Exhaled Nitric Oxide as a Surrogate Marker for Obstructive Sleep Apnea Severity Grading: An In-Hospital Population Study

Figures & data

Table 1 Characteristics of the OSA Patients in 3 Severity Sub-Groups

Parameters	Mild OSA (n=17)	Moderate OSA (n=23)	Severe OSA (n=83)	p-value
Age (year)	54 (31–76)	57 (43–83)	52 (30–76)	0.0422
Gender (Female/Male)	7/10	8/15	15/68	0.214
Current smoking	3 (3.04%)	2 (4.11%)	17 (14.84%)	0.197
Hypertension	8 (8.29%)	12 (11.22%)	40 (40.49%)	0.033
Type 2 diabetes	2 (2.76%)	5 (3.74%)	13 (13.49%)	0.0793
Ischemic heart disease	3 (2.9%)	3 (3.93%)	15 (14.17%)	0.052
Lipid dysfunction	4 (4.84%)	4 (6.54%)	27 (23.62%)	0.254
Asthmatics	1 (0.55%)	2 (0.75%)	1 (2.70%)	0.1675
COPD	4 (3.18%)	3 (4.3%)	16 (15.52%)	0.113
BMI (kg/m2)	24.6 (18.5–30.6)	25.9 (22.7–37.3)	28.7 (23.3–39.4)	0.0002
Neck circumference (cm)	38 (33.2–44.2)	39 (35.1–41.5)	41 (36.0–47.5)	0.00002
Waist circumference	92 (75.8–109.2)	121.4 (84.2–121.4)	104 (91.0–125.3)	0.0007
Systolic BP (mmHg)	130 (100–152)	120 (110–140)	130 (110–150)	0.370
Diastolic BP (mmHg)	80 (60–92)	80 (60–89)	80 (60–100)	0.3027
Blood glucose	83.0 (64.6–158.8)	99.0 (73.0–218.9)	97.5 (76.0–181.95)	0.3612
HDL	44.0 (28.8–61.4)	38.0 (28.2–63.1)	41.0 (28.1–67.8)	0.4398
LDL	44.0 (28.8–61.4)	140.4 (76.31–209.8)	110.3 (53.2–181.8)	0.0039
Triglyceride	138 (65.2–315.8)	153 (70.2–399.3)	178.5 (89.15–547.6)	0.0841
FEV1 (% pred)	81.0 (34.6–102.4)	75.0 (31.0–105.4)	78.0 (46.2–98.8)	0.9018
FEV1/FVC (%)	83.0 (59.0–91.6)	79.0 (40.4–90.0)	82.0 (57.3−93.9)	0.3348
FVC (%pred)	82.0 (35.8–110.6)	73.0 (60.1–98.9)	80.0 (50.0–101.9)	0.9513

Notes: Categorical variables were described as frequency (proportion), continuous variables were described as median (95% CI). p-values were based on Chi-squared test for categorical variables and Kruskal–Wallis H-test for continuous variables.

Abbreviations: COPD, chronic obstructive pulmonary disease; BP, blood pressure; BMI, body mass index; HDL, high density lipid; LDL, low density lipid; FEV1, forced expiratory volume in one second; FVC, forced vital capacity.

Figure 1 Distribution of 25 parameters among 3 clinical subgroups.

Notes: Each panel consists of a stratified Kernel density plot, visualizing the distribution of a numeric variable within 3 OSA severity subgroups (Mild in green, Moderate in orange and Severe in red).

Abbreviations: Sys_BP, systolic blood pressure; Dia_BP, diastolic blood pressure; BMI, body mass index; HDL, high density lipid; LDL, low density lipid; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; FENO, fractional exhaled nitric oxide; J’AWNO, bronchial nitric oxide flow; CANO, alveolar concentration of nitric oxide; ppb, part per billion; ESS, Epworth sleepiness scale; VAS, visual analog scale; HDL, high density lipid; LDL, low density lipid; SpO2, pulse oxygen saturation.

Table 2 Sleepiness Score and Polygraphy Metrics Among 3 OSA Severity Sub-Groups

Parameters	Mild OSA (n=17)	Moderate OSA (n=23)	Severe OSA (n=83)	p-value
ESS	6.0 (2.4–16.0)	9.0 (1.1–17.8)	10.0 (3.0–17.9)	0.0957
VAS	5 (0–10)	5 (1–10)	5 (1.1–10)	0.9149
PICHOT	16 (3.4–24.0)	16 (1.1–23.9)	13 (1.1–28.9)	0.6052
AHI (n/h)	9.0 (5.0–13.2)	22.0 (18.0–26.9)	62.0 (33.1–91.0)	< 0.0001
SpO2 min	84.0 (61.4–89.2)	73.0 (54.6–85.9)	63.0 (51.0–82.9)	< 0.0001
SpO2 average	95.0 (92.0–96.0)	93.0 (91.1–95.0)	91.0 (77.0–94.0)	< 0.0001

Notes: All variables were described as median (95% CI). p_values were based Kruskal–Wallis H-test for continuous variables.

Abbreviations: ESS, Epworth score scale; VAS, visual analog scale; AHI, apnea-hypopnea index; SpO2, pulse oxygen saturation.

Figure 2 Correlation network of 25 parameters.

Notes: In this correlation network, each node (in orange) indicates a clinical or functional parameter, the node size is proportional to number of significant correlations between that parameter to others.

Abbreviations: Sys_BP, systolic blood pressure; Dia_BP, diastolic blood pressure; BMI, body mass index; HDL, high density lipid; LDL, low density lipid; FEV1, forced expiratory volume inone second; FVC, forced vital capacity; FENO, fractional exhaled nitric oxide; J’AWNO, bronchial nitric oxide flow; CANO, alveolar concentration of nitric oxide; ppb, part per billion; ESS, Epworth sleepiness scale; VAS, visual analog scale; HDL, high density lipid; LDL, low density lipid; SpO2, pulse oxygen saturation.

Table 3 Distribution of Exhaled NO Metrics Within 3 OSA Severity Sub-Groups

Parameters	Mild OSA (n=17)	Moderate OSA (n=23)	Severe OSA (n=83)	p-value
FENO 50 mL/s (ppb)	10.64 (5.55–24.91)	13.37 (5.84–28.56)	13.52 (6.12–24.69)	0.4764
FENO 100 mL/s (ppb)	11.98 (7.10–22.90)	15.49 (6.35–27.46)	12.11 (4.83–21.17)	0.1100
FENO 150 mL/s (ppb)	9.8 (4.41–16.6)	13.1 (4.85–23.90)	10.0 (4.62–20.49)	0.0759
FENO 350 mL/s (ppb)	8.14 (3.68–10.33)	9.11 (5.54–17.87)	7.02 (2.70–14.08)	0.1694
J’AWNO (nl/min)	11.2 (1.88–55.52)	33.9 (1.65–71.84)	36.2 (6.05–92.19)	0.010
CANO (ppb)	6.49 (0.65–10.1)	7.79 (4.16–14.27)	5.20 (1.24–12.65)	0.015

Notes: All variables were described as median (95% CI). p_values were based Kruskal–Wallis H-test for continuous variables, ppb: a fractional concentration of part per billion (10⁻⁹) or nl/L.

Abbreviations: FENO, fractional exhaled nitric oxide; J’AWNO, bronchial nitric oxide flow; CANO, alveolar concentration of nitric oxide; ppb, part per billion.

Table 4 Results of Pair-Wise Comparison for Exhaled NO Parameters

Parameters	Mild vs Moderate	Moderate vs Severe	Severe vs (Mod + Mild)
FENO 50 mL/s (ppb)	0.335	0.957	0.456
FENO 100 mL/s (ppb)	0.2733	0.031	0.073
FENO 150 mL/s (ppb)	0.096	0.026	0.121
FENO 350 mL/s (ppb)	0.398	0.06	0.092
J’AWNO (nl/min)	0.048	0.459	0.021
CANO (ppb)	0.044	0.004	0.037

Notes: This table represents the p values of pair-wise comparisons of 6 exhaled NO parameters (first columns), using Conover statistical test with Bonferroni correction. The difference is considered statistically significant at a p-value threshold of 0.05.

Abbreviations: FENO, fractional exhaled nitric oxide; J’AWNO, bronchial nitric oxide flow; CANO, alveolar concentration of nitric oxide; ppb, part per billion.

Figure 3 Impact of OSA severity on the result of multi-flow exhaled NO measurement.

Notes: This regression plot reproduces the SC Georges’s bi-compartment linear model: VNO = J’AWNO + CANO *VE, exploring the exhaled nitric oxide production rate (VNO, nl/min) to the sampling flow rate (VE). Based on this model, we determine the J’AWNO (bronchial nitric oxide flow) as the intercept of the regression line, and CANO (alveolar concentration of nitric oxide) as the regression slope. The graph illustrates how OSA (obstructive sleep apnea) severity (mild in green, moderate in orange, and severe red) modifies the J’AWNO and CANO values.