Sensitization to Aspergillus fumigatus as a risk factor for bronchiectasis in COPD

Figures & data

Table 1 Study group characteristics

Characteristic	Control	COPD	P-values
Patients (n)	50	300
Men (%)	37 (74.0)	215 (71.7)	0.7337
Age, years	62 (58–68)	67 (61–74)	0.0002
Pack-years	35.5 (26.8–46.8)	48.9 (34.0–64.1)	0.0001
Current smokers (%)	26 (52)	125 (42)	0.1781
BMI, kg/m^2	27.3 (23.9–29.4)	24.1 (20.7–27.5)	0.0004
FEV1, L	2.9 (2.4–3.4)	1.2 (0.9–1.6)	NA
FEV1, % pred	104 (92–111)	43 (34–58)	NA
DL,co, mmol/min/Kpa	7.5 (6.1–8.9)	3.8 (3.0–5.0)	NA
DL,co, % pred	83 (78–94)	46 (36–58)	NA
GOLD 1/2/3/4, %	NA	5.7/32.0/45.7/16.7	NA
GOLD assessment A/B/C/D, %	NA	4.0/21.3/5.3/69.3	NA
Vitamin D, μg/L	28.5 (21.2–35.5)	17.3 (12.4–23.1)a	<0.0001
Modified Reiff score ≥2 (%)	5 (10)	99 (33)	0.0010

Notes: Data are presented as n, n (%), median (interquartile range) or %.

a Based on 240 COPD patients after exclusion of subjects taking vitamin D supplements. P-values <0.05 are shown in bold.

Abbreviations: COPD, chronic obstructive pulmonary disease; BMI, body mass index; FEV₁, forced expiratory volume in 1 second; % pred, percentage predicted; DL,co, diffusion capacity of the lung for carbon monoxide; GOLD, Global Initiative for Chronic Obstructive Lung Disease; NA, not applicable.

Table 2 Total IgE and A fum-specific antibodies

Variables	Control	COPD	P-values
Patients (n)	50	300
Total IgE, kU/L	42.5 (16.5–105.5)	52.0 (17.0–198.5)	0.3068
Total IgE >114, kU/L (%)	11 (22)	103 (34.3)	0.0849
A fum extract IgE (%)	1 (2)	31 (10.3)	0.0584
rAsp f1 IgE (%)	1 (2)	36 (12)	0.0332
rAsp f2 IgE (%)	1 (2)	7 (2)	0.8839
rAsp f3 IgE (%)	1 (2)	20 (6.7)	0.1983
rAsp f4 IgE (%)	0 (0)	3 (1)	0.4776
rAsp f6 IgE (%)	0 (0)	4 (1.3)	0.4115
Sensitized in total (%)a	2 (4)	55 (18.3)	0.0110
A fum IgG, mg/L	20.7 (9.6–42.8)	31.0 (15.9–48.5)	0.0473

Notes: Data are presented as n, median (interquartile range) or n (%). P-values <0.05 are shown in bold.

a Sensitization to at least one of the A fum allergens including the extract.

Abbreviations: COPD, chronic obstructive pulmonary disease; A fum, Aspergillus fumigatus; rAsp f1, A fum recombinant f1; rAsp f2, A fum recombinant f2; rAsp f3, A fum recombinant f3; rAsp f4, A fum recombinant f4; rAsp f6, A fum recombinant f6.

Table 3 IgE against A fum extract and rAsp f1 in a contingency table

	rAsp f1 IgE present	rAsp f1 IgE absent	Row total
A fum extract IgE present	17 (7.5)	14 (4.7)	31 (10.3)
A fum extract IgE absent	19 (6.3)	250 (83.3)	269 (89.7)
Column total	36 (12.0)	264 (88.0)	300 (100)

Note: Data are presented as n (%).

Abbreviations: A fum, Aspergillus fumigatus; rAsp f1, A fum recombinant f1.

Figure 1 Total IgE and A fum-specific antibodies in patients with COPD versus controls.

Notes: Antibody levels were measured in plasma by ImmunoCAP fluoroenzyme immunoassay using an ImmunoCAP 1000 instrument (Phadia AB, Uppsala, Sweden). (A) Median values of total IgE. No significant difference between controls and COPD, P=0.3068. (B) Proportions of subjects with IgE against different A fum allergens: extract of A fum, A fum recombinant f1 (rAsp f1), A fum recombinant f2 (rAsp f2), A fum recombinant f3 (rAsp f3), A fum recombinant f4 (rAsp f4) and A fum recombinant f6 (rAsp f6). Total shows the proportion of participants sensitized against at least one of the tested allergens (*P<0.05). (C) Median values of A fum-specific IgG. Difference between COPD and control was significant (**P=0.0473).
Abbreviations: COPD, chronic obstructive pulmonary disease; A fum, Aspergillus fumigatus; rAsp f1, A fum recombinant f1; rAsp f2, A fum recombinant f2; rAsp f3, A fum recombinant f3; rAsp f4, A fum recombinant f4; rAsp f6, A fum recombinant f6.

Table 4 A fum-sensitized COPD patients versus A fum-non-sensitized COPD patients

Characteristic	COPD patients non-sensitized to A fum	COPD patients sensitized to A fum	P-values
Patients (%)	245 (81.7)	55 (18.3)
Men (%)	169 (69.0)	46 (83.6)	0.0293
Age, years	67 (61–74)	68 (64–74)	0.2767
BMI, kg/m^2	24.4 (20.9–27.7)	23.3 (19.7–26.9)	0.0785
Pack-years	48.0 (33.5–63.8)	52.5 (35.3–66.0)	0.3518
Current smoking (%)	99 (40.6)	26 (47.3)	0.3629
ICS (%)	197 (80.4)	49 (89.1)	0.1299
FEV1, L	1.18 (0.86–3.93)	1.70 (0.83–2.86)	0.7632
FEV1, % pred	43 (34–58)	41 (33–56)	0.4461
DL,co, mmol/min/Kpa	3.9 (3.0–9.6)	3.6 (2.7–7.7)	0.4038
DL,co, % pred	47 (37–59)	42 (32–58)	0.1618
GOLD 1/2/3/4, %	5.7/33.1/44.5/16.7	5.5/27.3/50.9/16.4	0.8291
GOLD assessment A/B/C/D, %	3.7/22.5/4.9/69.0	5.5/16.4/7.3/70.9	0.6515
≥2 exacerbations/year (%)	102 (41.6)	28 (50.9)	0.2096
Vitamin D, μg/La	18.1 (12.4–24.8)	16.2 (12.4–21.2)	0.2057
Vitamin D ≤20 μg/L (%)a	112 (56.9)	30 (69.8)	0.1185
A fum IgG, mg/L	27.7 (13.9–44.4)	43.2 (27.0–66.0)	<0.0001
Modified Reiff score ≥2 (%)	74 (30.2)	25 (45.5)	0.0297
Sputum PPM (%)b	94 (59.5)	30 (76.9)	0.0436

Notes: Data are presented as n (%), median (interquartile range) or %.

a Based on 240 COPD patients after exclusion of subjects taking vitamin D supplements: 197 non-sensitized and 43 sensitized patients.

b Based on 197 patients of whom sputum results were available: 158 non-sensitized and 39 sensitized patients. P-values <0.05 are shown in bold.

Abbreviations: COPD, chronic obstructive pulmonary disease; A fum, Aspergillus fumigatus; BMI, body mass index; ICS, inhaled corticosteroids; FEV₁, forced expiratory volume in 1 second; % pred, percentage predicted; DL,co, diffusion capacity of the lung for carbon monoxide; GOLD, Global Initiative for Chronic Obstructive Lung Disease; PPM, potential pathogenic microorganisms.

Table 5 A fum sensitization and bronchiectasis in COPD

Variables	COPD patients (n)	Modified Reiff score ≥2 (%)	P-values
IgE A fum extract	31	12 (38.7)	0.4752
IgE A fum extract or rAsp f1–f4 and rAsp f6	55	25 (45.5)	0.0297
IgE A fum extract without recombinants	9	0 (0)
IgE rAsp f1	36	18 (50)	0.0208
IgE rAsp f3	20	12 (60)	0.0079

Notes: Data are presented as n and n (%). P-values <0.05 are shown in bold.

Abbreviations: COPD, chronic obstructive pulmonary disease; A fum, Aspergillus fumigatus; rAsp f1, A fum recombinant f1; rAsp f2, A fum recombinant f2; rAsp f3, A fum recombinant f3; rAsp f4, A fum recombinant f4; rAsp f6, A fum recombinant f6.

Figure 2 Potential pathogenic microorganisms present in sputum samples of COPD patients by A fum sensitization status.

Notes: Occurrence of different species in sputum cultures. *P<0.05.
Abbreviations: COPD, chronic obstructive pulmonary disease; A fum, Aspergillus fumigatus; MRSA, methicillin-resistant Staphylococcus aureus.

Table 6 Association of bronchiectasis (modified Reiff score ≥2) and sensitization to rAsp f1 or rAsp f3 in COPD by a logistic regression model

Variables	In all COPD patients (n=300)		In COPD patients with sputum samples (n=197)
	OR (95% CI)	P-values	OR (95% CI)	P-values
Sensitization to rAsp f1 or rAsp f3	2.8 (1.42–5.53)	0.0030	3.4 (1.56–7.48)	0.0021
Gender	1.5 (0.81–2.75)	0.1953	1.8 (0.82–4.04)	0.1424
Age	1.0 (1.00–1.07)	0.0349	1.03 (0.99–1.07)	0.2064
BMI	1.0 (0.91–1.01)	0.1198	0.96 (0.89–1.03)	0.2155
DL,co, % pred	1.0 (0.97–1.00)	0.1353	0.98 (0.96–1.01)	0.1572
≥2 exacerbations/year	1.6 (0.97–2.72)	0.0642	2.11 (1.13–3.94)	0.0188
PPM in sputum	NA		0.68 (0.35–1.32)	0.2573

Note: P-values <0.05 are shown in bold.

Abbreviations: COPD, chronic obstructive pulmonary disease; rAsp f1, A fum recombinant f1; rAsp f3, A fum recombinant f3; OR, odds ratio; CI, confidence interval; BMI, body mass index; DL,co, diffusion capacity of the lung for carbon monoxide; % pred, percentage predicted; PPM, potential pathogenic microorganisms; NA, not applicable.