Increased urinary l-histidine in patients with asthma–COPD overlap: a pilot study

Figures & data

Table 1 Comparison of the baseline characteristics of chronic inflammatory airway diseases

Parameters	Asthma n = 32	COPD n = 38	ACO n = 37	P-value
Age, years	57.0 (47.0–66.8)a	67.0 (61.5–74.5)	64.0 (57.0–71.5)	0.001
Sex, male, n (%)	12 (37.5)	37 (97.4)	33 (89.2)	<0.001
BMI (kg m^−2)	23.2 (21.5–26.9)	22.3 (20.6–23.9)	24.6 (21.3–27.3)	0.039
Smoker, n (%)	3 (9.4)a	38 (100.0)	37 (100.0)c	<0.001
Ex-smoker, n (%)	1 (3.1)	17 (44.7)	23 (62.2)
Current smoker, n (%)	2 (6.3)	21 (55.3)	14 (37.8)
Smoking amount (pack-years)	0.0 (0.0–0.0)a	40.0 (33.8–54.8)	35.0 (20.0–44.5)c	<0.001
Comorbidities, n (%)
Allergic rhinitis	19 (59.4)a	2 (5.3)b	17 (45.9)	<0.001
Heart diseases	12 (37.5)	16 (42.1)	16 (43.2)	0.585
Symptom scores
mMRC	0.0 (0.0–1.0)a	1.0 (0.0–2.0)	0.0 (0.0–1.0)	0.015
CAT	–	14.0 (10.0–22.0)	12.0 (9.5–16.8)	0.050
ACT	23.0 (21.0–24.0)	–	20.0 (14.0–22.3)c	0.001
SGRQ	10.5 (5.1–15.0)a	16.9 (11.0–32.6)	15.3 (8.1–23.6)	0.008
PFTs
FEV1, L	2.6 (2.0–2.8)a	1.7 (1.0–2.5)	1.9 (1.6–2.4)c	<0.001
FEV1, %	91.0 (78.3–102.8)a	66.5 (35.8–76.3)	65.0 (49.0–71.5)c	<0.001
FEV1/FVC, %	76.0 (71.3–80.8)a	54.0 (34.8–58.3)	56.0 (44.5–64.5)c	<0.001
FEF 25%–75%	64.5 (47.0–92.8)a	21.5 (10.8–28.5)	27.0 (16.5–37.0)c	<0.001
BDR, mL	105.0 (32.5–150.0)	50.0 (17.5–142.5)b	290.0 (200.0–400.0)c	<0.001
TLC, %	101.5 (94.3–108.5)a	108.5 (102.8–117.0)	110.0 (103.5–116.0)c	0.013
FRC, %	107.0 (92.3–123.0)a	141.5 (128.8–157.0)	130.0 (110.0–149.5)c	<0.001
RV, %	103.5 (86.3–125.8)a	142.0 (132.8–155.8)	138.0 (120.5–153.0)c	<0.001
DLCO, %	97.0 (90.3–110.8)a	69.5 (47.5–98.8)	90.0 (67.5–98.5)c	<0.001
FeNO, ppb	22.0 (17.0–35.0)	18.0 (11.5–25.5)	20.0 (10.3–35.8)	0.198
Frequent exacerbator, n (%)	1 (3.1%)	5 (13.2%)	6 (16.2%)	0.204

Notes: Data are presented as median (IQR) for continuous variables and percentage (number) for categorical variables.

a Significantly different between asthma and COPD;

b significantly different between COPD and ACO;

c significantly different between asthma and ACO.

Abbreviations: ACO, asthma–COPD overlap; ACT, asthma control test; BDR, bronchodilator response; BMI, body mass index; CAT, COPD assessment test; DL_CO, diffusing capacity of the lung for carbon monoxide; FEF, forced expiratory flow; FeNO, fractionated exhaled nitric oxide; FEV₁, forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; IQR, interquartile range; mMRC, modified Medical Research Council; PFTs, pulmonary function tests; RV, residual volume; SGRQ, St George Respiratory Questionnaire; TLC, total lung capacity.

Figure 1 Differential urinary metabolic profiles in patients with asthma–COPD overlap (ACO), asthma, and COPD.

Notes: (A) Discrimination of the urine metabolome between patients with ACO and those with asthma by using orthogonal signal correction partial least squares-discriminant analysis (OPLS-DA). Intercepts: R² = 0.964 and Q² = 0.153. (B) Discrimination of the urine metabolome between patients with ACO and those with COPD by using OPLS-DA. Intercepts: R² = 0.971 and Q² = 0.0466. (C) Discrimination of the urine metabolome between patients with asthma and those with COPD by using OPLS-DA. Intercepts: R² = 0.963 and Q² = 0.163.

Figure 2 Urinary l-histidine levels in chronic inflammatory airway diseases according to disease classifications.

Notes: (A) Urinary l-histidine levels in patients with asthma, COPD, and ACO. (B) Urinary l-histidine levels in patients with asthma, COPD, smoking related obstructive asthma, and COPD with a very positive BDR and/or blood eosinophilia. *P < 0.05, **P < 0.01.
Abbreviations: ACO, asthma-COPD overlap; BDR, bronchodilator response.

Figure 3 Correlation between urinary l-histidine levels and parameters.

Notes: (A) Correlation between urinary L-histidine levels and SGRQ. (B) Correlation between urinary l-histidine levels and ACT. (C) Correlation between urinary l-histidine levels and BDR (D) Correlation between urinary l-histidine levels and FEV₁. (E) Correlation between urinary l-histidine levels and FEV₁/FVC.
Abbreviations: ACT, asthma control test; BDR, bronchodilator response; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume; SGRQ, St George Respiratory Questionnaire; TLC, total lung capacity.

Table 2 Comparison between frequent exacerbator and non-frequent exacerbator

Parameters	Frequent exacerbator n = 12	Non-frequent exacerbator n = 95	P-value
Age, years	61.5 (54.3–72.3)	64.0 (57.0–70.0)	0.667
Sex, male	10 (83.3%)	72 (75.8%)	0.547
Smoker	10 (83.3%)	64 (67.3%)	0.010
Ex-smoker	9 (75.0%)	35 (36.8%)
Current smoker	1 (8.3%)	29 (30.5%)
Smoking amount (pack-years)	37.5 (12.5–48.8)	40.0 (33.8–54.8)	0.301
Urine l-histidine level	61,917.8 (6,200.0–153,053.1)	12,226.3 (0.0–48,566.3)	0.032

Note: Data are presented as median interquartile range for continuous variables and percentage (number) for categorical variables.

Figure 4 Urinary l-histidine levels for each category of patients with Th-2 features of ACO as agreed upon by experts.

Notes: (A) Urinary l-histidine levels in patients with and without a documented history of asthma before 40 years of age or a BDR≥ mL of FEV₁. (B) Urinary l-histidine levels in patients with and without BDR≥ 200 mL of FEV₁ and exceeding the baseline values by 12% on 2 or more visits. (C) Urinary l-histidine levels in patients with blood eosinophil count ≥300 cells μL⁻¹ and <300 cells μL⁻¹.
Abbreviations: ACO, asthma–COPD overlap; BDR, bronchodilator response; FEV₁, forced expiratory volume in 1 second.