Predicting In-Hospital Treatment Failure (≤7 days) in Patients with COPD Exacerbation Using Antibiotics and Systemic Steroids

Figures & data

Figure 1. Study flow diagram.

Table 1. Baseline characteristics of enrolled patients according to treatment failure criteria

Variables	All patients (N = 110)	Patients With In-Hospital Treatment Success (N = 94)	Patients With In-Hospital Treatment Failure (N = 16)	P
Male, %	93.6	93.5	93.8	0.976
Age, years	70.5 ± 9.6	70.2 ± 9.3	72.1 ± 11.5	0.471
FEV1, liters	1.07 (0.90; 1.55)	1.09 (0.92; 1.52)	0.88 (0.59; 1.25)	0.036
FEV1, % predicted	45 (36; 58)	49 (36; 60)	39 (23.7; 48.5)	0.033
COPD-GOLD stage: A/B/C/D, %	1.1/36.6/45.6/16.7	1.3/39.2/45.6/13.9	0/18.1/45.5/36.4	0.238
mMRC dyspnea grade: I/II/III/IV	4.5/33.6/53.6/8.3	5.3/37.2/51.1/6.4	0/12.5/68.8/18.8	0.082
LTOT, %	20.9	19.1	31.3	0.271
Rate of previous events (events per patient)†
Exacerbations	1.74	1.60	2.50	0.002
Exacerbations requiring hospitalizations	0.94	0.89	1.44	0.032
Chronic co-morbidities, %
Congestive heart failure	25.7	23.4	40	0.172
Chronic renal failure	0.9	1.1	0	0.679
Diabetes	15.5	14.9	18.8	0.693
Non-cirrhotic liver disease	1.8	2.1	0	0.556
Neurologic disease	8.2	9.6	0	0.196
Non-active cancer	8.2	7.4	12.5	0.495
Use of inhaled medications, %
SABA (salbutamol/terbutaline, % of users)	71.3 (94.4/5.6)	69.6 (93.3/6.7)	81.3 (100/0)	0.340
LABA (formoterol/salmeterol, % of users)	64.5 (29.2/70.8)	66.3 (27.6/72.4)	53.3 (42.9/57.1)	0.330
Anticholinergics (ipratropium/tiotropium, % of users)	69.2 (41.6/58.4)	71.4 (38.8/61.2)	56.3 (60/40)	0.225
ICS (budesonide/fluticasone, % of users)	63.2 (40/60)	63 (39.3/60.7)	64.3 (44.4/55.6)	0.928
Use of theophylline, %	7.5	6.5	13.3	0.352
Vaccination, %
Anti-pneumococcal	23.5	24.7	15.4	0.459
Flu	69.6	68.5	76.9	0.539

Data are shown as percentage of patients, mean ± SD or median (1^st quartile; 3^rd quartile), unless otherwise stated. Percentages calculated on non-missing data.

†In a period of 1 year previous the hospitalization index.

Abbreviations: FEV₁ indicates forced expiratory volume in the 1^st second; mMRC, modified medical research council dyspnea scale; LTOT, long-term oxygen therapy; SABA, short action β₂ agonist; LABA, long action β₂ agonist; ICS, inhaled corticosteroids.

Table 2. Clinical, microbiological and antibiotic-related variables

Variables	All patients	Patients With In-Hospital Treatment Success	Patients With In-Hospital Treatment Failure	P
Temperature, °C	37 (36.5; 37.5)	37 (36.5; 37.5)	36.7 (36.2; 37.4)	0.473
Chills, %	30.0	31.9	18.8	0.288
Cough, %	79.1	83	56.3	0.015
Pleuritic pain, %	11.8	12.8	6.3	0.455
Dyspnea, %	97.3	96.8	100	0.469
Characteristics of sputum, % Absence/mucous/purulence	10/9.1/80.9	9.6/9.6/80.9	12.5/6.3/81.3	0.868
Anthonisen criteria, % Type I/type II/type III	40.6/31.1/28.3	42.2/30/27.8	31.3/37.5/31.3	0.702
Respiratory rate, breaths per minute	24 (20; 30)	24 (20; 30)	27.5 (20; 30.5)	0.202
Heart rate, beat per minute	95 (82.5; 105)	95 (82.5; 104)	100.5 (81; 123.7)	0.224
Systolic arterial pressure, mmHg	149.5 (131.2; 165.7)	150 (132.5; 166.5)	149 (114; 165)	0.355
Diastolic arterial pressure, mmHg	80 (71; 90)	80 (71; 90)	80 (71; 86)	0.719
pH	7.41 (7.38; 7.43)	7.41 (7.38; 7.43)	7.37 (7.35; 7.40)	0.087
PCO2, mmHg	46 (40.6; 53.1)	46 (39; 52)	50 (46; 60)	0.086
PaO2/FiO2	266 (233; 280)	266 (238; 280)	233 (214.2; 328)	0.641
HCO^3, mmol/L	28 (25.8; 31.7)	28 (25; 31.7)	28.9 (27; 32)	0.425
BE, mmol/L	3 (1.3; 5.8)	3 (1.3; 5.7)	3.7 (1.9; 6.2)	0.574
Bacterial pathogen identified, n (%)*	35 (100)	25 (26.6)	10 (62.5)	0.004
Bacterial etiology, n (%)**				0.599
Streptococcus pneumoniae	5 (14)	3 (12)	2 (20)
Staphylococcus aureus	3 (9)	3 (12)	0 (0)
Haemophilus influenzae	8 (23)	6 (24)	2 (20)
Haemophilus parainfluenzae	4 (11)	3 (12)	1 (10)
Pseudomonas aeruginosa	7 (20)	4 (16)	3 (30)
Moraxella catarrhalis	3 (9)	2 (8)	1 (10)
Chlamydia pneumoniae	1 (3)	1 (4)	0 (0)
Enterobacteriaceae†	3 (9)	3 (12)	0 (0)
Legionella pneumophila	1 (3)	0 (0)	1 (10)
Class of antibiotics used, %				0.043
Penicillins, n (%) Amoxicillin/Clavulanate	47 (42.7)	35 (37.2)	12 (75)
Cephalosporins, n (%) Ceftriaxone, Cefotaxime, Cefuroxime and Cefepime	13 (11.8)	12 (12.8)	1 (6.3)
Fluoroquinolones, n (%) Ciprofloxacin, Moxifloxacin, Levofloxacin	45 (40.9)	42 (44.7)	3 (18.7)
Macrolides, n (%) Azithromycin, Clarithromycin	5 (4.5)	5 (5.3)	0 (0)

Data are shown as number of patients (percentage), mean ± SD or median (1^st quartile; 3^rd quartile), unless otherwise stated. Percentages calculated on non-missing data.

*Percentage calculated in total patients for each group.

**Percentage calculated in total patients with etiological diagnosis confirmed for each group.

†Including Escherichia coli and Proteus mirabilis.

Abbreviations: BE indicates base excess; HCO³, serum bicarbonate; PaCO₂, partial arterial carbon dioxide pressure; PaO₂/FiO₂, ratio of partial arterial oxygen pressure to the fraction of inspired oxygen.

Table 3. Laboratory and serum biomarker measurements

Variables	Sample	Patients With In-Hospital Treatment Success	Patients With In-Hospital Treatment Failure	P
Assessment at day 1
Total leukocytes, counts x 10^9/L	n = 109	10.1 (7.6; 13.2)	9.7 (8.1; 11.3)	0.637
Hematocrit, %	n = 109	45 (41.2; 49)	44.5 (41.5; 46.6)	0.513
Glucose, mg/dL	n = 108	126.6 (108; 159)	126.3 (99.2; 133.5)	0.528
Creatinine, mg/dL	n = 109	0.9 (0.8; 1.1)	1 (0.7; 1.3)	0.737
Sodium, mmol/L	n = 109	136.6 (134; 138.9)	135 (131; 138.7)	0.245
Potassium, mEq/L	n = 109	4.4 (4; 4.8)	4.2 (3.5; 4.9)	0.480
AST, IU/L	n = 88	22 (18; 30)	25 (19; 35)	0.682
ALT, IU/L	n = 89	18.5 (13.6; 25.7)	17 (11; 20)	0.284
Total bilirubin, mg/dL	n = 75	0.8 (0.6; 1.2)	0.6 (0.6; 0.9)	0.456
CPK, mcg/L	n = 84	74 (43.3; 115.1)	107.5 (63.3; 216)	0.252
LDH, IU/L	n = 88	363.5 (247.7; 474.2)	278 (198; 435.2)	0.291
CRP (mg/dL)	n = 109	6.7 (1.65; 15.85)	16.1 (7.37; 27.99)	0.007
PCT (ng/mL)	n = 109	0.09 (0.09; 0.27)	0.32 (0.14; 0.66)	0.009
TNF-α (pg/mL)	n = 108	10 (6; 20)	19 (11.2; 40.7)	0.009
IL-1 (pg/mL)	n = 109	4 (0; 11)	6.5 (3; 20.2)	0.081
IL-6 (pg/mL)	n = 109	9 (0; 78.5)	51 (3.5; 123.7)	0.134
IL-8 (pg/mL)	n = 108	2 (0; 14.5)	12 (2.2; 45.5)	0.044
IL-10 (pg/mL)	n = 109	0 (0; 7.7)	7 (0.5; 17.2)	0.020
Assessment at day 3
CRP (mg/dL)	n = 108	1.22 (0.30; 3.60)	2.80 (1.12; 6.17)	0.043
PCT (ng/mL)	n = 108	0.09 (0.09; 0.29)	0.09 (0.09; 0.78)	0.386
TNF-α (pg/mL)	n = 108	11 (6.5; 22.5)	17 (8.2; 22.7)	0.242
IL-1 (pg/mL)	n = 108	4 (0; 8)	6 (2.2; 33.2)	0.136
IL-6 (pg/mL)	n = 108	6 (0; 28)	10 (0; 56)	0.659
IL-8 (pg/mL)	n = 105	0 (0; 3)	2 (0; 21)	0.049
IL-10 (pg/mL	n = 107	9 (0; 18.2)	11.5 (0.5; 34.7)	0.331

Data are shown as median (1^st quartile; 3^rd quartile).

Abbreviations: ALT indicates alanine transaminase; AST, aspartate transaminase; CPK, creatine phosphokinase; CRP, C-reactive protein; IL, interleukin; LDH, Lactate dehydrogenase; PCT, procalcitonin; TNF-α, tumour necrosis factor-alpha; IL, interleukin.

Table 4. Significant univariate and multivariate logistic regression analyses predicting the probability of early in-hospital treatment failure

	Univariate			Multivariate*
Variables	OR	95% CI	P	OR	95% CI	P
No of previous exacerbations† (≥2 vs. ≤1)	3.55	1.05 to 11.97	0.041	–	–	–
mMRC (+1 point)	3.10	1.25 to 7.66	0.014	–	–	–
Cough at admission (Yes vs. No)	0.26	0.08 to 0.81	0.020	0.20	0.05 to 0.75	0.018
Class of antibiotics used (Penicillins or Cephalosporins vs. Fluoroquinolones or Macrolides)	4.33	1.15 to 16.20	0.029	5.63	1.26 to 25.07	0.023
CRP day 1 (+1 mg/dL)	1.08	1.02 to 1.13	0.003	1.07	1.01 to 1.13	0.014
TNF-α day 1 (+1 pg/mL)	1.06	1.02 to 1.10	0.002	–	–	–
IL-1 at day 3 (+1 pg/mL)	1.02	1.00 to 1.04	0.043	–	–	–
IL-8 at day 3 (+1 pg/mL)	1.03	1.00 to 1.07	0.034	–	–	–

*Hosmer and Lemeshow test: p = 0.723.

†In a period of 1 year previous the hospitalization index.

Abbreviations: OR indicates odds ratio; CI, confidence interval; mMRC, modified medical research council dyspnoea scale; CRP, C-reactive protein; TNF-α, tumour necrosis factor-alpha; IL, interleukin.

Table 5. Internal validation of prediction model using nonparametric bootstrap technique

Variables	Original	Bias	SE	95% BCa CI
Cough at admission (Yes vs. No)	-1.594	-0.207	1.604	-3.434 to -0.222
Class of antibiotics used
(Penicillins or Cephalosporins vs. Fluoroquinolones or Macrolides)	1.729	0.931	4.009	0.270 to 20.073
CRP day 1 (+1 mg/dL)	0.073	0.008	0.039	0.013 to 0.171

Abbreviations: SE indicates standard error; BCa, adjusted bootstrap confidence interval; CI, confidence interval; CRP, C-reactive protein.

Table 6. Clinical outcomes evaluated during hospitalization and in the follow-up

Variables	Patients With In-Hospital Treatment Success	Patients With In-Hospital Treatment Failure	p
LOS†, days	7 (6; 8)	13 (7.5; 25)	<0.001
Mental status alteration†	6.5	25	0.018
Duration of antibiotic therapy†, days	6 (4; 8)	11 (8; 16)	<0.001
Total doses of systemic steroids†, mg	300 (212; 396)	456 (264; 1200)	0.033
Mortality, %
On day 30	1.1	18.1	0.001
On day 90	2.2	25	<0.001
At 1 year	14.0	40	0.014
Re-hospitalization for a new episode, %
In a period of 30 days	18.3	46.2	0.022
In a period of 90 days	20.4	53.8	0.009
In a period of 1 year	25.8	54.5	0.047

Data are shown as percentage of patients or median (1^st quartile; 3^rd quartile), unless otherwise stated. Percentages calculated on non-missing data.

†Calculated during total period of hospitalization.

Abbreviations: LOS indicates length of stay in hospital.

Table 7.  Clinical evaluation and outcomes according class of antibiotics

Variables	Patients Using Penicillins or Cephalosporins (N = 60)	Patients Using Fluoroquinolones or Macrolides (N = 50)	P
Bacterial pathogen identified (N = 35), n (%)*	23 (38.3)	12 (24)	0.108
Documented antibiotic resistance (N = 23)			<0.001
To the same class of antibiotics used, n (%)	14 (60.8)	0 (0)
To other class of antibiotics, n (%)	0 (0)	5 (21.8)
To the same and other classes of antibiotics, n (%)	3 (13)	1 (4.4)
Patients in who class of antibiotics was changed (N = 8)†			0.018
With penicillins or cephalosporins, n (%)	–	1 (12.5)
With fluoroquinolones or macrolides, n (%)	6 (75)	–
With aminoglycosides, n (%)§	1 (12.5)	0 (0)
PaO2/FiO2	266 (247.6; 300)	259.5 (223; 279.2)	0.087
CRP at day 1, mg/dL	13 (3.21; 18.7)	5 (1.15; 12)	0.017
CRP at day 3, mg/dL	1.45 (0.5; 5.7)	1.45 (0.35; 3.2)	0.349
PCT at day 1, ng/mL	0.15 (0.09; 0.47)	0.09 (0.09; 0.21)	0.024
PCT at day 3, ng/mL	0.09 (0.09; 0.44)	0.09 (0.09; 0.18)	0.631
LOS†, days	6 (4; 11)	6 (4; 8.2)	0.671
Mental status alteration‡, %	11.9	6	0.291
Duration of antibiotic therapy‡, days	7 (4; 10)	6 (4; 9)	0.403
Total doses of systemic steroids‡, mg	340 (220; 471)	300 (230; 390)	0.490

Data are shown as number of patients (percentage), or median (1^st quartile; 3^rd quartile), unless otherwise stated. Percentages calculated on non-missing data.

*Percentage calculated in total patients for each group.

†During period of evaluation of in-hospital treatment failure (from day 1 to day 7).

§Used for a Pseudomonas aeruginosa multi-antibiotic resistance.

‡Calculated during total period of hospitalization.

Abbreviations: CRP indicates C-reactive protein; PCT, procalcitonin; LOS, length of stay in hospital.