Change in inflammation in out-patient COPD patients from stable phase to a subsequent exacerbation

Figures & data

Table 1 Patient characteristics of the patients who had an exacerbation during the trial (n = 45), and of the total study population (n = 114)

	Patients with exacerbation	Total study population
Male/female	37/8	93/21
Age, yearsa	65 (58–71)	64 (59–71)
Smoked, pack-yearsa	38 (26–49)	40 (27–51)
Smoking status, current/ex	21/24	47/67
Body mass index, kg/m^2a	25 (24–28)	26 (24–28)
FEV1, % pred a	61 (48–73)	63 (52–73)
FEV1/IVC, %	44 (38–53)	63 (51.7–72.7)
Reversibility, % of preda	8.9 (5.3–11.0)	8.9 (5.5–11.8)
CCQ-scorea	1.7 (1.3–2.1)	1.7 (1.3–2.6)

a Median (interquartile range).

Abbreviations: n, number; pred, predicted; CCQ, Clinical COPD Questionnaire.

Table 2 Cellular inflammatory parameters

	Stable	Exacerbation
Sputum
Total cells × 10^6/mL	7.9 (2.1–19.2)	9.0 (4.0–29.8)*
Eosinophil, %	2.7 (0.8–5.8)	2.8 (0.8–4.8)
Eosinophil × 10^6/mL	0.2 (0.1–0.4)	0.3 (0.1–0.7)*
Neutrophils, %	71.7 (65.3–80.0)	72.0 (62.1–86.1)
Neutrophils × 10^6/mL	5.8 (1.5–13.4)	6.1 (2.1–24.1)*
Macrophages, %	20.7 (14.5–26.8)	17.7 (10.1–24.9)
Macrophages × 10^6/mL	1.4 (0.5–3.7)	2.1 (0.6–4.1)
Lymphocytes, %	0.3 (0.0–1.3)	0.8 (0.3–1.3)*
Lymphocytes × 10^6/mL	0.02 (0.00–0.10)	0.07 (0.03–0.20)*
Blood
Leukocytes × 10^9/mL	6.6 (6.0–8.2)	7.5 (5.9–9.1)*
Eosinophil, %	3.2 (2.2–5.8)	2.9 (1.9–5.8)
Eosinophil, × 10^9/mL	0.2 (0.2–0.3)	0.2 (0.1–0.4)
Neutrophils, %	61.0 (55.4–65.9)	63.0 (57.2–68.2)
Neutrophils, × 10^9/mL	4.2 (3.5–4.9)	4.6 (3.4–6.1)*
Monocytes, %	10.1 (8.3–11.0)	8.8 (7.9–10.8)
Monocytes, × 10^9/mL	0.6 (0.5–0.8)	0.7 (0.6–0.8)
Lymphocytes, %	24.4 (20.2–28.8)	22.9 (20.4–27.1)
Lymphocytes, × 10^9/mL	1.6 (1.4–2.0)	1.7 (1.4–2.0)

Note: 41 of 45 patients had an adequate sample for sputum cell differential analysis at both stable phase and exacerbation.

Median (interquartile range).

* significant difference (p < 0.05).

Table 3 Inflammatory biomarkers

	Stable	Exacerbation	p-value
Sputum
LTB-4 ng/mL	0.4 (0.2–0.7)	0.5 (0.3–1.1)	0.03
TNF-α pg/mL	1.6 (1.6–8.7)	4.6 (1.6–31.5)	0.37
IL-6 pg/mL	287 (183–637)	361 (164–783)	0.24
IL-8 μg/mL	1.5 (0.9–4.4)	2.0 (1.2–6.3)	0.07
MCP-1 pg/mL	119 (63–560)	210 (137–385)	0.01
MPO μg/mL	9.2 (5.3–31.0)	15.1 (8.4–56.0)	0.08
ECP μg/mL	85.4 (49.6–319.5)	187.0 (81.3–295.0)	0.03
Serum
IL-6 pg/mL	0.4 (0.1–4.0)	0.6 (0.1–9.9)	0.03
TNF-α pg/mL	4.9 (3.3–6.8)	4.5 (2.6–6.9)	0.90
sICAM ng/mL	109 (91–129)	118 (105–132)	0.13
CRP mg/L	3.4 (1.8–8.2)	3.6 (1.5–17.1)	0.07
Sputum/serum
Albumin ratio	1.7 (0.9–3.5)	2.0 (1.1–3.3)	0.03

Median (interquartile range). Analyzed for differences with paired t-tests.

Abbreviations: LTB4, leukotriene-B4; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein-1; MPO, myeloperoxidase; ECP, eosinophilic cationic protein; sICAM, soluble intercellular adhesion molecule; CRP, C-reactive protein.

Table 4a Differences between bacterial and non-bacterial exacerbations (sputum parameters)

Sputum	Cross-sectional values at exacerbation		Change from stable phase to exacerbation (%)
	Bacterial exacerbation	Non-bacterial exacerbation	Bacterial exacerbation	Non-bacterial exacerbation
total cell × 10^6/mL^††	51.1 (21.2–66.6)*	7.60 (2.94–22.9)	269 (44–3183)^‡	−5 (−36 to −95)
eosinophil × 10^6/mL^††	0.49 (0.22–1.30)	0.29 (0.06–0.79)	134 (−22 to −1460)	51 (−34 to −174)
neutrophil × 10^6/mL^††	47.4 (13.2–60.2)*	4.85 (1.91–17.2)	203 (35–760)^‡	4 (−39 to −87)
lymphocyte × 10^6/mL^‡†	0.22 (0.05–0.56)	0.07 (0.03–0.21)	949 (33–3815)	114 (−31 to −482)
ECP μg/mL^††	247 (139–1001)	187 (96.9–279)	137 (9–222)	50 (−20 to −183)
LTB4 ng/mL^‡‡	1.43 (0.71–2.01)*	0.43 (0.34–0.59)	164 (50–347)^‡	0 (−26 to −54)
MPO μg/mL^††	57.7 (30.4–89.9)*	12.6 (6.29–34.6)	349 (−2 to −955)	7 (−34 −102)
IL-6 pg/mL^††	680 (267–1251)	325 (153–733)	116 (52–610)^‡	−16 (−47 to −77)
IL-8 μg/mL^† †	7.78 (3.52–9.90)*	1.74 (0.92–4.47)	149 (0–444)	6 (−23 to −72)
TNF-a pg/mL^‡‡	56.8 (43.3–69.7)*	3.43 (1.60–7.73)	1580 (91–583)^‡	0 (−17 to −110)
MCP-1 pg/mL^††	283 (177–799)	194 (131–360)	141 (11–376)	41 (−32 to −171)
Sputum/serum albumin^‡‡	3.06 (2.44–3.65)	1.99 (1.14–3.11)	51 (15–85)	35 (−21 to −100)

Table 4b Differences between bacterial and non-bacterial exacerbations (blood parameters)

	Cross-sectional values at exacerbation		Change from stable phase to exacerbation (%)
	Bacterial exacerbation	Non-bacterial exacerbation	Bacterial exacerbation	Non-bacterial exacerbation
Blood/serum
leukocytes × 106/mL†^†	8.95 (7.95–10.3)*	6.60 (5.70–8.15)	24 (1–53)‡	2 (−5 to −18)
neutrophil × 106/mL†^†	6.47 (4.87–7.62)*	3.84 (3.34–5.63)	23 (5–69)	4 (−14 to −25)
sICAM μg/mL†‡	11.2 (10.3–13.9)	12.1 (10.5–13.3)	11 (−5 to −26)	4 (−3 to −13)
CRP mg/L‡‡	9.08 (4.56–26.2)	2.6 (1.4–15.3)	143 (39–740)‡	1 (−42 to −87)
IL-6 pg/mL‡‡	4.86 (1.22–10.0)	0.40 (0.10–10.7)	670 (119 to –2225)‡	0 (−2 to −126)
TNF-a pg/mL‡†	4.50 (2.33–7.36)	4.60 (2.61–7.00)	−7 (−23 to −21)	−11 (−21 to −13)

Notes: Data presented as median (IQR).

† Tested for differences by T-test;

‡ Tested for differences by Mann-Witney-U-test;

* p < 0.05 for the difference in cross-sectional values between bacterial and non bacterial exacerbations;

‡ p < 0.05 for the difference in percentage change from stable to exacerbation values between bacterial and non-bacterial exacerbations.

Abbreviations: LTB4, leukotriene-B4; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; IL-8, interleukin-8; MCP-1, monocyte chemo-attractant protein-1; MPO, myeloperoxidase; ECP, eosinophilic cationic protein; CRP, C-reactive protein.

Figure 1 Receiver operating characteristic curves for distinguishing a bacterial cause of exacerbations with inflammatory markers. On the curve, several biomarker concentration levels are presented, which provides an indication for optimal cut-off points and their corresponding predictive values. a) sputum tumor necrosis factor-α (TNF-α), b) blood C-reactive protein (CRP), c) sputum myeloperoxidase (MPO).