Skip to main content

Exhaled carbon monoxide in asthmatics: a meta-analysis

Abstract

Background

The non-invasive assessment of airway inflammation is potentially advantageous in asthma management. Exhaled carbon monoxide (eCO) measurement is cheap and has been proposed to reflect airway inflammation and oxidative stress but current data are conflicting. The purpose of this meta-analysis is to determine whether eCO is elevated in asthmatics, is regulated by steroid treatment and reflects disease severity and control.

Methods

A systematic search for English language articles published between 1997 and 2009 was performed using Medline, Embase and Cochrane databases. Observational studies comparing eCO in non-smoking asthmatics and healthy subjects or asthmatics before and after steroid treatment were included. Data were independently extracted by two investigators and analyzed to generate weighted mean differences using either a fixed or random effects meta-analysis depending upon the degree of heterogeneity.

Results

18 studies were included in the meta-analysis. The eCO level was significantly higher in asthmatics as compared to healthy subjects and in intermittent asthma as compared to persistent asthma. However, eCO could not distinguish between steroid-treated asthmatics and steroid-free patients nor separate controlled and partly-controlled asthma from uncontrolled asthma in cross-sectional studies. In contrast, eCO was significantly reduced following a course of corticosteroid treatment.

Conclusions

eCO is elevated in asthmatics but levels only partially reflect disease severity and control. eCO might be a potentially useful non-invasive biomarker of airway inflammation and oxidative stress in nonsmoking asthmatics.

Background

Asthma is a chronic inflammatory disorder of the airways, associated with airway hyperresponsiveness (AHR) that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particular at night or in the early morning [1]. The assessment of airway inflammation is likely to play an important role in the future management of asthma. However, the "gold standard" for assessment of airway inflammation, bronchial biopsy, is invasive and too expensive to perform on a regular basis. Hence, much attention is paid to the non-invasive measurement of airway inflammation, such as induced sputum and of surrogates such as exhaled nitric oxide (eNO).

The level of eNO is elevated in asthmatics, even when asymptomatic [2–4], and shows a good response to corticosteroids [5, 6]. However, the measurement of eNO is expensive, limiting its use in primary care and most specialist clinics.

Some studies have reported that exhaled carbon monoxide (eCO), which is used as an indicator of smoking [7], is significantly increased in asthmatics not treated with corticosteroids [8, 9]. CO in the body is mainly derived from the degradation of hemoglobin by the enzyme heme oxygenase (HO) [10]. It has been found that the expression of the inducible isoform, HO-1, is increased in alveolar macrophages in asthmatics in association with increased exhaled CO [9]. These findings suggested that eCO may be a candidate of non-invasive biomarker of airway inflammation.

However, several studies have failed to replicate these early results [11, 12]. We therefore performed a meta-analysis of the published evidence to determine whether eCO is increased in asthmatic adults and children, and whether eCO may reflect the clinical severity or be influenced by corticosteroids.

Methods

A comprehensive literature search from 1997 to 2009 in English language was performed in Medline (using PubMed as the search engine), Embase and Cochrane databases. The search terms were 'exhaled CO', 'expired CO', 'carbon monoxide', 'asthma', 'bronchial spasm', 'bronchoconstriction', 'bronchial hyperreactivity', 'airway inflammation', 'wheeze' and 'wheezing'. (Additional file 1)

A priori inclusion criteria was: 1) observational studies; 2) comparing eCO levels between adults or children with an established diagnosis of asthma and healthy control subjects or comparing eCO levels in the same asthmatic population before and after steroid treatment; 3) both asthmatic patients and healthy subjects were nonsmokers, since smoking status could significantly affect eCO levels [7]. Exclusion criteria included: 1) asthmatic patients with systemic diseases, such as diabetes, sepsis [13, 14] and 2) studies without healthy subjects as the control group.

A systematic search including a title screen, abstract review, and full text article review. Each study was evaluated independently by two investigators (JZ and YS). Any disagreements about adjudications were resolved through the third party (XY). For each eligible study, we extracted data including number of participants (n), age, gender, clinical feature, treatment, method measuring eCO, and the mean value (mean), standard deviation (SD), 95% confidence interval (CI), or standard error of mean (SEM) of exhaled CO. SEM or 95%CI was transformed to SD, using standard statistical conversions.

Review Manager (Version 5, The Cochrane Collaboration) was used to generate the weighted mean differences (WMD) of eCO between asthmatics and healthy subjects. I 2 statistic was tested for heterogeneity. We used a fixed effects model when I 2 was equal or less than 50%, and a random effects model when I 2 was greater than 50%. Meta-regression analysis on the time of publication was performed by STATA (Version 9.2, STATA Corporation, College Station). Subgroup analysis was performed, according to: 1) whether the study group consisted of adult or children, 2) whether the participants were treated with corticosteroids (systemic or inhaled), 3) the clinical severity of asthma. Publication bias was evaluated through visual inspection of funnel plots, the Begg's test [15] and the Egger's Asymmetry test [16], calculating by STATA. Publication bias may be present if P value is less than 0.05.

Results

Figure 1 shows the results of the search for articles. Of the total 644 articles, 184 duplicates and 349 irrelevant studies were excluded after screening the titles. A further 82 articles failed to meet the inclusion criteria after abstract review. Among the remaining 29 articles, 6 studies did not have healthy control groups and 5 studies did not provide sufficient eCO data such as mean value, SD, 95%CI or SEM. We subsequently tried to contact the authors by email to obtain further information without success. Finally, 18 articles were included in our meta-analysis [17–34]. 4 studies directly provided SD of eCO, 2 studies used 95%CI and the remaining studies provided SEM. As no unequal variances were mentioned in these studies, the classical t-test was used to transform 95%CI into SD. The characteristics of the 18 studies were listed in the Additional file 2, 3. There were no evidence of publication bias (Begg's test: P = 0.843; Egger's Asymmetry test: P = 0.211; Figure 2 shows the Funnel plot). The heterogeneity between different studies is significant (I 2 = 75%), therefore, we performed a meta-regression analysis on the time of publication. The τ2 estimate is 0.3782, which means the time of publication could only partly explain the heterogeneity.

Figure 1
figure 1_893

Results of the systematic literature search.

Figure 2
figure 2_893

Begg's funnel Plot.

1. Overall eCO levels in asthmatics and healthy subjects

Data was pooled from 15 studies irrespective of the age of the participants, the severity of disease or treatment. The overall WMD of eCO between asthmatics and healthy subjects was 1.25 ppm (95% CI 0.92 to 1.58; I 2 = 75%; Random effects model). Asthmatic patients showed significantly higher eCO levels as compared to healthy subjects. (Figure 3)

Figure 3
figure 3_893

Overall eCO levels in asthmatics. The WMD of eCO levels between asthmatics and healthy subjects is 1.25 ppm (95%CI: 0.92 to 1.58) using the random effects model. Test for heterogeneity I 2 = 75%. SD: standard deviation; IV: inverse variance; CI: confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide.

2. eCO levels in childhood and adult asthma

There were 7 articles focused on childhood asthma and 7 on adult asthma. The remaining article [31] studied a population above 10 years old and, therefore, could not be included as either childhood or adult asthma. The WMD of eCO between asthmatic children and healthy children was 0.95 ppm (95% CI 0.65 to 1.24; I 2 = 59%; Random effects model). And the WMD of eCO between asthmatic adults and healthy adults was 1.49 ppm (95% CI 0.84 to 2.14; I 2 = 73%; Random effects model). Both asthmatic children and asthmatic adults showed significant higher eCO levels compared to healthy children and healthy adults respectively. (Figure 4)

Figure 4
figure 4_893

eCO levels in childhood and adult asthma. The WMD of eCO levels between asthmatic children and healthy children is 0.95 ppm (95%CI: 0.65 to 1.24) using the random effects model. Test for heterogeneity I 2 = 59%. The WMD of eCO levels between asthmatic adults and healthy adults is 1.49 ppm (95%CI: 0.84 to 2.14) using random effects model. Test for heterogeneity I 2 = 73%. SD: standard deviation; IV: inverse variance; CI: confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide.

3. eCO levels in steroid-free and steroid-treated asthmatics

13 articles mentioned steroid-free asthmatics (defined as either steroid naïve or not receiving regular inhaled or systemic corticosteroids and treated by on-demand β2-agonist), and 8 articles mentioned steroid-treated asthmatics (defined as current use of inhaled or systemic corticosteroids irrespective of β2-agonist or montelukast use). The WMD of eCO was 1.39 ppm (95%CI 0.82 to 1.95; I 2 = 91%; Random effects model) between steroid-free asthmatics and healthy subjects, and 0.79 ppm (95%CI 0.35 to 1.23; I 2 = 84%; Random effects model) between steroid-treated asthmatics and healthy subjects. Both steroid-free and steroid-treated asthmatics had significantly higher eCO levels than healthy subjects. Steroid-treated asthmatic patients had lower eCO levels compared to steroid-free asthmatic patients (0.79 ppm vs 1.39 ppm) but this failed to reach statistical significance. (Figure 5)

Figure 5
figure 5_893

eCO levels in steroid-free and steroid-treated asthmatics. The WMD of eCO levels between steroid-free asthmatics and healthy subjects is 1.39 ppm (95%CI: 0.82 to 1.95) using the random effects model. Test for heterogeneity I 2 = 91%. The WMD of eCO levels between steroid-treated asthmatics and healthy adults is 0.79 ppm (95%CI: 0.35 to 1.23) using the random effects model. Test for heterogeneity I 2 = 84%. SD: standard deviation; IV: inverse variance; CI: confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide.

4. eCO levels in different asthma severities

According to the GINA [1] criteria, there are 4 categories of disease severity: intermittent, mild persistent, moderate persistent and severe persistent asthma. However, due to the limited information provided by the articles, we could not differentiate mild persistent asthma from moderate persistent asthma. Therefore, we separated the subjects into three groups: intermittent asthma (4 articles), mild + moderate persistent asthma (8 articles) and severe persistent asthma (2 articles). The WMD of eCO was 0.31 ppm (95%CI 0.16 to 0.46; I 2 = 11%; Fixed effects model) between intermittent asthmatics and healthy subjects (Figure 6), 0.84 ppm (95%CI 0.48 to 1.20; I 2 = 62%; Random effects model) between mild + moderate persistent asthmatics and healthy subjects, and 2.20 ppm (95% CI 0.29 to 4.10; I 2 = 68%; Random effects model) between severe persistent asthmatics and healthy subjects (Figure 7). The eCO levels were higher across all asthma severities as compared to healthy subjects. Furthermore, both mild + moderate persistent and severe persistent asthmatics showed significantly higher eCO levels than intermittent asthmatics. However, the eCO level of mild + moderate persistent asthma did not differ significantly from that of severe persistent asthma.

Figure 6
figure 6_893

eCO levels in intermittent asthmatics. The WMD of eCO levels between intermittent asthmatics and healthy subjects is 0.31 ppm (95%CI: 0.16 to 0.46) using the fixed effects model. Test for heterogeneity I 2 = 11%. SD: standard deviation; IV: inverse variance; CI confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide.

Figure 7
figure 7_893

eCO levels in mild + moderate persistent and severe persistent asthmatics. The WMD of eCO levels between mild + moderate persistent asthmatics and healthy subjects is 0.84 ppm (95%CI: 0.48 to 1.20) using the random effects model. Test for heterogeneity I 2 = 62%. The WMD of eCO levels between severe persistent asthmatics and healthy subjects is 2.20 ppm (95%CI: 0.29 to 4.10) using the random effects model. Test for heterogeneity I 2 = 68%. SD: standard deviation; IV: inverse variance; CI: confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide.

5. eCO levels in different asthma control states

We attempted to classify asthma control status into 3 categories: controlled, partly controlled and uncontrolled [1]. However, some studies did not provide enough information to distinguish between controlled and partly controlled disease. Thus, we divided subjects into 2 groups: controlled + partly controlled group (6 articles) and uncontrolled group (3 articles). The WMD of eCO was 1.20 ppm (95%CI 0.39 to 2.01; I 2 = 91%; Random effects model) between controlled + partly controlled asthmatics and healthy subjects, and 2.12 ppm (95%CI 0.56 to 3.68; I 2 = 95%; Random effects model) between uncontrolled asthmatics and healthy subjects. Both controlled + partly controlled asthma and uncontrolled asthma showed significantly higher eCO levels as compared to healthy subjects. There was no statistical difference in eCO levels between controlled + partly controlled and uncontrolled asthma. (Figure 8)

Figure 8
figure 8_893

eCO levels in different asthma control states. The WMD of eCO levels between controlled + partly controlled asthmatics and healthy subjects is 1.20 ppm (95%CI: 0.39 to 2.01) using the random effects model. Test for heterogeneity I 2 = 91%. The WMD of eCO levels between uncontrolled asthmatics and healthy adults is 2.12 ppm (95%CI: 0.56 to 3.68) using the random effects model. Test for heterogeneity I2 = 95%. SD: standard deviation; IV: inverse variance; CI: confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide.

6. eCO levels in asthmatics before and after steroid treatment

There were 7 articles focusing on the influence of corticosteroid treatment on eCO, including 4 studies with inhaled corticosteroids, 2 studies with oral glucocorticoids and the remaining study with both inhaled and oral corticosteroids (the details of the studies are shown in Additional file 3). The WMD of eCO in asthmatics before and after steroid treatment was 1.98 ppm (95%CI 0.53 to 3.43; I 2 = 94%; Random effects model) indicating that eCO was significantly reduced by steroid treatment. (Figure 9)

Figure 9
figure 9_893

eCO levels before and after steroid treatment. The WMD of eCO levels before and after steroid treatment is 1.98 ppm (95%CI: 0.53 to 3.43) using the random effects model. Test for heterogeneity I 2 = 94%. SD: standard deviation; IV: inverse variance; CI: confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide.

Discussion

This meta-analysis based on 15 studies in 632 asthmatics and 734 healthy subjects demonstrates that eCO was increased in both adults and children with asthma, irrespective of steroid treatment, disease severity or level of asthma control (Figure 10). Apart from asthma, other diseases such as allergic rhinitis, bronchiectasis, lower and upper respiratory tract infections, interstitial lung disease and cystic fibrosis have also shown an increased production of eCO [10]. eCO was even found to be elevated in asymptomatic atopic subjects [35]. These findings suggest that increased eCO level may be an indicator of airway inflammation but it does not discriminate between diseases.

Figure 10
figure 10_893

eCO WMD (95%CI) between different asthma groups and healthy subjects. There were no significant differences in eCO levels between steroid-free and steroid-treated asthmatics, mild + moderate persistent and severe persistent asthma, controlled + partly controlled and uncontrolled asthma. However, the eCO level of intermittent asthma was significantly lower than mild + moderate persistent asthma. CI: confidence interval; WMD: weighted mean difference; eCO: exhaled carbon monoxide; â–²: mean of WMD between asthmatics and healthy subjects; vertical line: 95%CI of WMD between asthmatics and subjects.

Endogenous CO in the expired air is mainly derived from the degradation of hemoglobin by HO [10]. Many mediators present in inflamed airways, including interleukin-1β, tumor necrosis factor-α, interferon-γ and hydrogen peroxide could induce HO-1 [35]. In vivo challenge with allergen, but not methacholine, also results in increased eCO levels, suggesting that an inflammatory response and not bronchoconstriction per se is necessary to enhance HO-1 activity and/or expression [36]. HO-1 is present in alveolar macrophages; however, there is conflicting evidence as to whether HO-1 is expressed in the airway epithelium and whether HO-1 is up-regulated in asthmatics [9, 37, 38]. Harju et al [38] showed that HO-1 was up-regulated in the alveolar macrophages of steroid-free asthmatics, and Horvath et al [9] also found increased expression of HO-1 in alveolar macrophages in asthmatics associated with increased exhaled CO. In contrast, Lim et al [37] demonstrated that HO-1 was equally expressed in alveolar macrophages from asthmatics and healthy subjects. This discrepancy was explained by the possibility that the airway was already exposed to daily oxidant stresses such as environment pollutants, and therefore the expression of HO-1 was probably already maximal in asthmatics and healthy subjects. Alternatively, the techniques used may not have been sensitive enough to quantify differences when HO-1 was highly expressed and enzymic activity was not measured.

The level of eCO in intermittent asthmatics was significantly lower than mild + moderate persistent and severe persistent asthmatics, suggesting that eCO may be correlated with disease severity. However, no statistical significance was found between mild + moderate persistent asthmatics and severe persistent asthmatics. There was much greater variability in the 95%CI of WMD for eCO in severe persistent asthma compared with other groups. This probably reflects the fact that only 2 studies were included in this group and the sample size (46 severe persistent asthmatics and 30 healthy subjects) was small, which decreased the statistical power. A similar reason probably underlies the variability in the uncontrolled asthma group. Thus, further investigation is needed to address whether eCO could reflect asthma control status.

Our meta-analysis demonstrated that the eCO level in steroid-treated asthmatics was not significantly different from that in steroid-free subjects although the average level of eCO is increased in steroid-free subjects. The lack of statistical significance may relate to the small sample size. In addition, this may possibly also reflect the wide variability in airway inflammation seen in subjects with differing degrees of asthma severity and degrees of control, or the fact that steroids may not affect HO-1 activity or expression. However, our meta-analysis did demonstrate a significant effect of a formal steroid intervention on eCO levels supporting in vitro data showing that steroids are able to directly down-regulate HO-1 promoter activity and expression [39].

Although steroid treatment could reduce the eCO concentrations in asthmatics, the eCO response might be less sensitive to steroid treatment than that of eNO [26, 33]. Recent studies demonstrated that using eNO to guide treatment did not result in lower exacerbation frequency as compared to traditional asthma management [40, 41]. It is possible that the eNO level is too sensitive to steroid treatment, and therefore, the underlying inflammation may still persist despite a significantly decreased eNO level. Hence, treatment based on the less steroid-sensitive eCO level, which correlates with asthma severity to some degree and is reduced after steroid treatment, could be of benefit.

There are some further limitations to using eCO as an indicator of airway inflammation. The most obvious one is that active and passive smoking status can remarkably affect the eCO level. Both healthy subjects and asthmatic subjects who were current smokers showed significantly higher eCO levels than their nonsmoking control subjects [42, 43]. The eCO level of some healthy smoking subjects could be much higher than the level of nonsmoking severe persistent asthmatics reported previously [25]. Furthermore, Ece et al [23], demonstrated a significant relationship between passive smoking and eCO concentration in both healthy and asthmatic children. Thus, when using eCO levels to assess airway inflammation, the active and passive smoking status must be taken into consideration.

Another major limitation is the lack of standardization of eCO measurement. One study included in the meta-analysis used an infrared detection method and the others used an electrochemical method. There was no significant difference in WMD between asthmatics and healthy subjects when the study using infrared method was included (WMD: 1.25 ppm; 95%CI: 0.92 to 1.58; Random effects model; I 2 = 75%) or not (WMD: 1.33 ppm; 95%CI: 0.99 to 1.66; Random effects model; I 2 = 74%). Since the eCO values of nonsmoking healthy subjects in this meta-analysis are similar to those reported previously [42] we did not exclude studies due to their different measurements.

Conclusions

eCO is elevated in non-smoking asthmatics and correlates with disease severity to some extent. Whether eCO reflects asthma control requires further investigation. Although eCO could not distinguish steroid-treated from steroid-free patients in a cross-sectional analysis, formal steroid treatment significantly reduced eCO levels. eCO might be a potentially useful non-invasive biomarker of airway inflammation and oxidative stress in nonsmoking asthmatics but further work is needed in this area.

Abbreviations

eCO:

exhaled carbon monoxide

AHR:

airway hyperresponsiveness

eNO:

exhaled nitric oxide

HO:

heme oxygenase

ppm:

parts per million

SD:

standard deviation

CI:

confidence interval

SEM:

standard error of mean

WMD:

weighted mean difference

IV:

inverse variance

References

  1. Global Initiative for asthma [http://www.ginasthma.com/] 2008.

  2. Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ: Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994,343(8890):133–135.

    Article  CAS  PubMed  Google Scholar 

  3. Persson MG, Zetterstrom O, Agrenius V, Ihre E, Gustafsson LE: Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994,343(8890):146–147.

    Article  CAS  PubMed  Google Scholar 

  4. Habib SS: Elevated exhaled nitric oxide (NO) in asymptomatic asthmatics taking bronchodilators on demand with controlled body composition. J Pak Med Assoc 2009,59(3):147–150.

    PubMed  Google Scholar 

  5. Kharitonov SA, Yates DH, Barnes PJ: Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996,153(1):454–457.

    Article  CAS  PubMed  Google Scholar 

  6. Baraldi E, Azzolin NM, Zanconato S, Dario C, Zacchello F: Corticosteroids decrease exhaled nitric oxide in children with acute asthma. J Pediatr 1997,131(3):381–385.

    Article  CAS  PubMed  Google Scholar 

  7. Jarvis MJ, Russell MA, Saloojee Y: Expired air carbon monoxide: a simple breath test of tobacco smoke intake. Br Med J 1980,281(6238):484–485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zayasu K, Sekizawa K, Okinaga S, Yamaya M, Ohrui T, Sasaki H: Increased carbon monoxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1997,156(4 Pt 1):1140–1143.

    Article  CAS  PubMed  Google Scholar 

  9. Horvath I, Donnelly LE, Kiss A, Paredi P, Kharitonov SA, Barnes PJ: Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress. Thorax 1998,53(8):668–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kharitonov SA, Barnes PJ: Exhaled markers of pulmonary disease. American journal of respiratory and critical care medicine 2001,163(7):1693–1722.

    Article  CAS  PubMed  Google Scholar 

  11. Zetterquist W, Marteus H, Johannesson M, Nordvall SL, Ihre E, Lundberg JON, Alving K: Exhaled carbon monoxide is not elevated in patients with asthma or cystic fibrosis. European Respiratory Journal 2002,20(1):92–99.

    Article  CAS  PubMed  Google Scholar 

  12. Kong PM, Chan CC, Lee P, Wang YT: An assessment of the role of exhaled carbon monoxide in acute asthmatic exacerbations in hospitalised patients. Singapore Med J 2002,43(8):399–402.

    CAS  PubMed  Google Scholar 

  13. Paredi P, Biernacki W, Invernizzi G, Kharitonov SA, Barnes PJ: Exhaled carbon monoxide levels elevated in diabetes and correlated with glucose concentration in blood: a new test for monitoring the disease? Chest 1999,116(4):1007–1011.

    Article  CAS  PubMed  Google Scholar 

  14. Zegdi R, Perrin D, Burdin M, Boiteau R, Tenaillon A: Increased endogenous carbon monoxide production in severe sepsis. Intensive Care Med 2002,28(6):793–796.

    Article  PubMed  Google Scholar 

  15. Begg CB, Mazumdar M: Operating characteristics of a rank correlation test for publication bias. Biometrics 1994,50(4):1088–1101.

    Article  CAS  PubMed  Google Scholar 

  16. Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 1997,315(7109):629–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Antczak A, Kharitonov SA, Montuschi P, Gorski P, Barnes PJ: Inflammatory response to sputum induction measured by exhaled markers. Respiration 2005,72(6):594–599.

    Article  PubMed  Google Scholar 

  18. Zayasu J, Sekizawa K, Okinaga S, Yamaya M, Ohrui A, Sasaki H: Increased carbon monoxide in exhaled air of asthmatic patients. American Journal of Respiratory and Critical Care Medicine 1997,156(4 I):1140–1143.

    Article  CAS  PubMed  Google Scholar 

  19. Horvath I, Donnelly LE, Kiss A, Paredi P, Kharitonov SA, Barnes PJ: Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: A new marker of oxidative stress. Thorax 1998,53(8):668–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ: Increased 8-isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. American Journal of Respiratory and Critical Care Medicine 1999,160(1):216–220.

    Article  CAS  PubMed  Google Scholar 

  21. Paredi P, Leckie MJ, Horvath I, Allegra L, Kharitonov SA, Barnes PJ: Changes in exhaled carbon monoxide and nitric oxide levels following allergen challenge in patients with asthma. European Respiratory Journal 1999,13(1):48–52.

    Article  CAS  PubMed  Google Scholar 

  22. Uasuf CG, Jatakanon A, James A, Kharitanov SA, Wilson NM, Barnes PJ: Exhaled carbon monoxide in childhood asthma. Journal of Pediatrics 1999,135(5):569–574.

    Article  CAS  PubMed  Google Scholar 

  23. Ece A, Gurkan F, Haspolat K, Derman O, Kirbas G: Passive smoking and expired carbon monoxide concentrations in healthy and asthmatic children. Allergologia et Immunopathologia 2000,28(5):255–260.

    CAS  PubMed  Google Scholar 

  24. Khatri SB, Ozkan M, McCarthy K, Laskowski D, Hammel J, Dweik RA, Erzurum SC: Alterations in exhaled gas profile during allergen-induced asthmatic response. American Journal of Respiratory and Critical Care Medicine 2001,164(10 I):1844–1848.

    Article  CAS  PubMed  Google Scholar 

  25. Yamaya M, Hosoda M, Ishizuka S, Monma M, Matsui T, Suzuki T, Sekizawa K, Sasaki H: Relation between exhaled carbon monoxide levels and clinical severity of asthma. Clinical and Experimental Allergy 2001,31(3):417–422.

    Article  CAS  PubMed  Google Scholar 

  26. Zanconato S, Scollo M, Zaramella C, Landi L, Zacchello F, Baraldi E: Exhaled carbon monoxide levels after a course of oral prednisone in children with asthma exacerbation. Journal of Allergy and Clinical Immunology 2002,109(3):440–445.

    Article  CAS  PubMed  Google Scholar 

  27. Yilmaz O, Ozturk F, Bakirtas A, Cengizlier R, Turktas I: Exhaled carbon monoxide levels in children with bronchial asthma. Pediatric Asthma, Allergy and Immunology 2003,16(3):155–162.

    Article  Google Scholar 

  28. Beck-Ripp J, Latzin P, Griese M: Exhaled carbon monoxide is not flow dependent in children with cystic fibrosis and asthma. European journal of medical research 2004,9(11):518–522.

    CAS  PubMed  Google Scholar 

  29. Rosias PPR, Dompeling E, Dentener MA, Pennings HJ, Hendriks HJE, Van Iersel MPA, Jobsis Q: Childhood asthma: Exhaled markers of airway inflammation, asthma control score, and lung function tests. Pediatric Pulmonology 2004,38(2):107–114.

    Article  PubMed  Google Scholar 

  30. Ohara Y, Ohrui T, Morikawa T, He M, Yasuda H, Yamaya M, Sasaki H: Exhaled carbon monoxide levels in school-age children with episodic asthma. Pediatric Pulmonology 2006,41(5):470–474.

    Article  PubMed  Google Scholar 

  31. Grover RS, Kumar R: Exhaled carbon monoxide levels: As a marker of clinical severity and control of asthma. Journal of Asthma 2008,45(8):677–680.

    Article  CAS  PubMed  Google Scholar 

  32. Lim S, Groneberg D, Fischer A, Oates T, Caramori G, Mattos W, Adcock I, Barnes PJ, Chung KF: Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: Effect of inhaled corticosteroids. American Journal of Respiratory and Critical Care Medicine 2000,162(5):1912–1918.

    Article  CAS  PubMed  Google Scholar 

  33. Kharitonov SA, Donnelly LE, Montuschi P, Corradi M, Collins JV, Barnes PJ: Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma. Thorax 2002,57(10):889–896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yamaya M, Sekizawa K, Ishizuka S, Monma M, Sasaki H: Exhaled carbon monoxide levels during treatment of acute asthma. European Respiratory Journal 1999,13(4):757–760.

    Article  CAS  PubMed  Google Scholar 

  35. Horvath I, Barnes PJ: Exhaled monoxides in asymptomatic atopic subjects. Clin Exp Allergy 1999,29(9):1276–1280.

    Article  CAS  PubMed  Google Scholar 

  36. Paredi P, Leckie MJ, Horvath I, Allegra L, Kharitonov SA, Barnes PJ: Changes in exhaled carbon monoxide and nitric oxide levels following allergen challenge in patients with asthma. European Respiratory Journal 1999,13(1):48–52.

    Article  CAS  PubMed  Google Scholar 

  37. Lim S, Groneberg D, Fischer A, Oates T, Caramori G, Mattos W, Adcock I, Barnes PJ, Chung KF: Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: effect of inhaled corticosteroids. Am J Respir Crit Care Med 2000,162(5):1912–1918.

    Article  CAS  PubMed  Google Scholar 

  38. Harju T, Soini Y, Paakko R, Kinnula VL: Up-regulation of heme oxygenase-I in alveolar macrophages of newly diagnosed asthmatics. Respir Med 2002,96(6):418–423.

    Article  CAS  PubMed  Google Scholar 

  39. Lavrovsky Y, Drummond GS, Abraham NG: Downregulation of the human heme oxygenase gene by glucocorticoids and identification of 56b regulatory elements. Biochem Biophys Res Commun 1996,218(3):759–765.

    Article  CAS  PubMed  Google Scholar 

  40. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR: Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005,352(21):2163–2173.

    Article  CAS  PubMed  Google Scholar 

  41. Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, Pavord ID: The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 2007,176(3):231–237.

    Article  CAS  PubMed  Google Scholar 

  42. Middleton ET, Morice AH: Breath carbon monoxide as an indication of smoking habit. Chest 2000,117(3):758–763.

    Article  CAS  PubMed  Google Scholar 

  43. Sato S, Nishimura K, Koyama H, Tsukino M, Oga T, Hajiro T, Mishima M: Optimal Cutoff Level of Breath Carbon Monoxide for Assessing Smoking Status in Patients with Asthma and COPD. Chest 2003,124(5):1749–1754.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This meta-analysis was supported by National Natural Science Foundation of China (NO.30700342), "the Six Great Talents" (09-B1-001) and Health Promotion Project of Jiangsu Province.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Xin Yao or Mao Huang.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All authors read and met ICMJE criteria for authorship. JZ, MH, XY and RY designed this study. JZ, XY and YS extracted data. JZ, XY, RY, JB performed the analysis. JZ wrote the first draft of the manuscript. XY, IMA and PJB critically revised. All authors read and approved the final manuscript.

Electronic supplementary material

Additional file 1: Search Strategy. Document detailing the search strategy used. (DOC 30 KB)

12931_2010_893_MOESM2_ESM.DOC

Additional file 2: Studies included in the meta-analysis examining eCO levels in asthmatics and healthy subjects. Data are expressed as #mean ± SEM; *mean ± SD; +95%CI; M: male, F: female, n: the number of participants, ppm: parts per million, FEV1: forced expiratory volume in one second; eCO: exhaled carbon monoxide; ICS: inhaled corticosteroids; L: low dose of inhaled corticosteroids; M: medium dose of inhaled corticosteroids; H: high dose of inhaled corticosteroids. (DOC 108 KB)

12931_2010_893_MOESM3_ESM.DOC

Additional file 3: Studies included in the meta-analysis examining eCO levels in asthmatics before and after steroid treatment. Data are expressed as #mean ± SEM; *mean ± SD; +95%CI; M: male, F: female, n: the number of participants, ppm: parts per million, FEV1: forced expiratory volume in one second; eCO: exhaled carbon monoxide; ICS: inhaled corticosteroids; L: low dose of inhaled corticosteroids; M: medium dose of inhaled corticosteroids; H: high dose of inhaled corticosteroids. (DOC 40 KB)

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Zhang, J., Yao, X., Yu, R. et al. Exhaled carbon monoxide in asthmatics: a meta-analysis. Respir Res 11, 50 (2010). https://doi.org/10.1186/1465-9921-11-50

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1465-9921-11-50

Keywords