Invest Clin 65(1): 99 - 108, 2024 https://doi.org/10.54817/IC.v65n1a09

Corresponding author: Quanlin Jia, Department of Pulmonary and Critical Care Medicine, Shanxi Changzhi Se-

cond People’s Hospital, Changzhi, 046000, Shanxi Province, China. E-mail: yanmushan185071612@163.com

Effect of fractional exhaled carbon monoxide

on patients with sleep apnea-hypopnea

syndrome and its mechanism.

Quanlin Jia1, Li Guo1, Xinhua Zheng1, Guangwei Li1 and Lu Liu2

1Department of Pulmonary and Critical Care Medicine, Shanxi Changzhi Second

People’s Hospital, China.

2Department of Special Care Ward, Shanxi Changzhi Second People’s Hospital,

Changzhi, China.

Keywords: Sleep-disordered breathing; fractional exhaled carbon monoxide; eosinophils;

erythrocyte sedimentation rate; C-reactive protein.

Abstract. Sleep-disordered breathing (SDB) is a common sleep disorder as-

sociated with chronic airway inflammation and lung function impairment. This

article aimed to investigate the fractional exhaled carbon monoxide (FeCO)

expression level in obstructive sleep apnea-hypopnea syndrome (OSAHS) and

its correlation with disease indicators. Subjects with OSAHS, asthma, chronic

obstructive pulmonary disease (COPD), and healthy subjects were selected to

collect clinical data. FeCO concentration, eosinophil (Eos), erythrocyte sed-

imentation rate (ESR), C-reactive protein (CRP), FEV1, and FEV1/FVC were

measured. The Pearson correlation coefficient and receiver operating charac-

teristic (ROC) curve were used for statistical analysis. The FeCO concentra-

tion, Eos count, ESR and CRP levels, and lung function in the OSAHS group

were higher than the healthy and COPD groups (p<0.05) and slightly lower

than the asthma group. FeCO was positively correlated with Eos, ESR, and CRP

(p<0.05), but there was no apparent correlation between FeCO and lung func-

tion. FeCO has a high sensitivity and specificity in the diagnosis of OSAHS.

There is chronic airway inflammation and systemic inflammation in patients

with OSAHS. Lung function impairment in patients with OSAHS is mild, but

some limitations remain. FeCO may be an auxiliary diagnostic index particu-

larly valuable in diagnosing OSAHS.

100 Jia et al.

Investigación Clínica 65(1): 2024

Efecto de la fracción exhalada de monóxido de carbono

en pacientes con síndrome de apnea-hipopnea del sueño

y su mecanismo.

Invest Clin 2024; 65 (1): 99 – 108

Palabras clave: Respiración alterada durante el sueño; fracción de monóxido de carbono

exhalado; eosinófilos; velocidad de sedimentación globular; proteína

C-reactiva.

Resumen. Los trastornos respiratorios del sueño (TRS) son un desorden

del sueño común asociado con inflamación crónica de las vías respiratorias y

deterioro de la función pulmonar. Este artículo tuvo como objetivo investigar el

nivel fraccional de exhalación de monóxido de carbono (FeCO) en el síndrome

de apnea-hipopnea obstructiva del sueño (SAHOS) y su correlación con los indi-

cadores de la enfermedad. Se seleccionaron sujetos con SAHOS, asma, enferme-

dad pulmonar obstructiva crónica (EPOC) y sujetos sanos para recopilar datos

clínicos. Se midieron la concentración de FeCO, eosinófilos (Eos), velocidad de

sedimentación globular (ESR), proteína C reactiva (PCR), FEV1 y FEV1/FVC.

Para el análisis estadístico se utilizaron el coeficiente de correlación de Pearson

y la curva de características operativas del receptor (ROC). La concentración

de FeCO, el recuento de Eos, los niveles de VSG y PCR y la función pulmonar

en el grupo de OSAHS fueron claramente más altos que en los grupos sanos y

con EPOC (p<0,05) y ligeramente más bajos que en el grupo de asma. FeCO

se correlacionó positivamente con Eos, ESR y CRP (p<0,05), pero no hubo

correlación aparente entre FeCO y la función pulmonar. El FeCO mostró una

alta sensibilidad y especificidad en el diagnóstico del SAHOS. Existe inflama-

ción crónica de las vías respiratorias e inflamación sistémica en pacientes con

SAHOS. El deterioro de la función pulmonar en pacientes con SAHOS es leve,

pero persisten algunas limitaciones. El FeCO puede ser un índice diagnóstico

auxiliar particularmente valioso en el diagnóstico del SAHOS.

Received: 06-08-2023 Accepted: 07-11-2023

INTRODUCTION

Sleep-disordered breathing (SDB) is a

common sleep disorder. SDB refers to dis-

eases in which the respiratory system is dam-

aged during sleep, resulting in weakened

respiratory function and decreased oxygen-

ation 1,2. Etiologically, SDB can be caused by

a variety of reasons. The most common cause

of SDB is obstructive sleep apnea-hypopnea

syndrome (OSAHS), which is apnea and hy-

popnea caused by airway obstruction. Other

causes may include neuromuscular disorders

(such as muscle weakness and spinal cord

injury), central hypoventilation syndrome

(such as obesity and craniocerebral injury),

and the effects of certain medications 3,4. The

clinical symptoms of SDB include nocturnal

snoring, frequent sleep disruption, apnea,

oxygen desaturation, poor sleep quality, day-

time sleepiness, and inattention. Long-term

failure to receive adequate treatment may

Fractional exhaled CO in patients with sleep apnea-hypopnea syndrome 101

Vol. 65(1): 99 - 108, 2024

lead to severe consequences such as cardio-

vascular disease, metabolic disorders, and

cognitive impairment 5.

Researchers are committed to improv-

ing the diagnosis and screening methods of

SDB, including improving and developing

sleep monitoring technology to improve the

early identification and intervention of the

disease. In addition, the etiology and mecha-

nism of SDB are also being actively explored,

including abnormalities in respiratory con-

trol centers, changes in neck and upper air-

way structures 6,7. These studies contribute

to a better understanding of the disease and

provide a basis for developing therapeutic

methods. Treatment for SDB continues to

evolve and includes behavioral and lifestyle

changes such as weight loss, improved sleep

position, and avoidance of alcohol and seda-

tives. In addition, surgical intervention may

be an option for some specific etiologies,

such as obstructive sleep apnea syndrome,

due to structural abnormalities of the up-

per airway. Surgical methods include palatal

tonsillectomy, palatal ptosis, and uvula sur-

gery to expand airway access 8,9. The use of

drug therapy in SDB is relatively limited and

is usually reserved for specific conditions or

in combination with other treatments. Some

medications can enhance respiratory func-

tion by stimulating respiratory centers or

improving muscle tone.

Fractional exhaled carbon monoxide

(FeCO) is the carbon monoxide gas dis-

charged from the lungs through the respi-

ratory system. It is a colorless, odorless gas

produced during combustion reactions dur-

ing metabolic processes, especially tobacco

combustion 10,11. Carbon monoxide enters

the circulation mainly through gas exchange

between the alveoli and capillaries and is

then expelled from the lungs by respiration.

FeCO measurement can be performed by a

carbon monoxide breath test, which mea-

sures the concentration of carbon monoxide

in the breath and thus assesses the produc-

tion and metabolism of carbon monoxide

in the body. The measurement of FeCO can

be used as one of the indicators to evaluate

exposure to combustion products or envi-

ronmental pollutants, as well as to monitor

the degree of inflammation and oxidative

stress12-14. Studies have shown a correlation

between SDB and FeCO levels 15. The lack of

oxygenation caused by apnea and hypopnea

during sleep in patients with SDB may lead

to an increased demand for oxygen, affect-

ing the metabolism and excretion of carbon

monoxide. Therefore, FeCO levels may vary in

patients with SDB. Some studies have shown

that FeCO levels may be valuable in assessing

SDB 16-17. The repeated hypoventilation and

hypoxia events during sleep in patients with

SDB may lead to oxidative stress and inflam-

mation. Carbon monoxide is a biomarker re-

lated to oxidative stress and inflammation.

Therefore, some studies have attempted to

assess the oxidative stress and inflammation

status of SDB patients by measuring FeCO

levels 18,19. In addition, it has been suggested

that FeCO levels may be associated with the

severity and prognosis of SDB. Higher FeCO

levels may be associated with more severe

disease and poor prognosis, including an in-

creased risk of cardiovascular complications

20. Despite some association observations,

there is currently insufficient evidence to

support using FeCO levels as a diagnostic cri-

terion or an independent diagnostic indica-

tor for SDB. The diagnosis of SDB relies pri-

marily on polysomnography, which assesses

respiratory events, oxygenation measures,

and other relevant parameters. In conclu-

sion, although there may be a correlation

between FeCO and SDB, further studies are

needed to clarify its exact value in diagnos-

ing and evaluating SDB.

MATERIALS AND METHODS

Study subjects

Forty-eight patients with OSAHS who

were treated in the Respiratory Department

of Shanxi Changzhi Second People’s Hospital

from February 2021 to October 2022 were

enrolled in the OSAHS group, 50 patients

102 Jia et al.

Investigación Clínica 65(1): 2024

with asthma as asthma group, 52 patients

with chronic obstructive pulmonary disease

(COPD) as COPD group, and 48 healthy peo-

ple who underwent physical examination in

the same period as a healthy group. There

were no apparent differences in gender,

age, course of disease, and smoking history

among the four groups.

Inclusion criteria

OSAHS group: aged between 18 and

65 years old. Patients were diagnosed with

moderate or severe OSAHS according to the

diagnostic criteria of the American Academy

of Sleep Medicine (AASM). The patients had

apparent symptoms of sleep apnea, such as

frequent snoring, poor sleep quality, and

daytime sleepiness.

Asthma group: aged between 18 and 65

years. Asthma was diagnosed according to

the Global Initiative for Asthma (GINA) di-

agnostic criteria. Asthma-related symptoms

such as cough, shortness of breath, and dys-

pnea were present.

COPD group: aged between 40 and 85

years. COPD was diagnosed according to

the diagnostic criteria of the Global Initia-

tive for Chronic Obstructive Lung Disease

(GOLD). Respiratory symptoms included

chronic cough, expectoration, and associ-

ated lung function impairment.

Healthy group: aged between 18 and 65

years old. No respiratory disease was diag-

nosed as OSAHS, asthma, or COPD. There

were no obvious respiratory or sleep-related

symptoms.

Exclusion criteria

Patients with severe heart disease, kid-

ney disease, nervous system disease, or other

serious underlying diseases. Patients under-

going respiratory surgery or treatment. Pa-

tients with severe cognitive or communica-

tion impairments and unable to cooperate

with the trial requirements.

Healthy group: Patients with any chron-

ic disease or other serious health problems.

History of smoking within 24 hours.

The Medical Ethics Committee of

Shanxi Changzhi Second People’s Hospital

approved the trial, and all patients signed an

informed consent.

FeCO concentration detection

We ensured the breath analyzer was in

working condition and calibrated the instru-

ment to ensure accurate measurements. The

breath analyzer was kept clean and free of

dirt or residue. We made the subjects sit or

stand, ensuring they were comfortably ex-

haling. The subjects were instructed to take

several deep breaths to verify adequate ven-

tilation of the lungs. We explained the pro-

cedure and purpose of the test and informed

the subject to keep breathing normally dur-

ing the test. The test subjects were connect-

ed to the breath analyzer (U-breath BA200,

Zhejiang E-link care Medical Technology Co.,

LTD.) using an appropriate-size mask or ex-

piratory tube. The connection site was well-

sealed to avoid gas leakage. The subjects

could breathe normally and pass the breath

into the breath analyzer through the mouth.

The breath analyzer measured and recorded

the concentration of carbon monoxide in

the breath.

Two or three breath measurements were

carried out to obtain a stable average. The

results of each measurement were recorded,

including the time, date, and measurement

value. For each subject tested, the average

FeCO concentration was calculated.

Detection of other indicators

Eosinophils (Eos): Samples were ex-

tracted from the peripheral blood of the

tested subjects, venous whole blood samples

were collected using an anticoagulant collec-

tion vessel, and Eos counts were performed

in an automated blood cell analyzer (BC-

760 CS, Mindray Medical International Co.,

LTD.) under laboratory conditions. Samples

were placed into the hematology analyzer

for analysis according to the instrument’s

instructions. The hematology analyzer mea-

sured the number of Eos in the sample and

Fractional exhaled CO in patients with sleep apnea-hypopnea syndrome 103

Vol. 65(1): 99 - 108, 2024

generated the results. Average Eos absolute

count: 0-0.4×109/L for adults.

Erythrocyte sedimentation rate (ESR):

samples were extracted from the peripher-

al blood of the tested subjects, and venous

whole blood samples were collected using

anticoagulant blood collection vessels. A

certain amount of blood samples was taken

and placed in the ESR tube of an ESR instru-

ment (BK-ESR40, Shandong Biobasebaby

Technology Co., LTD.). The ESR tube was

placed vertically in the ESR meter, allowing

the blood to drop freely. The ESR tube was

placed into the ESR meter for measurement

according to the device’s specifications and

instructions. The erythrocyte sedimentation

rate in the ESR tube was recorded, and the

normal ESR range was 0-20mm/h for adult

females and 0-15mm/h for adult males.

C-reactive protein (CRP): samples were

extracted from the peripheral blood of the

tested subjects, and venous whole blood

samples were collected using anticoagulant

blood collection tubes. The blood samples

were sent to the laboratory, and the CRP level

in the blood was quantitatively measured by

the immunofluorescence method. According

to the method, sample processing and mea-

surements were performed according to the

corresponding operating instructions. The

CRP concentration in the blood was record-

ed or reported based on the measurements.

The normal concentration should generally

be less than 10mg/L.

Pulmonary function

FEV1 (the volume of air expelled from

the beginning of forced exhalation to the

end of one second of exhalation) and FEV1/

FVC (the ratio of forced expiratory volume

in one second to forced vital capacity) were

measured by adopting a pulmonary func-

tion instrument (MSA99, Beijing Maibang

Photoelectric Instrument Co., LTD.). First,

the pulmonary function meter was in nor-

mal working condition, performing the nec-

essary calibration and verification with a

respirator mask of the appropriate size. The

subjects were placed in a comfortable posi-

tion. The test procedure and purpose were

explained to the subjects, and necessary

instructions were provided. A respirator

of the appropriate size was adopted to the

subjects’ mouth according to the require-

ments of the spirometer, making sure the

mask was well sealed to avoid gas leakage.

The subjects began to take normal resting

breaths as directed by the spirometer. Next,

the subjects were asked to take a maximal,

hard breath, taking in as much air as pos-

sible and then forcing to expel air. Immedi-

ately after a hard inhalation, the subjects

were asked to perform a hard exhalation,

then push the air out of the lungs as hard

as possible, ending the exhalation entirely

as quickly as possible. The spirometer auto-

matically measured and recorded FEV1 and

FVC. Based on the measured FEV1 and FVC

results, the FEV1/FVC ratio was calculated.

Statistical analysis

IBM SPSS 20.0® software was adopted

for data statistical analysis, analysis of vari-

ance was adopted, and the measurement

data were expressed as the mean ± stan-

dard deviation (X±SD). Count data were

expressed as a percentage (%). The χ2 test

and the Pearson correlation analysis were ap-

plied. The significance level was p<0.05, in-

dicating that the difference was statistically

significant.

RESULTS

Comparison of FeCO concentrations,

Eos counts, ESR, CRP, FEV1 and FEV1/

FVC values

The FeCO concentration of the OSAHS

group was higher than the healthy and COPD

groups (p<0.05), but slightly lower than

the asthma group. In the OSAHS group had

Eos count, ESR level, CRP level, FEV1 value,

and markedly higher FEV1/FVC value than

healthy and COPD groups (p<0.05), but a

lower EOS count, inferior ESR level, inferior

104 Jia et al.

Investigación Clínica 65(1): 2024

CRP level, lower FEV1 value and lower FEV1/

FVC value than the asthma group (p<0.05).

(Fig. 1).

Correlation analysis between FeCO

and each index

Pearson analysis was used to analyze the

correlation between FeCO and various indica-

tors. It can be observed that FeCO was positive-

ly correlated with Eos, ESR, and CRP (p<0.05),

and there was no apparent correlation between

FeCO and lung function (Table 1).

The diagnostic value of FeCO for OSAHS

was analyzed using the receiver operating

characteristic (ROC) curve. The sensitivity

(0.857) and specificity (0.835) of FeCO in

Fig. 1. Contrast of fractional exhaled carbon monoxide (FeCO) concentrations (Fig. 1A), Eosinophil (Eos)

comparison (Fig. 1B), Contrast of Erythrocyte sedimentation rate (ESR) levels (Fig. 1C), Con-

trast of C-reactive protein (CRP) (Fig.1D), Contrast of Forced expiratory volume (FEV1) values

(Fig. 1E), Contrast of Forced expiratory volume/forced vital capacity (FEV1/FVC) values (Fig. 1F).

[Note: * relative to healthy group (p<0.05), # relative to COPD group (p<0.05)].

Fractional exhaled CO in patients with sleep apnea-hypopnea syndrome 105

Vol. 65(1): 99 - 108, 2024

diagnosing OSAHA were both high. The area

under the ROC curve was 0.824, and the

95% interval was 0.77-0.89 (Fig. 2).

DISCUSSION

This article explored the value of FeCO

as a potential biomarker in diagnosing and

evaluating OSAHS. FeCO has shown its po-

tential as a rapid and non-invasive detection

index in many respiratory diseases. However,

studies on its application and relevance in

OSAHS are still limited. To further under-

stand the potential role and diagnostic value

of FeCO in OSAHS patients, asthma patients,

COPD patients, and healthy controls, FeCO

concentration was compared, and correla-

tion analysis with other clinical indicators

was carried out.

The FeCO concentration in the OSAHS

group was still higher than against healthy

and COPD groups, which may result from

chronic airway inflammation and poor oxy-

genation due to SDB caused by OSAHS. Eos

is a type of white blood cell whose increase

is often associated with airway inflammation

and allergic reactions. The high Eos count in

the OSAHS group may reflect airway inflam-

mation and abnormal gas exchange caused

by OSAHS 21. As against the asthma group,

the Eos count of the OSAHS group was low-

er, which may be due to the different patho-

logical mechanisms of OSAHS and asthma.

The high level of ESR in the OSAHS group

may be related to the chronic airway inflam-

mation and hypoxia caused by OSAHS. As

against the asthma group, the OSAHS group

had a lower ESR level, possibly due to the dif-

ferent inflammatory mechanisms and course

of disease between OSAHS and asthma 22.

CRP is an acute-phase protein, and its

increase is usually associated with inflam-

matory responses and tissue damage. In the

OSAHS group, higher CRP levels may reflect

the presence of abnormal gas exchange and

Table 1

Correlation analysis between fractional exhaled carbon monoxide and each index.

Indicators OSAHS group

(n=48)

r P

Asthma group

(n=50)

r P

COPD group

(n=52)

r P

Eos 0.725 0.015 0.625 0.024 0.719 0.017

ESR 0.562 0.036 0.465 0.044 0.611 0.032

CRP 0.762 0.008 0.633 0.028 0.768 0.014

FEV10.135 0.332 0.089 0.527 0.125 0.343

FEV1/FVC 0.128 0.346 0.077 0.593 0.059 0.665

OSAHS= obstructive sleep apnea-hypopnea syndrome, COPD= chronic obstructive pulmonary disease, Eos= eo-

sinophil, ESR= erythrocyte sedimentation rate, CRP= C-reactive protein, FEV1= Forced expiratory volume, FVC=

forced vital capacity.

Fig. 2. Receiver Operating Characteristic (ROC)

curve of FeCO (fractional exhaled carbon

monoxide) in the diagnosis of OSAHS (ob-

structive sleep apnea-hypopnea syndrome).

106 Jia et al.

Investigación Clínica 65(1): 2024

chronic inflammation. In contrast, CRP lev-

els were lower in the OSAHS group than in

the asthma group, which may result from

differences in inflammatory mechanisms

and pathological processes between OSAHS

and asthma 23. FEV1 is an essential indica-

tor in pulmonary function testing to evalu-

ate expiratory flow rate. The OSAHS group

suggested higher FEV1 values, which may

reflect the relatively mild airway stenosis

caused by OSAHS. This situation may be be-

cause OSAHS is mainly caused by partial up-

per airway obstruction, unlike asthma and

COPD. The FEV1/FVC ratio was adopted to

assess the degree of airway obstruction. The

OSAHS group suggested higher FEV1/FVC

values, which may imply that lung function

limitation caused by airway stenosis is rela-

tively mild in OSAHS patients. Zhao et al. 24

discussed the role of FeCO in the auxiliary

diagnosis and evaluation of allergic rhinitis

(AR). They selected AR patients for compari-

son with healthy controls. Symptom scores

distinguished the severity of AR disease, and

the FeCO tested both groups. The results

suggested that the level of FeCO in the AR

group was higher than that in healthy people

and positively correlated with the severity of

AR symptoms. The detection of FeCO can

monitor the changes in AR and has high ac-

curacy as an indicator for the auxiliary diag-

nosis of AR.

The positive correlation between FeCO

and Eos, ESR, and CRP (p<0.05) indicated

that FeCO might be associated with inflam-

matory processes. These indicators play an

essential role in the inflammatory response

so that the elevated FeCO may reflect the

presence of chronic airway inflammation

in OSAHS patients. In terms of lung func-

tion, the correlation between FeCO and lung

function is not apparent, which may mean

that the relationship between FeCO and

the degree of lung function impairment in

OSAHS is unclear. Using ROC curve analysis,

the value of FeCO in diagnosing OSAHS can

be evaluated. The high sensitivity, specificity

and large area under the ROC curve indicat-

ed that FeCO may be adopted as a potential

auxiliary diagnostic index for the screening

and diagnosis of OSAHS.

The correlation between FeCO and

OSAHS suggests that FeCO may serve as a

valuable indicator to reflect the presence

of chronic airway inflammation and play a

role in the diagnosis of OSAHS. It should be

noted that as an auxiliary diagnosis meth-

od, FeCO still needs to be comprehensively

evaluated in combination with other clini-

cal information. The diagnosis of OSAHS is

usually based on a comprehensive analysis of

medical history, physical examination, sleep

monitoring, and pulmonary function test-

ing. As an index, although FeCO has shown

a specific diagnostic value in the experimen-

tal results, it still needs to be combined with

other clinical indicators to make a compre-

hensive judgment.

In conclusion, FeCO level was increased

in OSAHS patients and was associated with

chronic airway inflammation, systemic in-

flammatory response, and mild pulmonary

dysfunction. In addition, FeCO has shown

potential as an auxiliary diagnostic index and

has a particular value in diagnosing OSAHS.

However, there are some limitations in this

article, such as the limited number of study

samples and age and gender differences

across groups that may affect the interpre-

tation of the results. Therefore, future stud-

ies are needed to further explore the physi-

ological mechanism of FeCO in OSAHS and

optimize the diagnostic threshold and its

application in clinical practice. The clinical

significance of this article is that it provides

a new potential indicator for early screening

and diagnosis of OSAHS.

Funding

None

Conflict of competence

The authors declare no conflict of in-

terest.

Fractional exhaled CO in patients with sleep apnea-hypopnea syndrome 107

Vol. 65(1): 99 - 108, 2024

Authors’ ORCID Number

• Quanlin Jia: 0000-0002-4875-4798

• Li Guo: 0000-0002-2529-7643

• Xinhua Zheng :0000-0003-3171-173X

• Guangwei Li :0000-0002-9995-1695

• Lu Liu :0000-0002-7701-7519

Authors’ Participation

QJ and LG contributed to the concep-

tualization of the study, the design of the

methodology, the acquisition of data, and

the analysis and interpretation of data. XZ

contributed to the drafting and revision of

the manuscript. GL was actively involved in

data collection and played a key role in the

statistical analysis. LL contributed to the in-

terpretation of results and critically revised

the manuscript. All authors participated in

the final approval of the version to be pub-

lished and agreed to be accountable for the

accuracy and integrity of the work.

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