S, Reddy SR, Chelluri LK, Prasad CE. Detection of Helicobacter pylori infection in patients with obstructive airway diseases with sero techniques using highly specific IgG antibodies for Helicobacter pyloriantigen. Asian Pac J Trop Dis 2014;4(Suppl):366–72. [9] Siva R, Birring SS, Berry M, Rowbottom A, Pavord ID. Peptic ulceration, Helicobacter pylori seropositivity and
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chronic obstructive pulmonary disease. Respirology 2013; 18:728–31. [10] Minov J, Karadzinska-Bislimovska J, Vasilevska K, Risteska-Kuc S, Stoleski S, Mijakoski D. Helicobacter pylori infection in never-smoking male patients with chronic obstructive pulmonary disease and its relation to lung function. Am J Immunol 2012;8:146–53. [11] Tabaru A, Gorguner M, Akgun M, Meral M, Sahin A. Helicobacter pylori infections in chronic obstructive pulmonary disease. Eurasian J Med 2012;44:144–8. [12] Clarke M, Horton R. Bringing it all together: LancetCochrane collaborate on systematic reviews. Lancet 2001; 357:1728. [13] Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12. [14] Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. [15] Egger M, Smith GD. Misleading meta-analysis. BMJ 1995;311:753–4. [16] Athanasiou T, Al-Ruzzeh S, Kumar P, Crossman MC, Amrani M, Pepper JR, et al. Off-pump myocardial revascularization is associated with less incidence of stroke in elderly patients. Ann Thorac Surg 2004;77:745–53. [17] Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al.; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–55. [18] American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:77–120. [19] Hashemi SH, Nadi E, Hajilooi M, Seif-Rabiei MA, Roustaei U. Relationship between Helicobacter pylori infection and chronic obstructive pulmonary disease. Acta Med Iran 2011;49:721–4. [20] Gencer M, Ceylan E, Yildiz Zeyrek F, Aksoy N. Helicobacter pylori seroprevalence in patients with chronic obstructive pulmonary disease and its relation to pulmonary function tests. Respiration 2007;74:170–5. [21] Sørhaug S, Langhammer A, Waldum HL, Hveem K, Steinshamn S. Increased serum levels of chromogranin A in male smokers with airway obstruction. Eur Respir J 2006;28:542–8. [22] Behrendt CE. Mild and moderate-to-severe COPD in nonsmokers: distinct demographic profiles. Chest 2005;128: 1239–44. [23] Roussos A, Philippou N, Krietsepi V, Anastasakou E, Alepopoulou D, Koursarakos P, et al. Helicobacter pylori seroprevalence in patients with chronic obstructive pulmonary disease. Respir Med 2005;99:279–84. [24] Prónai L, Schandl L, Orosz Z, Magyar P, Tulassay Z. Lower prevalence of Helicobacter pylori infection in patients with inflammatory bowel disease but not with chronic obstructive pulmonary disease – antibiotic use in the history does not play a significant role. Helicobacter 2004;9:278–83.
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[25] Fullerton D, Britton JR, Lewis SA, Pavord ID, McKeever TM, Fogarty AW. Helicobacter pylori and lung function, asthma, atopy and allergic disease - a populationbased cross-sectional study in adults. Int J Epidemiol 2009;38:419–26. [26] Jun ZJ, Lei Y, Shimizu Y, Dobashi K, Mori M. High seroprevalence of Helicobacter pylori in chronic bronchitis among Chinese population. Tohoku J Exp Med 2006;208: 327–31. [27] Kanbay M, Gur G, Akcay S, Yilmaz U. Helicobacter pylori seroprevalence in patients with chronic bronchitis. Respir Med 2005;99:1213–6. [28] Roussos A, Tsimpoukas F, Anastasakou E, Alepopoulou D, Paizis I, Philippou N. Helicobacter pylori seroprevalence in patients with chronic bronchitis. J Gastroenterol 2002; 37:332–5. [29] Rosenstock SJ, Jørgensen T, Andersen LP, Bonnevie O. Association of Helicobacter pylori infection with lifestyle, chronic disease, body-indices, and age at menarche in Danish adults. Scand J Public Health 2000;28:32–40. [30] Caselli M, Zaffoni E, Ruina M, Sartori S, Trevisani L, Ciaccia A, et al. Helicobacter pylori and chronic bronchitis. Scand J Gastroenterol 1999;34:828–30. [31] Adriani A, Repici A, Hickman I, Pellicano R. Helicobacter pylori infection and respiratory diseases: actual data and directions for future studies. Minerva Med 2014;105:1–8. [32] Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori: association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 1995;270:17771–7. [33] Roussos A, Philippou N, Gourgoulianis KI. Helicobacter pylori infection and respiratory diseases: a review. World J Gastroenterol 2003;9:5–8. [34] Ogihara A, Kikuchi S, Hasegawa A, Kurosawa M, Miki K, Kaneko E, et al. Relationship between Helicobacter pylori infection and smoking and drinking habits. J Gastroenterol Hepatol 2000;15:271–6. [35] Brenner H, Rothenbacher D, Bode G, Adler G. Relation of smoking and alcohol and coffee consumption to active Helicobacter pylori infection: cross sectional study. BMJ 1997;315:1489–92. [36] Parasher G, Eastwood GL. Smoking and peptic ulcer in the Helicobacter pylori era. Eur J Gastroenterol Hepatol 2000;12:843–53. [37] Ito Y, Azuma T, Ito S, Miyaji H, Hirai M, Yamazaki Y, et al. Analysis and typing of the vacA gene from cagA-positive strains of Helicobacter pylori isolated in Japan. J Clin Microbiol 1997;35:1710–4. [38] Peterson WL, Graham DY. Helicobacter pylori. In: Feldman M, Scharschmidt BF, Sleisenger MH, editors. Gastrointestinal and liver disease. Pathophysiology, diagnosis, management. 6th ed. Philadelphia, PA: WB Saunders; 1998. p 604–19. [39] Chung KF. Cytokines in chronic obstructive pulmonary disease. Eur Respir J 2001;34:50–9. [40] Kountouras J, Boura P, Lygidakis NJ. Omeprazole and regulation of cytokine profile in Helicobacter pylori-infected patients with duodenal ulcer disease. Hepatogastroenterology 2000;47:1301–4.
ORIGINAL ARTICLE
Association of Helicobacter pylori infection with chronic obstructive pulmonary disease and chronic bronchitis: a meta-analysis of 16 studies
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Feng Wang1, Juan Liu2, Yun Zhang1 & ping Lei1 From the 1Department of Gerontology, General Hospital of Tianjin Medical University, Tianjin, PR China, and 2Department of Internal Medicine, Tianjin Union Medicine Center & Tianjin People’s Hospital, Tianjin, PR China
Abstract Background: Chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB) are common respiratory diseases globally. The aim of this meta-analysis was to quantify the risk of these two diseases being associated with Helicobacter pylori infection. Methods: A literature search was performed to identify studies published before 5 June 2014 for relevant risk estimates. Fixed and random effect meta-analytical techniques were conducted for COPD and CB. Results: Sixteen observational studies involving 1390 patients with COPD, 734 with CB and more than 13 000 controls were included. Helicobacter pylori infection was associated with an increased risk of COPD and CB [odds ratio (OR) 2.07, 95% confidence interval (CI) 1.81–2.36, p for heterogeneity 0.05; and OR 1.57, 95% CI 1.33–1.86, p for heterogeneity 0.08]. We discovered a significant association between CagA-positive strains and risk for COPD (OR 3.46, 95% CI 2.29–5.25, p for heterogeneity 0.20). Conclusions: Our meta-analysis suggested a potential relationship between H. pylori infection and the development of COPD and CB.
Keywords: Chronic bronchitis, chronic obstructive pulmonary disease, Helicobacter pylori, meta-analysis
Introduction Helicobacter pylori (HP) is a microaerophilic spiralshaped Gram-negative bacterium, which colonizes the human gastric mucosa. The prevalence of infection reaches 70% in many areas [1]. More than half of the world’s population are infected [2], typically before the age of 5 years [3]. Over the past few decades, compelling data have emerged suggesting that HP infection could cause peptic ulcer disease and gastric malignancies [4,5]. Recent studies suggested an increased HP prevalence in patients with various extraintestinal disorders, including cardiovascular diseases and diabetes mellitus [6,7]. Many studies have investigated the role of HP in the pathogenesis of respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB), and obtained conflicting results [8–11]. Because of insufficient evidence for the role of HP infection
in COPD and CB, we conducted a meta-analysis to examine this relationship. Materials and methods Literature search Studies were selected on the basis of a structured literature search in Medline and Embase. Search parameters were ‘Helicobacter pylori [MeSH Terms]’, ‘Helicobacter pylori [Text Word]’, ‘H. pylori [Text Word]’, ‘Campylobacter pylori [Text Word]’, ‘C. pylori [Text Word]’, ‘Lung Diseases, Obstructive [MeSH Terms]’, ‘COPD [Text Word]’, ‘Chronic obstructive pulmonary diseases [Text Word]’, ‘Pulmonary Emphysema [MeSH Terms]’, ‘Emphysema [MeSH Terms]’, ‘Emphysema [Text Word]’, ‘Bronchitis, Chronic [MeSH Terms]’, ‘Chronic bronchitis [Text Word]’ and their combinations. References in
Correspondence: Professor Ping Lei, Department of Gerontology, General Hospital of Tianjin Medical University, Tianjin 300052, PR China. E-mail: [email protected] (Received 28 June 2014; accepted 13 November 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.989539
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articles were checked and suitable studies were selected. The date of the most recent search was 5 June 2014.
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Study selection We performed all selections in duplicate. The final inclusion of studies was determined by consensus, and when this failed, a third author adjudicated. The following inclusion criteria were used: studies that compared the prevalence of HP infection in patients with and without COPD, and studies that compared the prevalence of HP infection in patients with and without CB. Studies that did not meet these inclusion criteria were excluded. Non-English-language articles were excluded.
was dichotomous variables, expected data (events/ total) of each study were obtained. If the data type was continuous variables, expected data (mean, standard deviation and total) were used. We compiled all data into RevMan 5.2. Pooling was performed using both the fixed effects and the random effects method. If results were homogeneous (p for heterogeneity 0.05), the fixed effects model was reported. If not, the random effects model was reported. The effect measures estimated were odds ratio (OR) for dichotomous data and standard mean difference (SMD) for continuous data reported with 95% confidence intervals (95% CIs). An OR was considered statistically significant if the 95% CI did not include the value 1 and an SMD was considered statistically significant if the 95% CI did not include the value 0.
Data extraction Two trained research personnel independently extracted the following data according to a prespecified protocol: first author, year of publication, country, ethnicity, age, gender, smoking history, socioeconomic status of participants, study size, case type, control type, detection method for HP and results of pulmonary function tests. All data were double entered.
Data analysis Our meta-analysis was performed according to recommendations from the Cochrane Collaboration, Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines [12,13] and was conducted using Review Manager Version 5.2 (RevMan 5.2; The Cochrane Collaboration, Software Update, Oxford, UK). If the data type
Bias and heterogeneity assessment First, graphical exploration with funnel plots was used to evaluate publication bias [14,15]. Secondly, a sensitivity analysis was performed. Each study was sequentially removed from the analysis to determine its contribution to the overall effect size. Thirdly, all studies were scored using the Newcastle-Ottawa Scale with some modifications to match the needs of this study [16]. This scoring system was a self-composed and empirical system, which evaluated studies based on participant selection, comparability and outcome assessment (Table I). Therefore, we did not define the concept of ‘high-quality studies’, but high score studies were separately analyzed. Fourthly, we assessed heterogeneity among meta-analyses using the chisquared test for heterogeneity with a 5% level of statistical significance.
Table I. Self-composed scoring system for quality assessment in the meta-analysis.a. Checklist Participant selection 1. Definition of the case 2. Exclusion criteria of the case 3. Representativeness of the case 4. Definition of the control 5. Representativeness of the control Comparability 6. Matched variables Outcome assessment 7. Detection of Helicobacter pylori 8. Data collection 9. Non-response rate
Description Use generally accepted diagnostic criteria Remove cases with other diseases or conditions Select cases randomly from community or select consecutive cases from hospital Use healthy controls or controls without related diseases Select controls randomly from community or select controls from the same unit where cases are selected Controls are matched to cases by potential confounding factors Use generally accepted method to detect the bacteria Select data from medical record or structured interview where blind to case/control status Declare same rate for both groups
aScoring criteria: if yes, one point; if no or not described, zero.
COPD and Helicobacter pylori
Definition and diagnosis COPD was diagnosed by a post-bronchodilator forced expiratory volume in one second (FEV1)/ forced vital capacity (FVC) ratio of less than 70% and the severity of COPD was classified by spirometric data [17]. CB was diagnosed as the presence of chronic productive cough for 3 months in each of successive years, in a patient in whom other causes of chronic cough have been excluded [18]. Results Infect Dis Downloaded from informahealthcare.com by SUNY Health Sciences Center on 03/29/15 For personal use only.
Eligible studies Of the 107 studies found with the search parameters described above, 13 studies were eligible. Searching the listed references by hand revealed three more studies. The major reasons why 94 studies did not meet the inclusion criteria were that they were reviews, comments, news or case reports with no original data (46), other topic studies (35) or articles not in English (13). The characteristics and quality scores of 16 included studies [8–11,19–30] are presented in Table II. Three included studies [19,23,27] selected control subjects from patients with pulmonary diseases other than COPD and CB. Four included studies [8,11,20,26] selected control subjects from
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healthy people. The other nine studies did not clearly mention the source of control subjects, and were designated ‘normal subjects’. Helicobacter pylori versus chronic obstructive pulmonary disease We found 10 studies reporting on the relationship between HP infection and COPD risk. The random effect pooled OR was 2.31 (95% CI 1.74–3.07, p for heterogeneity 0.003). After excluding one study [10] which received four scores, another meta-analysis showed that the fixed effect pooled OR was 2.07 (95% CI 1.81–2.36, p for heterogeneity 0.05) (Figure 1). Several subgroup meta-analyses were conducted, and the results are shown in Table III. Two studies evaluated infection with a CagA-positive strain and COPD risk. The fixed effect pooled OR was 3.46 (95% CI 2.29–5.25, p for heterogeneity 0.20). However, no significant relationship between HP infection and one major pulmonary function index level was found in COPD patients. Helicobacter pylori versus chronic bronchitis We found six included studies focusing on the relationship between HP infection and risk for CB. The
Table II. Characteristics of studies included in the meta-analysis. First author Helicobacter pylori [8] Pawar [9] Siva [10] Minov [11] Tabaru [19] Hashemi [20] Gencer [21] Sørhaug [22] Behrendt [23] Roussos [24] Prónai Helicobacter pylori [25] Fullerton [26] Jun [27] Kanbay [28] Roussos [29] Rosenstock [30] Caselli
Year
Country
Study sizea
Case type
versus chronic obstructive pulmonary disease 2014 India 27/42 Hospital subjects 2013 UK 64/17 Hospital subjects 2012 Macedonia 84/84 Hospital subjects 2012 Turkey 50/20 Hospital subjects 2011 Iran 90/90 Hospital subjects 2007 Turkey 49/50 Hospital subjects 2006 Norway 354/499 Community subjects 2005 USA 495/7031 Community subjects 2005 Greece 126/126 Hospital subjects 2004 Hungary 135/200 Hospital subjects versus chronic bronchitis 2009 UK 315/2060 Community subjects 2006 China 46/48 Hospital subjects 2005 Turkey 68/95 Hospital subjects 2002 Greece 144/120 Hospital subjects 2000 Denmark 245/2668 Community subjects 1999 Italy 60/69 Hospital subjects
Control typeb
Bacteria detection
Matched variablesc
Quality score
Healthy subjects Normal subjects Normal subjects Healthy subjects Patients Healthy subjects Normal subjects Normal subjects Patients Normal subjects
HP seropositivity HP seropositivity HP seropositivity [14C]Urea breath test HP seropositivity HP seropositivity HP seropositivity HP seropositivity HP seropositivity [14C]Urea breath test
1, 2, 4 1, 3, 4 1 3 1, 2 1, 2, 3 – – 1, 2, 4 1
6 5 4 6 5 6 5 5 5 6
Normal subjects Healthy subjects Patients Normal subjects Normal subjects Normal subjects
HP HP HP HP HP HP
– 1, 2 1, 2, 4 1, 2, 4 – 1, 4
6 6 5 4 5 5
seropositivity seropositivity seropositivity seropositivity seropositivity seropositivity
HP, Helicobacter pylori. aNumber of participants with chronic obstructive pulmonary disease (COPD) or chronic bronchitis (CB)/Number of participants without these diseases. bPatients patients with pulmonary diseases other than COPD and CB; normal subjects healthy subjects or patients with pulmonary diseases other than COPD and CB. c1, age; 2, gender; 3, smoking history; 4, socioeconomic status; -, no matched variables; all matched variables were only used to calculate quality scores.
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Figure 1. Fixed effects meta-analysis of studies evaluating Helicobacter pylori infection and chronic obstructive pulmonary disease risk. The squares indicate point estimates of pathogenic effect, with the size of the square representing the weight attributed to each study, and 95% confidence intervals (CIs) are indicated by horizontal bars. The diamond represents the summary odds ratio (OR) from the pooled studies with 95% CIs. ‘Case favour’ represents ‘in favour of an association between H. pylori and COPD’. ‘Control favour’ represents ‘in favour of no association between H. pylori and COPD’.
random effect pooled OR was 2.04 (95% CI 1.45– 2.85, p for heterogeneity 0.01). Another metaanalysis excluding one study [28] that received low
scores (four scores) was conducted, and the fixed effect pooled OR was 1.57 (95% CI 1.33–1.86, p for heterogeneity 0.08) (Figure 2).
Table III. Results of the meta-analysis in the chronic obstructive pulmonary disease (COPD) subgroup. Subgroup Disease severity Mild Moderate Severe Case type Hospital subjects Community subjects Control type Normal subjects Healthy subjects Patients Ethnicity Caucasian Oriental Economic level Developed countries Developing countries Bacteria detection Detect antibodies by ELISA [14C]Urea breath test Strains CagA-positive virulent strains Pulmonary function tests FEV1/FVC
No. of studies (study size)
OR/SMD (95% CI)c
pf
4 (108/211)a 4 (107/211)a 3 (73/191)a
2.76 (1.68 to 4.54)d 2.44 (0.99 to 5.97)d 4.48 (2.30 to 8.70)d
0.64 0.04 0.38
8 (625/629)a 2 (849/7530)a
2.36 (1.52 to 3.67)d 2.25 (1.50 to 3.38)d
0.009 0.02
5 (1132/7831)a 3 (126/112)a 2 (216/216)a
2.57 (1.75 to 3.76)d 2.27 (1.23 to 4.17)d 1.81 (0.70 to 4.64)d
0.002 0.39 0.02
9 (1447/8117)a 1 (27/42)a
2.34 (1.74 to 3.15)d 1.60 (0.38 to 6.81)d
0.002 -
4 (1039/7673)a 6 (435/486)a
2.20 (1.90 to 2.55)d 2.14 (1.20 to 3.79)d
0.05 0.005
8 (1289/7939)a 2 (185/220)a
2.54 (1.81 to 3.55)d 1.60 (1.05 to 2.43)d
0.002 0.78
2 (216/216)a
3.46 (2.29 to 5.25)d
0.20
4 (236/73)b
0.19 (0.46 to 0.07)e
0.75
ELISA, enzyme-linked immunosorbent assay; FVC, forced vital capacity; FEV1, forced expiratory volume in one second. aNumber of participants with COPD/Number of participants without COPD. bNumber of COPD patients with Helicobacter pylori infection/Number of COPD patients without H. pylori infection. cIf p for heterogeneity 0.05, the fixed effects model was reported; if not, the random effects model was reported. dOdds ratio (95% confidence interval). eStandard mean difference (95% confidence interval). fp value for heterogeneity.
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Figure 2. Fixed effects meta-analysis of studies evaluating Helicobacter pylori infection and chronic bronchitis risk. The squares indicate point estimates of pathogenic effect, with the size of the square representing the weight attributed to each study, and 95% confidence intervals (CIs) are indicated by horizontal bars. The diamond represents the summary odds ratio (OR) from the pooled studies with 95% CIs. ‘Case favour’ represents ‘in favour of an association between H. pylori and chronic bronchitis’. ‘Control favour’ represents ‘in favour of no association between H. pylori and chronic bronchitis’.
Discussion A previous systematic review published in 2014 investigating the same topic reported that no definite evidence of a causal relationship between HP infection and respiratory diseases was found, but it did not give enough original data and pooled results [31]. Therefore, the role of HP infection in the pathogenesis of CB and COPD remains controversial. According to the results of our meta-analysis, there was an approximately 60–100% increased risk for CB and a more than 100% increased risk for COPD in patients with HP infection. CagA-positive strains showed stronger pathogenicity in other HP-related diseases [32]. The metaanalysis suggested that a more than 200% increased risk of COPD may occur with CagA-positive strains. This is consistent with previous studies. However, there was not enough evidence to prove the relationship between HP infection and the severity of COPD, although our subgroup analysis suggested that the prevalence of infection may be higher in severe than in mild COPD. In addition, our meta-analysis did not reveal a relationship between HP infection and the level of one major lung function index. More studies on the relationship should be conducted in the future. In the subgroup analysis, the controls of two included studies [19,23] were patients with other chronic respiratory diseases, and gave adverse results. However, previous studies reported that the prevalence of HP may be increased in other respiratory diseases, such as lung cancer [33]. Thus, the differences in prevalence between cases and controls should be smaller in these two included studies than in other studies. This fact may underestimate the relationship between the bacteria and the COPD/ CB. Therefore, we did not believe that this could affect our conclusion. The two methods used to detect HP infection were the anti-HP immunoglobulin G (IgG) test and
the [14C]urea breath test (C14UBT). The anti-HP IgG test does not prove current infection. Positive serology indicates a present or a previous infection. Seronegative individuals may have been infected previously, and become seronegative after treatment. This could introduce bias in our meta-analysis. However, C14UBT is a reliable method with high sensitivity and specificity. Two subgroup meta-analyses separately using the anti-HP IgG test and C14UBT yielded the same results and, thus, confirmed our conclusion. In the meta-analysis, the included studies showed high quality and good homogeneity. Most of the studies had satisfactory quality assessment scores, except for two [10,28]. After excluding these two studies, all results were calculated by the fixed effects model. Sensitivity analysis was conducted, and did not demonstrate that any single study would lead to a statistically significant effect size in the metaanalysis. During the graphical exploration with funnel plots, a symmetrical inverted funnel shape was obtained (Figure 3) and no evidence of significant publication bias was found. All included studies in our meta-analysis were observational studies, with a case-control design. This potential limitation may cause ‘reverse causality’, and a causal relationship between the infection and the risk for pulmonary disease could not be confirmed. Recall bias was another limitation in the meta-analysis. However, two objective tests were used to detect HP infection, and all studies established COPD diagnosis by pulmonary function tests. All study data were obtained from medical records. These factors reduced the effects of recall bias on the conclusion. Age and socioeconomic status, which were related with both HP infection and COPD risk, should be considered as potential confounders in our metaanalysis. But most included studies were matched for age and several studies were also matched for
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Figure 3. Funnel plots of studies evaluating publication bias in the meta-analysis.
socioeconomic status. In the subgroup analysis, the studies from developed countries and developing countries gave the same results. Therefore, we believe that age and socioeconomic status were equally distributed between case and control groups. Smoking history, which was a major risk factor for COPD and CB, could be another confounding factor and certainly introduced recall bias. Data on the relationship between HP infection and smoking history are controversial. The prevalence of the infection in smokers has been variously reported as low, normal and high [34–36]. The relationship between smoking history and HP infection is unclear and most included studies did not match cases and controls for smoking history. Therefore, smoking history could be a potential limitation of the study, and deserves attention in future studies. One study from Asia [8] showed no significant relationship between HP infection and risk for COPD, in contrast to studies from nine Caucasian countries. However, based on a previous study, a greater proportion of the strains possessed CagA in Asia [37]. The likelihood of Asian patients carrying an aggressive strain should be higher and the association between the bacteria and the lung diseases should be even stronger. According to our judgment, the small sample size may be one reason why a contradictory result was obtained in this Asian study. More studies should be conducted in Asia. There are two hypothetical explanations for the relationship between HP infection and risk for CB and COPD. First, the bacteria were recovered from lung tissue and bronchoalveolar lavage fluid in previous studies [38], which implied that the bacteria may directly affect the lung tissue and lead to COPD. But HP would only survive in an acidic environment and it seems unlikely that it would stay long enough in the lungs to cause tissue damage. Secondly, several inflammatory factors, such as interleukin-1, interleukin-8 and tumor necrosis factors, were
related to the pathogenesis of CB and COPD [39]. These factors could be stimulated by HP infection, and eradication of the bacteria could lead to normalization of serum factor levels [40]. Therefore, the infection may trigger CB and COPD by inflammatory processes. However, more studies should be conducted to explore the mechanisms involved. In conclusion, our meta-analysis suggested a possible relationship between HP infection and the risk of COPD and CB. Declaration of interest: The authors have no interests to declare. References [1] Brown LM. Helicobacter pylori: epidemiology and routes of transmission. Epidemiol Rev 2000;22:283–97. [2] Bener A, Uduman SA, Ameen A, Alwash R, Pasha MA, Usmani MA, et al. Prevalence of Helicobacter pylori infection among low socio-economic workers. J Commun Dis 2002;34:179–84. [3] Rowland M, Daly L, Vaughan M, Higgins A, Bourke B, Drumm B. Age-specific incidence of Helicobacter pylori. Gastroenterology 2006;130:65–72. [4] Cohen H. Peptic ulcer and Helicobacter pylori. Gastroenterol Clin North Am 2000;29:775–89. [5] Xue FB, Xu YY, Wan Y, Pan BR, Ren J, Fan DM. Association of H. pylori infection with gastric carcinoma: a meta analysis. World J Gastroenterol 2001;7:801–4. [6] Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, et al. Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J 1994;71:437–9. [7] Jeon CY, Haan MN, Cheng C, Clayton ER, Mayeda ER, Miller JW, et al. Helicobacter pylori infection is associated with an increased rate of diabetes. Diabetes Care 2012; 35:520–5. [8] Pawar S, Reddy SR, Chelluri LK, Prasad CE. Detection of Helicobacter pylori infection in patients with obstructive airway diseases with sero techniques using highly specific IgG antibodies for Helicobacter pyloriantigen. Asian Pac J Trop Dis 2014;4(Suppl):366–72. [9] Siva R, Birring SS, Berry M, Rowbottom A, Pavord ID. Peptic ulceration, Helicobacter pylori seropositivity and
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[25] Fullerton D, Britton JR, Lewis SA, Pavord ID, McKeever TM, Fogarty AW. Helicobacter pylori and lung function, asthma, atopy and allergic disease - a populationbased cross-sectional study in adults. Int J Epidemiol 2009;38:419–26. [26] Jun ZJ, Lei Y, Shimizu Y, Dobashi K, Mori M. High seroprevalence of Helicobacter pylori in chronic bronchitis among Chinese population. Tohoku J Exp Med 2006;208: 327–31. [27] Kanbay M, Gur G, Akcay S, Yilmaz U. Helicobacter pylori seroprevalence in patients with chronic bronchitis. Respir Med 2005;99:1213–6. [28] Roussos A, Tsimpoukas F, Anastasakou E, Alepopoulou D, Paizis I, Philippou N. Helicobacter pylori seroprevalence in patients with chronic bronchitis. J Gastroenterol 2002; 37:332–5. [29] Rosenstock SJ, Jørgensen T, Andersen LP, Bonnevie O. Association of Helicobacter pylori infection with lifestyle, chronic disease, body-indices, and age at menarche in Danish adults. Scand J Public Health 2000;28:32–40. [30] Caselli M, Zaffoni E, Ruina M, Sartori S, Trevisani L, Ciaccia A, et al. Helicobacter pylori and chronic bronchitis. Scand J Gastroenterol 1999;34:828–30. [31] Adriani A, Repici A, Hickman I, Pellicano R. Helicobacter pylori infection and respiratory diseases: actual data and directions for future studies. Minerva Med 2014;105:1–8. [32] Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori: association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 1995;270:17771–7. [33] Roussos A, Philippou N, Gourgoulianis KI. Helicobacter pylori infection and respiratory diseases: a review. World J Gastroenterol 2003;9:5–8. [34] Ogihara A, Kikuchi S, Hasegawa A, Kurosawa M, Miki K, Kaneko E, et al. Relationship between Helicobacter pylori infection and smoking and drinking habits. J Gastroenterol Hepatol 2000;15:271–6. [35] Brenner H, Rothenbacher D, Bode G, Adler G. Relation of smoking and alcohol and coffee consumption to active Helicobacter pylori infection: cross sectional study. BMJ 1997;315:1489–92. [36] Parasher G, Eastwood GL. Smoking and peptic ulcer in the Helicobacter pylori era. Eur J Gastroenterol Hepatol 2000;12:843–53. [37] Ito Y, Azuma T, Ito S, Miyaji H, Hirai M, Yamazaki Y, et al. Analysis and typing of the vacA gene from cagA-positive strains of Helicobacter pylori isolated in Japan. J Clin Microbiol 1997;35:1710–4. [38] Peterson WL, Graham DY. Helicobacter pylori. In: Feldman M, Scharschmidt BF, Sleisenger MH, editors. Gastrointestinal and liver disease. Pathophysiology, diagnosis, management. 6th ed. Philadelphia, PA: WB Saunders; 1998. p 604–19. [39] Chung KF. Cytokines in chronic obstructive pulmonary disease. Eur Respir J 2001;34:50–9. [40] Kountouras J, Boura P, Lygidakis NJ. Omeprazole and regulation of cytokine profile in Helicobacter pylori-infected patients with duodenal ulcer disease. Hepatogastroenterology 2000;47:1301–4.
