Acute exacerbation of COPD with pulmonary embolism: a new d dimer cut off value

Acute exacerbation of COPD with pulmonary embolism A new D dimer cut off value Egyptian Journal of Chest Diseases and Tuberculosis xxx (2017) xxx–xxx Contents lists available at ScienceDirect Egyptian[.]

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Acute exacerbation of COPD with pulmonary embolism: A new D-dimer

cut-off value

a

Respiratory Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

b

Respiratory Medicine Department, Faculty of Medicine, October 6 University, Giza, Egypt

a r t i c l e i n f o

Article history:

Received 17 December 2016

Accepted 29 January 2017

Available online xxxx

Keywords:

COPD

D-dimer

Pulmonary embolism

a b s t r a c t

Background: The clinical symptoms and signs of chronic obstructive pulmonary disease (COPD) exacer-bation and pulmonary embolism (PE) may overlap; D-dimer is proven to be higher in patients suffering from COPD exacerbation

Objective: To obtain a new cut-off value of D-dimer in subjects with exacerbation of COPD for prospecting those with PE and to avoid unnecessary imaging or contrast-enhanced investigations

Methods: The study included 83 male subjects with acute exacerbation of COPD and 30 healthy control subjects Data on serum D-dimer levels, calculated age-adjusted D-dimer levels, and revised Geneva score were obtained for all participants COPD subjects were divided into three subgroups according to the revised Geneva score values; those with high D-dimer levels underwent chest computed tomography with pulmonary angiography (CTPA)

Results: Comparisons among the three subgroups revealed significant differences regarding exacerba-tions, hospitalisations per year, revised Geneva score results, D-dimer values, and positive CTPA results While there were no significant differences between the three subgroups and the control group with respect to age, smoking, and BMI, the D-dimer values showed significant differences Receiver operating characteristic (ROC) curve was analysed to calculate the cut-off value of the serum D-dimer level

Conclusion: Given that D-dimer levels are high in subjects having COPD exacerbation, determining a new cut-off value is mandatory to rule out PE and avoid unnecessary further investigations

Ó 2017 The Egyptian Society of Chest Diseases and Tuberculosis Production and hosting by Elsevier B.V This is an open access article under the CC BY-NC-ND license (

http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction

The clinical symptoms and signs of chronic obstructive

pul-monary disease (COPD) exacerbation and pulpul-monary embolism

(PE) can be identical Thus, diagnosis of PE in patients having COPD

exacerbation is a clinical challenge[1,2] Moreover, many studies

have shown that COPD is an independent hazard for PE owing to

several causes such as systemic inflammation, polycythaemia,

and immobility[3] Patients with COPD have almost double the

risk of PE and other venous thromboembolic incidents than those

with no COPD [4] Besides, micro-thromboembolism may also

influence the clinical symptoms of an acute exacerbation of COPD; clinical manifestations of PE-like dyspnoea and chest pain are non-specific, and it could be underestimated in subjects with COPD throughout episodes of exacerbation, which results in worsening

of the disease and delay in anticoagulant therapy, thereby leading

to poor outcomes[1] As COPD diagnosis depends mainly on the clinical characteristics, PE requires objective verification The real incidence of PE in COPD subjects who are suspected to have PE var-ies from 19% to 29%[1,5] In those patients with COPD who have diminished gas exchange and pulmonary vascular reserve, PE leads

to an increased one-year mortality rate[6,7]

It was proved that D-dimer is still the most useful test to exclude venous thromboembolism (VTE) with a negative predic-tive value of 98% An elevated D-dimer level gives a more precise risk assessment for VTE when combined with a clinical scoring sys-tem like the revised Geneva score [8] Moderate- and high-risk revised Geneva scores should identify almost all cases of PE[6,9] D-dimer measurement is a simple and rather noninvasive test that

http://dx.doi.org/10.1016/j.ejcdt.2017.01.008

0422-7638/Ó 2017 The Egyptian Society of Chest Diseases and Tuberculosis Production and hosting by Elsevier B.V.

This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).

Peer review under responsibility of The Egyptian Society of Chest Diseases and

Tuberculosis.

⇑ Corresponding author at: Respiratory Medicine Department, Ain Shams

University, Cairo, 28C, Opera City Compound, Sheikh Zayed, P.O.: 12563 Giza,

Egypt.

E-mail address: heshamatef@med.asu.edu.eg (H.A AbdelHalim).

Contents lists available atScienceDirect

Egyptian Journal of Chest Diseases and Tuberculosis

j o u r n a l h o m e p a g e : w w w s c i e n c e d i r e c t c o m

Please cite this article in press as: H.A AbdelHalim, H.H AboElNaga, Acute exacerbation of COPD with pulmonary embolism: A new D-dimer cut-off value,

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rules out PE without the need for additional imaging procedures;

unfortunately, there is still a debate about the efficacy of

D-dimer tests in diagnosing PE in patients suffering from acute

exacerbation of COPD [10,11] Irrespective of the presence of

venous thromboembolism, D-dimer levels are increased in patients

with COPD exacerbation With the advent of chest computed

tomography with pulmonary angiography (CTPA), it is now

possible to visualise the clot by an imaging technique and reliably

confirm the diagnosis of PE in COPD subjects This technique

carries high risk in some patients who are allergic to the

contrast agent or who have renal impairment and considerable

risk of contrast nephropathy Additionally, radiation exposure

and the high cost of CTPA manoeuvre necessitates the search for

a tool to reduce the need for unnecessary radiological investigation

The aim of the current study was to define a cut-off value of

D-dimer for PE in COPD patients with acute exacerbation

Methods

The study included 83 male subjects who were recruited from

the inpatient departments of respiratory medicine of Ain Shams

University and October 6 University Hospitals The subjects were

diagnosed with acute exacerbation of COPD based on clinical

man-ifestations according to the Anthonisen criteria [14] COPD was

confirmed based on clinical manifestations and spirometry

accord-ing to the criteria of the 2015 Global Initiative for Obstructive Lung

Disease [15] Thirty healthy subjects were recruited from the

health checkup programme department of the October 6

Univer-sity Hospital as a control group

The exclusion criteria for the COPD group were as follows: any

coagulation disorders, haematological diseases, hepatic or renal

diseases, recent myocardial infarction, receiving oral

anti-coagulant or anti-platelet remedy, proven malignancies, any

colla-gen vascular diseases, and surgery or transfusion of blood or blood

component in the previous 3 months

The following data were collected from all participating

subjects: full medical histories; anthropometric data, including

body weight, height, and calculated body mass index (BMI);

smoking history; and other clinical examinations such as chest

radiography, electrocardiogram, arterial blood gas analysis,

pre- and post-bronchodilator spirometry, kidney function tests,

serum D-dimer, calculated age-adjusted D-dimer, revised Geneva

scores, and CTPA

Probability for pulmonary embolism was obtained from the

revised Geneva score for each subject, following which the

partic-ipants were classified into three groups:

Group 1, low probability (31 subjects); group 2, intermediate

probability (42 subjects); and group 3, high probability (10

subjects)

The study was approved by the review board of the respiratory

medicine department of Ain Shams University, and written

informed consent was obtained from all subjects

Spirometry

The spirometry tests were performed at Ain Shams University

using a Spirometrics ENC Flowmate machine (Spring Valley, NY,

USA) and at October 6 University using a Spirobank G-USB,

class II machine (MIR SRL, S/N 806734; Rome, Italy) The tests

were performed before and 20 min after b2-agonist inhalation

(9% solution of 5 mg/mL salbutamol), administered through a

nebulizer The pre- and post-bronchodilator spirometry

parame-ters were measured according to the American Thoracic Society/

European Respiratory Society standards in all subjects[16]

D-dimer assessment D-dimer level was measured using the Tina-quantÒ D-dimer Test system (Boehringer, Mannheim, Sandhofer Strasse 116, Mannheim, Germany), which is a particle-enhanced immune-turbidimetric assay

CTPA CTPA was performed on a 64-channel multi-detector row CT scanner (Aquillion; Toshiba medical systems, Milwaukee, Wis., USA); it was conducted within 48 h of admission

Pulmonary embolism was diagnosed by direct visualisation of embolic material in the case of total occlusion of the pulmonary arterial lumen, by an intraluminal filling defect encircled by intravascular contrast at any level of the pulmonary arteries, or when vessel truncation implied the presence of occlusion Data analysis

The data were compared using one-way ANOVA tests with post hoc Bonferroni corrections or Kruskal–Wallis H tests for multiple groups Simple correlations between variables were examined using the Pearson’s product correlation coefficient Receiver oper-ating characteristic (ROC) curve was used to calculate cut-off points, area under the curve (AUC), sensitivity, and specificity The Statistical Package for the Social Sciences (SPSS version 17; SPSS, Inc., Chicago, IL, USA) statistical software was used for all sta-tistical analyses All tests were considered significant at P < 0.05

Results Initially, 90 patients were enrolled, but 7 chose to discontinue the study Finally, we included 83 male subjects (mean age, 56.18 ± 11.15) with COPD and 30 healthy male control subjects (mean age, 54.90 ± 7.88 years) who completed the study.Table 1

shows the patients’ demographic data

COPD subjects were divided into three subgroups according to the revised Geneva score values Comparisons among the three subgroups revealed significant differences regarding exacerba-tions, hospitalisations per year, revised Geneva score results, D-dimer values, and positive CTPA results While there were no significant differences between the three subgroups and the control group regarding age, smoking, and BMI, the D-dimer values differed significantly (Table 2)

The ROC curve was plotted to calculate the cut-off value of the serum D-dimer level along with calculation of the area under the curve (AUC), sensitivity, and specificity (Fig 1)

Table 1 Data description and comparison between the total COPD subjects and control subjects.

Mean ± SD Control p Age (years) 56.18 ± 11.15 54.90 ± 7.88 0.56 Smoking (Pack Years) 31.10 ± 17.29 31.10 ± 4.75 0.999 BMI (kg/m 2

) 19.93 ± 1.999 19.35 ± 2.18 0.19

Exacerbations (/year) 3.24 ± 2.099 – – Hospitalizations (/year) 2.23 ± 1.92 – – r-Geneva score 4.98 ± 4.01 – – D-Dimer (lg/ml) 3123.39 ± 920.43 361.29 ± 77.88 <0.001 Data are presented as mean ± SD.

BMI; body mass index, CAT; COPD assessment test, mMRC; moidified Medical Research Council, r-Geneva score; revised Geneva score.

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As clinical signs and symptoms of exacerbated COPD and PE

overlap, it is crucial to establish reliable noninvasive or minimally

invasive techniques for the diagnosis of PE[17]

Some studies suggested that COPD may increase biological

thrombotic activities[2,4,6,18], and PE is part of the differential

diagnosis of an acute exacerbation of COPD[4] Some researchers

proved that COPD is a risk factor for PE because of immobility,

polycythaemia, and systemic inflammation [3] The systemic

inflammation associated with COPD, especially the acute

inflam-matory responses of COPD exacerbation, are a result of the

activa-tion of the endothelial-coagulative system and a prothrombotic

condition that alters the blood coagulation status[5]

In this prospective study, the 83 included male subjects with moderate-to-severe COPD were diagnosed with acute exacerba-tion COPD subjects with low probability revised Geneva scores and negative CTPA findings for pulmonary embolism, showed sig-nificantly higher D-dimer levels than the control subjects This finding was in agreement with Akpinar et al who found signifi-cantly higher D-dimer levels in COPD patients than control sub-jects [11] Further, Kampolis et al concluded that patients hospitalised for COPD exacerbation with low clinical probability for PE present with higher-than-normal D-dimer levels, even without PE [19] These results were not consistent with that of Hartmann et al who proposed that existence of COPD does not influence the diagnostic importance of D-dimer level[17] There-fore, the applications of D-dimer testing vary markedly among patients with and without COPD The presence of COPD likely affects the probability of obtaining a reliable test result, and hence,

a new cut-off value should be implemented to consider the cost-effectiveness of CTPA to rule out presence of pulmonary VTE[11] Further, previous studies confirmed higher D-dimer levels in older subjects, which is common in COPD patients [13] In our study, the mean ages of the control and COPD subjects with and without PE were not significantly different Therefore, the age effect, which may bias the study results was reduced Besides,

we used an age-adjusted D-dimer value for elderly patients CTPA is a valuable imaging technique for diagnosing PE, but its high financial cost, especially in developing countries, taken together with its adverse effects have to be considered prior to use in a patient suspected of having PE Previous research proved the prevalence of concealed renal impairment in COPD patients with apparently normal serum creatinine levels[12], which may increase the adverse effect of the contrast agent in those patients Therefore, several studies have attempted to find tools to minimise the necessity of using such techniques[1,10,11,17,20]

In the present study, the combination of low D-dimer levels with low probability on the revised Geneva score excluded the presence of PE in patients with COPD exacerbation This agreed with the study by Monika et al who concluded that the combina-tion of low/intermediate probability scores and negative D-dimer (<500 ng/mL) effectively ruled out PE in patients having acute or exacerbated lung disease[8]

Some studies such as by Kampolis et al.[19]suggested the need for assigning a novel cut-off value for D-dimer in patients with COPD exacerbation

Table 2

Data description and comparison between the 3 COPD subgroups and the control group.

Low probability Intermediate probability High probability Control p

Ƒ (%) 31 (37.3%) 42 (50.6%) 10 (12.0%) 30

Age (years) 53.58 ± 10.33 57.93 ± 11.62 56.90 ± 11.11 54.90 ± 7.88 0.32 Smoking (pack Years) 31.76 ± 16.28 31.12 ± 19.26 29.00 ± 11.97 31.10 ± 4.75 0.97 BMI (kg/ m 2

) 19.55 ± 1.77 19.88 ± 1.86 21.30 ± 2.75 19.35 ± 2.18 0.06 CAT 24.58 ± 8.43 21.71 ± 7.27 19.80 ± 9.34 – 0.17 *

mMRC 3.10 ± 1.42 3.62 ± 1.27 3.80 ± 1.14 – 0.17 *

Exacerbations (/year) 2.03 ± 1.30 3.69 ± 2.24 5.10 ± 1.37 – <0.01 *

Hospitalizations (/year) 1.06 ± 1.03 2.43 ± 1.56 5.00 ± 2.36 – <0.01 *

r-Geneva score 1.23 ± 1.15 5.79 ± 1.68 13.20 ± 1.55 – <0.01 *

D-dimer (lg/ml) 2584.39 ± 900.35 3266.52 ± 740.74 4193.10 ± 386.65 361.29 ± 77.88 <0.01 D-Dimer value

High (f (%)) 29 (93.5%) 34 (81%) 7 (70%) – <0.01 *

Low (f (%)) 2 (6.5%) 8 (19%) 3 (30%) 30 (100%) 0.92 CTPA (f (%))

Positive (f (%)) 3 (9.7%) 2 (4.8%) 6 (60%) – 0.31 *

Negative (f (%)) 28 (90.3%) 40 (95.2%) 4 (40%) – <0.01 *

Data are presented as mean ± SD or frequency (percentage).

Ƒ (%); frequency (percentage) BMI; body mass index, CAT; COPD assessment test, mMRC; moidified Medical Research Council, r-Geneva score; revised Geneva score, CTPA; Computerized Tomography of chest with Pulmonary Angiography.

*

Comparisons between the 3 COPD subgroups.

Fig 1 Receiver operating characteristic (ROC) curve shows the optimal cut-off

value of 2348lg/mL, area under the curve (AUC) of 0.836, sensitivity of 0.909, and

specificity of 0.778.

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On the other hand, Raviv et al retrospectively used a greater

D-dimer level in all subjects with suspected PE who are assessed in

emergency departments to evaluate the possibility of the

diagno-sis, without considering the existence of COPD They noticed the

cut-off value to be 900 ng/mL with a sensitivity of 94.4%[21] In

another study, the suggested cut-off value of D-dimer to rule out

PE in subjects with COPD exacerbation was 0.95 pg/mL (sensitivity

70%, specificity 71%)[3]

In the current study, the COPD patients who suffered from

co-morbidities that may cause elevation of D-dimer levels besides

the influence of COPD and PE, such as malignancies and connective

tissue diseases, were excluded, so that the study population could

be representative of all COPD subjects without co-morbidities

In the present work, a cut-off level of 2348lg/mL for D-dimer

was calculated for the participating COPD subjects; our results

show that PE can be excluded below this cut-off value, (in

combi-nation with low probability revised Geneva scores)

In conclusion, D-dimer levels are high in subjects having COPD

exacerbation, suggesting that a new cut-off value is mandatory In

this study cohort, a D-dimer value of 2348lg/mL was determined

as the new cut-off value for excluding PE Moreover, combining

D-dimer values with revised Geneva score is helpful to exclude

PE and avoid unnecessary further investigations

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