Role of exhaled carbon monoxide in assessment of chronic obstructive airway disease severity

Background Chronic obstructive pulmonary disease (COPD) is a critical public health issue. Spirometric measurements are used to diagnose chronic obstructive lung disease, as per the guidelines of the GOLD initiative. Post-bronchodilator forced expiratory volume in 1 s (FEV1) is a predictor of mortality from COPD and helps to classify the disease’s severity. Smoking contributes to the high levels of exhaled CO. Evidence suggests that the exhaled CO level in COPD patients varies with degree of blockage and can be used to assess treatment response. Estimating the exhaled CO level can help assess airway inflammation and severity of airflow obstruction in individuals with COPD. Aim Evaluate role of exhaled CO in assessment of severity of COPD. Materials and methods This cross-sectional study included 132 patients who visited the outpatient clinics or were admitted to the Chest Department, Kasr Alainy Hospital, Faculty of Medicine, Cairo University. The study participants were divided into three groups: group 1 nonsmoker healthy control, group 2 smoker non-COPD, and group 3 smoker COPD which further divided according to GOLD 2023 into mild, moderate, and severe COPD. The smoking status, exhaled CO, and spirometry test including FEV1/FVC and FEV1 were measured for each patient. Results Exhaled CO was significantly increased in the smoker group (mean 9.69, SD 3.11) compared to the non-smoker group (mean 2.19, SD 0.98) with p -value < 0.001. Exhaled CO was also statistically significantly higher in the smoker COPD group (mean 10.45, SD 3.03) compared to the smoker non-COPD group (mean 7.05, SD 1.56) with p -value < 0.001. Although exhaled CO was increased in the severe COPD group compared to the mild and moderate group, there is no statistically significant difference between them. Conclusion Exhaled CO is a fast, sensitive, noninvasive, and well-established method test that can be used to identify smokers from nonsmokers with 98.9% sensitivity at 4.5 cutoff value. Also, exhaled CO levels in COPD patients vary with different degrees of airway obstruction.


Introduction
COPD is the third most frequently occurring disease that leads to death worldwide [1].Also, COPD is considered the most frequent cause of chronic disability and mortality throughout the world [2].Post-bronchodilator spirometry is the most effective way to measure airflow dynamics.Post-bronchodilator forced expiratory volume in 1 s (FEV1) is the cornerstone of classification of degrees of severity of COPD, and it is used to predict mortality from COPD [3].Smoking is the main environmental risk factor for COPD.Smokers are more prone for developing pulmonary complications and pulmonary function abnormalities, a higher rate of decrease in FEV1 per year, and higher COPD death rates than nonsmokers [4].Inflammation of the airways is a major feature of COPD, and it affects both the small and large air passages.Airway and systemic inflammation in COPD are responsible for progressive nature of the disease [5].Estimation of exhaled carbon monoxide is a fast, less invasive, and well-established test used to distinguish smokers from nonsmokers [6].Smokers with high risk of developing COPD may benefit from using exhaled carbon monoxide to diagnose the disease earlier even before the clinical and functional affection appear [7].This could achieve a remarkable improvement in COPD management.

Aim of the work
Evaluate the role of exhaled CO in the assessment of COPD severity.

Study design
This cross-sectional study was carried out between December 2022 and December 2023, and it included 132 individuals who visited the outpatient clinic or were admitted to the Chest Department, Kasr Alainy Hospital, Faculty of Medicine, Cairo University.Our study patients were divided into three groups: group 1 nonsmoker healthy control, group 2 smoker non-COPD, and group 3 smoker COPD which further divided according to GOLD 2023 into mild, moderate, and severe COPD and the  more severe group which were excluded from the study as they cannot perform the exhaled CO test.
Patients meeting the following inclusion criteria were enrolled: Patients with COPD seeking medical advice at Kasr Alainy Chest Department.
Patients with bronchial asthma, pneumonia, bronchogenic carcinoma, liver diseases, renal diseases, interstitial fibrosis, heart failure, and vascular diseases were excluded from the study.

Clinical information
• Full history and clinical examination including age, gender, assessment of smoking status, and chest X-ray • Exhaled CO by CO Check Pro device: A portable device designed for handheld use can measure the concentration of carbon monoxide CO (ppm) in exhaled breath based on an electrochemical fuel cell sensor.The individuals were asked to breath out completely to empty their lungs, fully inspire, and then hold their breath for as long as they can.After holding of breath for at least 10 s, they were asked to expire slowly into the CO Check Pro device and were encouraged to exhale fully to sample the exhaled air.
The device displays the concentration of exhaled CO in ppm and can convert it to percent carboxyhemoglobin (%COHb) using the mathematical relationships described by Jarvis et al. (1986) [8] for concentrations below 90 ppm and by Stewart et al. (1976) [9] for higher levels (Fig. 1).

Statistical methods
To present quantitative data, we used mean and standard deviation, as well as frequencies.The use of an unpaired t test to compare 2 groups and an ANOVA test when comparing more than 2 groups (Chan, 2003a).We utilized the Pearson correlation coefficient to establish correlations between quantitative variables.ROC curve was constructed with area under curve analysis performed to detect best cutoff value of exhaled CO for detection of smokers.Statistical significance is considered when p-values are less than 0.05.

Demographics of the study participants
This study was carried out at Kasr Alainy Faculty of Medicine, Cairo University, and included 132 individuals.They were divided into three groups: group 1 nonsmoker healthy control, group 2 smoker non-COPD, and group 3 smoker COPD which further divided according to GOLD 2023 into mild, moderate, and severe COPD.All of them were men with mean age 51.94 ± 12.66 years.Ninety-six were smokers, while 36 nonsmokers (Table 1).

Comparison between exhaled CO in the smoker and the nonsmoker groups
Exhaled CO was statistically significantly increased in the smoker group (mean 9.69 ± 3.11) in comparison to the non-smoker group (mean 2.19 ± 0.98) with p-value < 0.001 (Table 2).

Comparison between exhaled CO in the smoker COPD and smoker non-COPD groups
Exhaled CO was statistically significantly greater in the smoker COPD group (mean 10.45 ± 3.03) than the smoker non-COPD group (mean 7.05 ± 1.56) with p-value < 0.001 (Table 3).

Comparison between exhaled CO in the mild, moderate, and severe COPD groups
Exhaled CO was increased in the severe COPD group (mean 11.32 ± 3.15) more than mild (9.54 ± 3.32) and moderate (10.44 ± 2.43) COPD but without statistically significant difference p-value 0.122 (Table 4).There was a negative correlation between exhaled CO and FEV1 p-value 0.04 (Table 5).

Pearson correlation Sensitivity and specificity of exhaled CO in detection of smokers
The exhaled CO test can differentiate between smokers and nonsmokers with sensitivity 98.9% and specificity 100% at cutoff point 4.5 with p-value < 0.001 (Table 6).

Discussion
Oxidative stress is an important component of airway inflammation in COPD patients.Exhaled CO is a simple and rapid method used to detect and monitor airway inflammation and oxidative stress [10].
In our study, exhaled CO was increased significantly in the smoker group (mean 9.69 ± 3.11) compared to the nonsmoker group (mean 2.19 ± 0.98) with p-value < 0.001, and this was compatible with those of the former study [11].Minimal exposure to CO may occur during normal daily activity due to environmental pollution, passive smoking, and occupational exposure, and this explains the low level of exhaled CO among non-smokers group [12].
Our results show that cutoff value 4.5 ppm can differentiate smokers from nonsmokers with 98.9% sensitivity and 100% specificity compared to a previous study which found that exhaled CO at ≥ 7 ppm differentiated smokers from nonsmokers with sensitivity 93% and specificity 95% [13].
There is a strong relationship between the smoking habit of a given person and their blood concentration of carboxyhemoglobin (COHb) [14].Exhaled CO is considered the mirror of COHb, and it is in dynamic equilibrium with COHb [12].Also, exhaled CO was increased in the smoker COPD group (mean 10.45 ± 3.03) more than the smoker non-COPD group (mean 7.05 ± 1.56) with p-value < 0.001 which is similar to Montuschi et al. (2001) study [15].This is explained by increased oxidative stress in the COPD group.In our study, exhaled CO was higher in the severe COPD group (mean 11.32 ± 3.15) compared to between the mild (9.54 ± 3.32) and the moderate (10.44 ± 2.43) COPD but without statistically significant difference with p-value 0.122, and there was a negative correlation between exhaled CO and FEV1 with p-value 0.04 which is similar to results of Sivagnaname (2014) study [16], but our results were different from Montuschi et al. (2001) study [15] that found no negative correlation between exhaled CO levels and pulmonary function.
Our study had some limitation including small sample size and single-center location, and so we need further studies in other centers to prove these results.
In conclusion, exhaled CO is a fast, sensitive, noninvasive, and well-established method test that can be used to identify smokers from nonsmokers with 98.9% sensitivity at 4.5 cutoff value.Also, exhaled CO levels in COPD patients vary with different degrees of airway obstruction.

Fig. 1
Fig. 1 CO Check Pro device

Table 1
Demographics of the study participantsDM diabetes mellitus, HTN hypertension, COPD chronic obstructive airway disease

Table 2
Comparison between exhaled CO in the smoker and the nonsmoker groups

Table 3
Comparison between exhaled CO in the smoker COPD and smoker non-COPD groups

Table 4
Comparison between exhaled CO in the mild, moderate, and severe COPD groups

Table 5
Correlation between exhaled CO and FEV1 and FEV1/ FVC in COPD patients

Table 6
Sensitivity and specificity of exhaled CO in detection of smokers ROC curve for prediction of smokers using COArea under the curve p-value 95% confidence intervalLower bound Upper bound Cut off Sensitivity % Specificity % PPV % NPV % Accuracy