We analyzed the positivity of 39 allergen-specific IgE in all COPD patients. Concerning the perennial aeroallergens, the positivity for moth (35.4%), cockroach (23.1%), Dermatophagoides pteronyssinus (D. pteronyssinus, 21.5%), house dust (21.5%), and Candida (21.5%) was greater than 20% (Fig. 1). As for pollen allergens, the positivity for Japanese cedar (36.9%) and Japanese cypress (23.1%) exceeded 20%. As for foods or other allergens, the positivity for shrimp/lobster (18.5%), wheat (13.8%), and beef (12.3%) was higher than 10%.
We also compared the characteristics of patients who are positive with those who are negative for specific IgE (Fig. 2, Additional File 3). In patients with positive IgE for cockroach, residual volume (RV) was significantly higher (134.8% vs 114.0%), and FEV1 tended to be lower (71.0% vs 78.4%) compared with patients with negative IgE (Fig. 2). Contrarily, in patients with positive IgE for Japanese cedar, the diffusion capacity of carbon monoxide/alveolar volume (DLCO/VA) was significantly higher than in patients with negative IgE (87.0% vs 70.4%) (Fig. 2). The prevalence of patients with asthma symptom was significantly higher in house dust- and Japanese cedar-positive patients (Additional File 3). The prevalence of perennial allergic rhinitis was significantly higher in patients with positive specific IgE for all allergens, except for Japanese cedar, which causes seasonal rhinitis only in the spring season (Additional File 3).
Furthermore, we compared patient characteristics between ACO and non-ACO COPD (Table 1). In ACO, body mass index, the proportion of current smoker, blood eosinophil count, and FeNO were significantly higher and FEV1/FVC ratio was lower compared with non-ACO COPD. A significantly greater proportion of patients with ACO exhibited all the features of asthma, except for airway reversibility (Additional File 4).
Table 1
Comparison of patient characteristics between ACO and non-ACO COPD patients
| ACO | Non-ACO COPD | Total | P value |
Subject (n) | 29 | 34 | 63 | |
Sex male (%) | 86.2 | 82.4 | 84.1 | 0.68 |
Body mass index (kg/m2) | 24.2 ± 0.7 | 21.7 ± 0.6 | 22.8 ± 3.8 | < 0.01** |
Age (years) | 71.1 ± 1.4 | 74.7 ± 1.3 | 73.0 ± 1.0 | 0.060 |
Smoking status (Current/ex/never [%]) | 24.1/75.9/0 | 0/97.1/2.9 | 11.1/87.3/1.6 | < 0.01** |
Smoking history (pack-years) | 58.0 ± 6.4 | 62.7 ± 5.9 | 60.6 ± 34.2 | 0.59 |
FVC, %predicted | 107.1 ± 3.5 | 106.6 ± 3.3 | 106.8 ± 18.9 | 0.91 |
FEV1 (L) | 1.72 ± 0.12 | 1.87 ± 0.11 | 1.80 ± 0.66 | 0.37 |
FEV1, %predicted | 71.1 ± 4.3 | 81.0 ± 4.0 | 76.4 ± 23.7 | 0.10 |
FEV1/FVC ratio (%) | 51.2 ± 2.8 | 59.1 ± 2.6 | 55.5 ± 15.5 | 0.042* |
RV, % predicteda | 112.9 ± 5.4 | 116.6 ± 5.3 | 114.8 ± 27.0 | 0.63 |
DLco/VA, % predictedb | 81.4 ± 5.6 | 71.8 ± 5.5 | 76.5 ± 28.4 | 0.23 |
Airway reversibility (mL)c | 131.0 ± 23.7 | 90.8 ± 21.3 | 108.7 ± 109.3 | 0.21 |
Airway reversibility (%)c | 9.03 ± 1.8 | 5.2 ± 1.6 | 7.0 ± 8.5 | 0.10 |
Blood eosinophil count (cells/µl) | 250 ± 31 | 207 ± 29 | 227 ± 169 | 0.32 |
Serum total IgE (IU/mL) | 352 ± 86 | 236 ± 80 | 289 ± 466 | 0.33 |
FeNO (ppb)d | 33.7 ± 2.8 | 21.7 ± 2.6 | 27.1 ± 16.1 | < 0.01** |
ICS use before diagnosis of ACO (%) | 8 (27.6) | 3 (8.8) | 11 (17.5) | 0.08 |
LABA (%) | 82.8 | 73.5 | 77.8 | 0.38 |
LAMA (%) | 82.8 | 79.4 | 81.0 | 0.74 |
Theophylline (%) | 17.2 | 11.8 | 14.3 | 0.54 |
Notes:P < 0.05*, P < 0.01** between ACO and non-ACO COPD groups. RVa, DLco/VAb (ACO n = 25, non-ACO COPD n = 26), airway reversibilityc (ACO n = 21, non-ACO COPD n = 26), FeNOd (ACO n = 28, non-ACO COPD n = 34).
Abbreviations: ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease; DLco/VA, diffusing capacity of carbon monoxide/alveolar volume; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; ICS, inhaled corticosteroid; IgE, immunoglobulin E; LABA, long-acting β-agonists; LAMA, long-acting muscarinic receptor antagonist; RV, residual volume.
Next, we compared the positivity of specific IgE between ACO and non-ACO COPD (Table 2). Among various allergens, only the positivity for house dust and D. pteronyssinus was significantly higher in ACO. As for other perennial aeroallergens, the positivity for moth, Candida, and Malassezia was numerically higher in ACO without statistical significance. As for pollen, the positivity for Japanese cedar tended to be higher in ACO (P = 0.073). Concerning food allergens, the overall positivity for beef-specific IgE was low (8.6%); however, the positivity was significantly lower in ACO. We also analyzed the relationship between the value of IgE class and the proportion of patients diagnosed with ACO (Fig. 3). Only house dust- and D. pteronyssinus-specific IgE showed significant relationship between the class of specific IgE and ACO diagnosis.
Table 2
Comparison of positivity in specific IgE between ACO and non-ACO COPD
| ACO | Non- ACO COPD | Total | P value | | | ACO | Non- ACO COPD | Total | P value |
Perennial aeroallergen | Food allergen and latex |
Moth | 42.3 | 26.5 | 33.3 | 0.20 | Shrimp/lobster | 16.0 | 15.2 | 15.5 | 0.93 |
House dust | 41.4 | 11.8 | 25.4 | < 0.01** | Wheat | 16.0 | 9.1 | 12.1 | 0.42 |
D. pteronyssinus | 37.9 | 11.8 | 23.8 | 0.015* | Bananas | 16.0 | 6.1 | 10.3 | 0.22 |
Candida | 27.6 | 14.7 | 20.6 | 0.21 | Beef | 0.0 | 15.2 | 8.6 | 0.042* |
Cockroach | 23.1 | 17.7 | 20.0 | 0.60 | Crab | 4.0 | 12.1 | 8.6 | 0.28 |
Malassezia | 12.0 | 3.0 | 6.9 | 0.18 | Sesame | 4.0 | 9.1 | 6.9 | 0.45 |
Aspergillus | 7.1 | 2.9 | 4.8 | 0.44 | Buckwheat | 4.0 | 6.1 | 5.2 | 0.73 |
Dog dander | 4.0 | 2.9 | 3.4 | 0.82 | Apples | 0.0 | 6.1 | 3.5 | 0.21 |
Cat dander | 7.1 | 0.0 | 3.2 | 0.11 | Chicken | 0.0 | 6.1 | 3.5 | 0.21 |
Alternaria | 3.6 | 0.0 | 1.6 | 0.27 | Egg | 4.0 | 3.0 | 3.5 | 0.84 |
Pollen allergen | Peanuts | 4.0 | 3.0 | 3.5 | 0.84 |
Japanese cedar | 48.3 | 26.5 | 36.5 | 0.073 | Kiwis | 4.0 | 0.0 | 1.7 | 0.25 |
Japanese cypress | 23.1 | 24.2 | 23.7 | 0.92 | Milk | 0.0 | 3.0 | 1.7 | 0.38 |
Orchard grass | 17.2 | 5.9 | 11.1 | 0.15 | Pork | 0.0 | 3.0 | 1.7 | 0.38 |
Ragweed | 13.8 | 5.9 | 9.5 | 0.29 | Soybeans | 0.0 | 3.0 | 1.7 | 0.38 |
Timothy | 12.0 | 6.1 | 8.6 | 0.42 | Ovomucoid | 0.0 | 0.0 | 0.0 | − |
Alder | 4.0 | 9.1 | 6.9 | 0.45 | Rice | 0.0 | 0.0 | 0.0 | − |
Black birch | 4.0 | 9.1 | 6.9 | 0.45 | Tuna, mackerel, salmon | 0.0 | 0.0 | 0.0 | − |
Mugwort | 4.0 | 3.0 | 3.5 | 0.84 | Latex | 0.0 | 0.0 | 0.0 | − |
Notes:P < 0.05*, P < 0.01** between ACO and non-ACO COPD groups. Specific IgE was judged as positive when the class was equal to or greater than 1.
Abbreviations: ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease; D. pteronyssinus, Dermatophagoides pteronyssinus.
As the diagnostic criteria for ACO included FeNO and blood eosinophil count, in addition to IgE levels, we compared the utility of those biomarkers in ACO diagnosis by the ROC curve analysis. Although there were no significant relationships between those biomarkers (Additional File 5), the area under the curve for ACO diagnosis was comparable among three biomarkers: 0.711 for blood eosinophil count, 0.705 for total IgE, and 0.686 for FeNO (Fig. 4). The best cutoff value for diagnosis was 234 count/µl for blood eosinophils, 158 IU/mL for serum total IgE, and 31.0 ppb for FeNO.
The contribution of blood eosinophils, FeNO, and IgE was analyzed to further determine the relative importance of the different biomarkers in ACO diagnosis. In univariate analysis, the criteria, except for blood eosinophils, significantly contributed to ACO diagnosis (data not shown). Concerning IgE factors, all of the following criteria significantly contributed to ACO diagnosis: total IgE > 100 IU/mL, positive for house dust-specific IgE, and positive for D. pteronyssinus-specific IgE. In the three models for multivariate analyses (Table 3), all IgE criteria significantly contributed to ACO diagnosis, in addition to FeNO > 35 ppb criterion.
Table 3
Multivariate analysis of biomarkers for the diagnosis of ACO
| | OR | CI | P value |
Model 1 | Blood eosinophils > 300 µl | 2.63 | 0.580 | 11.901 | 0.2 |
FeNO > 35 ppb | 14.88 | 2.747 | 80.581 | < 0.01** |
IgE > 100 IU/mL | 7.72 | 1.897 | 31.460 | < 0.01** |
Model 2 | Blood eosinophils > 300 µl | 3.21 | 0.729 | 14.176 | 0.12 |
FeNO > 35 ppb | 8.33 | 1.891 | 36.727 | < 0.01** |
House dust IgE positive | 4.62 | 1.131 | 18.835 | 0.027* |
Model 3 | Blood eosinophils > 300 µl | 3.67 | 0.842 | 15.971 | 0.076 |
FeNO > 35 ppb | 8.10 | 1.848 | 35.511 | < 0.01** |
D. pteronyssinus IgE positive | 4.05 | 0.971 | 16.876 | 0.047* |
Notes: Specific IgE was judged as positive when the class was equal to or greater than 1.
Abbreviations: CI, confidence interval; D. pteronyssinus, Dermatophagoides pteronyssinus; FeNO, fraction of exhaled nitric oxide; IgE, immunoglobulin E; OR, odds ratios.