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Prevalence of pulmonary embolism in patients with acute exacerbations of COPD: A systematic review and meta-analysis

Journal logoUnlabelled imageAmerican Journal of Emergency Medicine 50 (2021) 606-617

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American Journal of Emergency Medicine

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Prevalence of pulmonary embolism in patients with acute Exacerbations of COPD: A systematic review and meta-analysis

Ryota Sato a,?, Daisuke Hasegawa b, Kazuki Nishida c, Kunihiko Takahashi d, Mary Schleicher e, Neal Chaisson a

a Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH, USA

b Department of Internal Medicine, Mount Sinai Beth Israel, Icahn School of Medicine, NY, USA

c Department of Biostatistics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan

d Department of Biostatistics, M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan

e The Cleveland Clinic Floyd D. Loop Alumni Library, Cleveland Clinic, OH, USA

a r t i c l e i n f o

Article history:

Received 26 July 2021

Received in revised form 7 September 2021 Accepted 13 September 2021

Keywords:

AECOPD

Chronic obstructive pulmonary disease Venous thromboembolism

Pulmonary embolism

a b s t r a c t

Study objective: Identification of pulmonary embolism (PE) in patients with acute exacerbation of chronic ob- structive pulmonary disease (AECOPD) carries significant Therapeutic implications. We aimed to investigate the prevalence of PE in patients with AECOPD.

Methods: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, and Embase. We registered the protocol at the PROSPERO (CRD42021230481). Two authors independently evaluated whether titles and ab- stracts met the eligibility criteria, which were as follows: (1), prospective study or cross-sectional study in case the protocol for workup of PE was specified in advance, (2) patients with AECOPD aged >= 18 years, and (3) inves- tigated the prevalence of PE or venous thromboembolism . Two authors independently extracted the se- lected patient and study characteristics and outcomes. We presented the results of all analyses with the use of random-effects models. The primary outcome was the prevalence of PE. Results: We included 16 studies (N = 4093 patients) in this meta-analysis. The prevalence of PE in patients with AECOPD was 12% [95% confidence interval (CI), 9 to 16%]. Substantial heterogeneity was observed (I2 = 94.8%). The pooled mortality was higher in patients with PE than those without (odds ratio 5.30, 95%CI: 2.48-11.30, p– value < 0.001).

Conclusion: In this meta-analysis, the prevalence of PE in patients with AECOPD was 12% and the mortality of pa- tients with PE was higher than those without. This suggests an acute necessity to develop validated Diagnostic strategies for identifying PE in patients with AECOPD.

(C) 2021

  1. Introduction

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide [1]. The clinical course of COPD is often com- plicated by acute exacerbation of COPD (AECOPD) that causes frequent visits to emergency rooms [2], hospitalizations [3], lower quality of life [4], and ultimately higher risk of death [5]. The association between

Abbreviation list: PE, pulmonary embolism; VTE, venous thromboembolism; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CTPA, Computed tomography pulmonary angiography; DVT, deep venous thromboembolism; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; MOOSE, Meta- analysis of Observational Studies in Epidemiology; CIs, confidence intervals; IQRs, inter- quartile ranges; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

* Corresponding author at: 9500 Euclid Avenue, Cleveland, OH 44195, USA.

E-mail address: [email protected] (R. Sato).

AECOPD and increased airway and systemic inflammation has been well-established [6,7].

It is well known that inflammation is associated with abnormal co- agulation. Hence, patients with COPD are at a higher risk than the gen- eral population for Thromboembolic events such as pulmonary embolism (PE) and venous thromboembolism [8]. A previous meta-analysis reported that the prevalence of PE in patients with AECOPD was 16.1%. Two-thirds of these had a clear indication for anti- coagulant therapy [9]. Several new, well-conducted studies have been published in the interval since this meta-analysis was performed. Given the preponderance of new data, including some which suggests that Asian populations have a lower prevalence of PE than Western pop- ulations [10-12], an opportunity to reevaluate the prevalence and pat- terns of PE in patients with AECOPD exists.

In this systematic review and meta-analysis, we sought to determine the pooled prevalence of PE in patients with AECOPD, and determine

https://doi.org/10.1016/j.ajem.2021.09.041

0735-6757/(C) 2021

R. Sato, D. Hasegawa, K. Nishida et al. American Journal of Emergency Medicine 50 (2021) 606617

the sensitivity of predictive models to diagnose acute PE in patients with AECOPD.

  1. Materials and methods
    1. Protocol

This study followed the PRISMA (Preferred Reporting Items for Sys- tematic Reviews and Meta-Analyses) statement [13] and MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines [14]. We registered the protocol of this systematic review and meta- analysis in PROSPERO (CRD42021230481).

    1. Search strategy

A comprehensive search of Medline, Embase, and the Cochrane Cen- tral Register of Controlled Trials was performed on 01/18/2021. The fol- lowing keywords were used for the search strategy: pulmonary embolism, venous thromboembolism, emphysema, and chronic ob- structive pulmonary disease. Details of our search strategy are shown in Supplementary Table 1.

    1. Study selection

We used EndNote (Thomson Reuters, Toronto, Ontario, Canada) to store citations and to remove duplicates. Two independent authors (R.S. and D.H.) screened titles and abstracts. Then, full texts were re- trieved and reviewed. The first and second screenings were performed using COVIDENCE website (https://www.covidence.org). In cases of dis- agreement between these two authors, we discussed in detail until a consensus was reached. Articles not written in English and articles of conference proceedings were excluded.

    1. Inclusion criteria

Inclusion criteria were as follows:

  1. Study type: Prospective design or cross-sectional design (in cases where the protocol for evaluation of PE was specified in advance).
  2. Patient population: Patients admitted for AECOPD
  3. Outcome: The prevalence of PE or VTE
    1. Data extraction

The data was extracted by two independent authors (R.S. and D.H.) using a standardized form. In the case of multiple publications from the same institutions or authors, the study period, type of population, interventions, and protocol registration were reviewed to avoid dupli- cate inclusion of a study population. Included studies’ and patients’ characteristics were collected.

    1. The primary and secondary outcomes

The primary outcome for our meta-analysis was the pooled preva- lence of PE in patients with presumed AECOPD. Secondary outcomes in- cluded location of PE in the lung, prevalence of VTE (defined as deep venous thromboembolism (DVT) of extremities or PE), and the compar- ison of in-hospital mortality between patients with and without PE. Based on concerns that Asian populations may have lower prevalence of PE compared to Western populations [10-12], we also performed a subgroup analysis to determine if the location where a study was con- ducted (Asian vs. non-Asian countries) influenced the prevalence of PE in this population. Finally, we performed a subgroup analysis to eval- uate whether computed tomography pulmonary angiography was performed in all patients or not.

    1. Quality assessment

Two authors (R.S. and D.H.) independently assessed the quality of included studies using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) score and the Newcastle-Ottawa Scale [15,16]. In cases where disagreement existed, these authors discussed until a consensus was reached.

    1. Statistical analysis

A double arcsine transformation was used to stabilize the variance for the pooled prevalence of PE in patients with AECOPD [17]. We ana- lyzed using the random-effect model. This analysis was performed using metaprop, a program in STATA software [18]. Heterogeneity be- tween subgroups were also evaluated using metaprop. The pooled prev- alence values were expressed with 95% confidence intervals (CI) and p– values. Statistical heterogeneity was calculated using Mantel-Haenszel chi-square test and I2 statistic as the proportion of total variability. Pub- lication bias was assessed by evaluating the symmetry of funnel plots for the mortality using both Begg’s rank correlation test and Egger’s lin- ear regression test. All of these analyses were performed using STATA software, V.14.0 (Stata Corporation, College Station, Texas, United States), and Comprehensive Meta-Analysis software version 3 (Biosta, Inc., New Jersey, USA) as appropriate. P-value of <0.05 was considered to be of statistical significance.

  1. Results
    1. Search results

Our search strategy returned 2832 articles (Medline: 672, Embase: 1950, Cochrane CENTRAL: 210). After removing duplicate titles, 2433 articles remained. Based on title and abstract review, 2377 articles were irrelevant to this study. The full texts of the remaining 56 studies were reviewed and assessed for eligibility. Of these, 20 studies [19-38] were included in our meta-analysis. Sixteen [21,22,24,27-38] studies were relevant to the prevalence of PE (4093 patients) and 17 studies [19-33,36-38] were relevant to the prevalence of VTE (4613 patients) (Fig. 1). We detected no evidence of publication bias when we assessed studies by funnel plot (Supplemental Fig. 1), Begg’s rank correlation test (p-value = 0.07), or by Egger’s regression test (p-value = 0.26).

    1. Characteristics of included studies

Included studies were published between 1998 and 2021. Charac- teristics of the included studies are summarized in Table 1. Characteris- tics of included patients are summarized in Table 2. Mean/median age of included studies ranged from 49 to 73 years old with 55-100% males. Five studies [23,27,32,35,38] reported the revised Geneva score [39]. Within these studies, the risk stratification was as follows: 290/1252 (23.2%) were low-risk, 913/1252 (72.9%) were intermediate-risk, and 49/1252 (3.9%) were high-risk. Three studies [27,32,37] reported Wells criteria [40]. Within these studies, 180/365 (49.3%) were low- risk, 170/365 (46.6%) were intermediate-risk, and 15/365 (4.1%) were high-risk. Studies that reported the score only in patients with con- firmed PE or VTE, or that did not report probabilities based on a low-, in- termediate, or high-risk classification scheme were not included in these numbers. Inclusion and exclusion criteria of included studies were shown in Supplemental Table 2. Clinical symptoms of included pa- tients were summarized in Supplemental Table 3. Patients with PE had significantly lower prevalence of increased sputum [odds ratio (OR):

0.36 (95%CI, 0.18-0.71, p-value = 0.003], while there were no signifi-

cant differences in other clinical symptoms between patients with PE and those without.

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R. Sato, D. Hasegawa, K. Nishida et al. American Journal of Emergency Medicine 50 (2021) 606617

    1. Outcomes

Outcomes were summarized in Table 3. Of the 4093 included pa- tients, the pooled prevalence of PE was 12% [95% confidence interval (CI): 9-16%] (Fig. 2). Six studies [23,24,27,32,33,38] reported the local- ization of PE as follows: main pulmonary trunk 28.0% (46/164), lobar ar- tery 11.0% (18/164), segmental branches 35.4% (58/164), and subsegmental branches 25.6% (42/164). The association between loca- tions of PE and the clinical outcomes such as the mortality was not re- ported. Of the 4613 patients included in the study, the pooled prevalence of VTE was 13% (95%CI: 10-17%) (Fig. 2). There were 6 and 8 studies that performed diagnostic tests for PE and VTE within 24 h of hospital admission. Among these 6 studies [24,27,30-33] and 8 stud- ies [20,24,25,27,28,31-33], the pooled prevalences were 18% (95% CI: 8-29%) and 14% (95% CI: 6-22%), respectively (Supplemental Fig. 2).

The prevalence of PE and VTE in studies conducted in Asian countries did not differ from those in non-Asian countries (PE: 10% vs. 13%, p-value = 0.41, VTE: 14% vs. 13%, p-value = 0.83, respectively). The prevalence of PE and VTE in studies where CTPA was performed in all

included patients was significantly higher than in studies that only per- formed CTPA for a select population (PE: 23% vs. 6%, p-value < 0.001, VTE: 29% vs. 9%, p-value < 0.001, respectively) (Supplemental Figs. 3

and 4).

In the six studies [27,28,32,33,37,38] that reported mortality, the presence of PE in patients with presumed AECOPD was associated with significantly higher mortality (OR: 5.30, 95%CI: 2.48-11.30, p– value < 0.001) (Supplemental Fig. 5).

    1. Quality assessment of included studies

We evaluated the STROBE scores of included studies (Table 1). The scores ranged from 9 to 22 points. We also evaluated the Newcastle- Ottawa Scales (NOS) (Supplemental Table 4) for included studies. The scores using this scale ranged from 4 to 7 points. Since this study was designed to investigate disease prevalence, some of the components of the NOS (eg. selection of non-exposed cohort and ascertainment of ex- posure) remained unscored for all included studies.

Image of Fig. 1

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart. Identification and selection of studies for inclusion.

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R. Sato, D. Hasegawa, K. Nishida et al. American Journal of Emergency Medicine 50 (2021) 606617

Image of Fig. 2

Fig. 2. Forest plot of prevalence of PE and VTE: Prevalence of PE and VTE in patients with AECOPD are shown. PE: pulmonary embolism, VTE: venous thromboembolism, AECOPD: acute exacerbation of chronic obstructive pulmonary disease.

  1. Discussion

Typical symptoms of PE include dyspnea, chest pain, and signs of Right heart failure [41]. Because these symptoms can mimic AECOPD, PE in this population is notoriously difficult to diagnose on the basis of history or physical examination alone. In our meta-analysis, we demon- strated that the prevalence of PE in patients suspected of having AECOPD was 12% and that of VTE was 13%. These findings suggest a lower prevalence of PE and DVT than a prior meta-analysis published in 2017 which included a much smaller cohort [9]. Even though most of the studies worked up for PE and VTE in inpatient settings, the pooled prevalences of PE and VTE were similar among studies where diagnostic tests for PE and VTE were performed within 24 h of hospital admission. Therefore, these prevalences may be applicable to the emergency de- partment setting, as well. Although these findings are notable, our study continues to show that the clinical impact of PE in patients with suspected AECOPD is high. In our study, the number of at-risk patients needed to diagnose one case of PE or VTE remains very low (approxi- mately 1 in 8).

Our study also confirmed that the clinical impact of PE in this popu- lation was significant. The pooled odds ratio of mortality among in- cluded studies was 5-fold higher in patients with PE compared to those without. In addition, the vast majority of PEs (74%) were identi- fied in clinically relevant locations (i.e., in a segmental or more proximal branch). These findings are notable because they highlight the relative frequency in which patients presenting with suspected AECOPD may re- quire therapeutic modification to include anticoagulation or even more aggressive antithrombotic measures [42,43].

In this study, the prevalence of PE was almost same as the preva- lence of VTE. Recall that our calculation of VTE included both PE and DVT. Our observation that the prevalence of PE and DVT were similar re- inforces the fact that upper or lower extremity Doppler is a poor substi- tute for CTPA to rule out PE, both in this population and in the general population. Whether this is a direct correlate of inflammation-induced endothelial damage within the pulmonary vasculature causing denovo PE during AECOPD [44] or simply a sequelae of DVT’s that migrated to the pulmonary arteries without residual thrombus is not clear. Regard- less of the reasons for the observation, it carries clinical relevance be- cause it suggests the need for clinicians to consider the possibility of PE in this population, even in situations where no evidence of current or prior DVT exists.

Given the potential impact of PE or VTE in patients with suspected AECOPD, several approaches to identifying PE have been proposed. Pro- posals range from employing CTPA in all patients with suspected AECOPD [23,27,30,31,33,35] to fairly restrictive use of CTPA [21,22,24,28,29,32,34,36-38]. Those who opt for a more restricted ap- proach point out that universal screening of all patients increases radia- tion exposure, risk for Contrast-induced nephropathy and increases the Economic burden to patients when incidental findings are identified on CT. On the other hand, the pooled prevalence of PE in this population suggests that the number of patients needed to screen for a single PE is just over 8 studies. As mentioned previously, at least 74% of these pa- tients would warrant a change from standard management of COPD ex- acerbation based on the location of the PE. It is also worth noting that other Screening tests with similar economic costs and risk of adverse outcomes are widely accepted despite a higher number needed to screen. For example, colonoscopy carries a number needed to screen of approximately 377 to diagnose a single case of colon cancer [45]. The complication rate of both CTPA and colonoscopy are reported at less than 1% [46,47].

In this study, we summarized the clinical presentations of included patients as shown in Supplemental Table 3. Although each clinical symptom was reported in only a few studies, we did note that patients with PE had significantly lower prevalence of increased sputum. On the other hand, the presence of cough, fever, pleuritic chest pain, and he- moptysis did not seem to differ between patients with and without PE or DVT. This finding is in contrast to those of a prior meta-analysis which suggested that pleuritic chest pain was the only significant clini- cal factor differentiating these patients [9].

Many of the studies included in our analysis employed clinical pre- diction models such as the Wells criteria and revised Geneva score to risk stratify patients in this population prior to screening for PE. While these prediction models are often helpful in separating patients with low probability of PE from those with an intermediate or high probabil- ity, their use in identifying a PE in a patient with AECOPD may be chal- lenging. For example, components of the Wells criteria include clinical factors common in both conditions such as heart rate (HR) >100 beats/min and history of recent immobilization. The revised Geneva scoring algorithm includes similar items such as age > 65 years and HR >95 beats/min. We found that the majority of patients in the Pooled analysis were risk stratified to intermediate- or high-risk groups in both revised Geneva score (76.8%) and Wells criteria (50.7%). It is also

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Table 1

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American Journal of Emergency Medicine 50 (2021) 606617

610

Characteristics of each study.

Authors

Country

Sample size

Setting

Study period

Definition of AECOPD

Diagnosis of PE

Outcomes

STROBE

Conturaud (2021)

France

740

Multi-center,

January

A sustained worsening of patients’ baseline symptoms

Clinical probability of PE was assessed in all patients

Primary: The prevalence of PE

22

prospective

2014 –

May 2017

(dyspnea, cough, sputum) beyond normal day-to-day

variability and a required treatment modification.

using the revised Geneva score. Patients with a high

clinical probability (revised Genova score >= 11) directly

in 48 h of admission

Secondary: VTE at admission,

proceeded to CTPA and legs US. For patients with low- to

VTE during 3-month follow-up,

intermediate- clinical probability (revised Genova

3-month all-cause mortality,

score < 11), a D-dimer test was performed. If D-dimer

alternative diagnosis to VTE at

was <500 ng/mL, pulmonary embolism was excluded.

admission.

The diagnostic work-up was initiated within 48 h.

Hassen (2019)

Tunisia

131

Single-center,

March

The definition was based on the Global Initiative for

The Wells score was evaluated in all patients. If Wells

Primary: The prevalence, risk

19

prospective

2013 –

Chronic obstructive lung disease with unknown

score > 2, CTPA was performed. If Wells score was 0 or 1,

factors of PE in patients with

May 2017

etiology and necessitating mechanical ventilation within

Doppler ultrasonography was performed. If DVT is found,

AECOPD requiring mechanical

the first 24 h.

then CTPA was also performed. The timing of work-up

ventilation.

was not specified.

Pang (2018)

China

1144

Multi-center,

June

Severely increased symptoms (dyspnea, cough, sputum,

All the enrolled patients underwent lower extremities

Primary: The prevalence of VTE

21

prospective

2009 –

fever) and failure to respond to initial treatments or

venous US on day 7-10 and a repeated US 7 days after if

or PE during hospitalization

October

2010

treatments at home.

patients had suspicious findings. CTPA was performed in patients with SPAP >=40 mmHg based on

echocardiography.

AbdelHalim

Egypt

83

Single-center,

Not

The definition was based on Anthonisen criteria (the

CTPA was performed within 48 h after the admission in

Primary: The predictive value

13

(2017)

prospective

reported

occurrence of increased dyspnea, sputum volume, upper

all patients.

and optimal cut-off of d-dimer

respiratory infection within the past 5 days, fever

for PE in patients with AECOPD.

without other cause, increased wheezing, increased

cough, or increase in respiratory rate or heart rate by 20%

as compared with baseline).

Shapira-Rootman

Israel

49

Single-center,

February

Any worsening of dyspnea sufficiently severe to warrant

D-dimer was checked on admission. If D-dimer was

Primary: The prevalence of PE,

20

(2015)

prospective

2010 –

an admission to the hospital.

>500 ng/mL, CTPA was performed. The timing of

the sensitivity and specificity of

August

work-up was not specified.

D-dimer in the diagnosis of PE.

2010

Akpinar (2014)

Turkey

172

Single-center,

May

Worsening in respiratory symptoms beyond the normal

CTPA was performed within 24 h of admission in all

Primary: The prevalence of PE

20

prospective

2011 –

day-to-day variations that led to a change in

patients. Doppler ultrasonography was also performed in

May 2013

medications.

all patients.

Choi (2013)

South

103

Single-center,

August

Acute deterioration from a stable condition, which

Pneumonia, pneumothorax, and congestive heart failure

Primary: Prevalence of PE and

19

Korea

prospective

2008-July

required hospitalization.

were excluded based on physical examination, chest

DVT in patients with AECOPD

2011

radiograph, and routine laboratory tests. After excluding

and predictors of PE.

these, CTPA was performed within 24 h of admission to

the hospital.

Kamel (2013)

Egypt

105

Single-center,

June

Not specified but all patients were hospitalized. But

All patients underwent venous doppler ultrasonography

Primary: Prevalence of VTE in

14

prospective

2011 –

and computed tomography venography of bilateral lower

patients with AECOPD

June 2012

extremities, and CTPA within 24 h.

Ristic (2013)

Serbia

631

Single-center,

January

The definition was based on the Global Initiative for

D-dimer was checked on admission. If D-dimer was

Primary: Prevalence and risk

20

prospective

2011 –

Chronic Obstructive Lung Disease.

>500 ng/mL, CTPA and venous doppler ultrasonography

factors of PE in patients with

November

of bilateral lower extremities were performed. The

AECOPD.

2012

timing of work-up was not specified.

Wang (2013)

China

208

Single-center,

September

Exacerbation was defined as an acute deterioration from

All patients underwent CTPA within 24 h of admission.

Primary: Prevalence of PE in

15

prospective

2006 –

a stable condition that required hospitalization.

patients with AECOPD with

June 2011

unknown etiology.

Dutt (2011)

India

100

Single-center,

February

An event in the natural course of the disease

All patients underwent venous doppler ultrasonography

Primary: Prevalence of DVT in

18

prospective

2005 –

characterized by a change in patients’ baseline dyspnea,

of bilateral lower extremities on the first day of

patients with AECOPD

February

cough, and/or sputum production that is beyond

hospitalization. The test was repeated on the seventh day

(incidence of PE was also

2007

day-to-day variations, acute in onset, and warranting a

of hospitalization. No specific strategy to detect PE was

reported).

change in regular medications.

reported.

Gunen (2010)

Turkey

131

Single-center,

Not

Not formally defined. But all patients required

All patients underwent CTPA within 24 h of admission.

Primary: Prevalence of VTE in

17

prospective

reported

hospitalization.

patients with AECOPD

(Incidence of PE was also

reported).

Duan (2010)

China

520

Single-center,

March

The definition was based on the Global Initiative for

*PE was not but VTE was assessed. All patients

Primary: Prevalence of VTE in

16

prospective 2007 –

March 2009

Chronic Obstructive Lung Disease. underwent venous doppler ultrasonography of bilateral lower extremities. The timing of work-up was not specified.

patients with AECOPD.

Lessiani (2008) Italy 100 Single-center,

prospective

December 2005 –

May 2006

The presence of two of three cardinal symptoms (worsening dyspnea, increase in sputum purulence, increase in sputum volume).

D-dimer was checked on admission. If D-dimer was

>500 ng/mL, both venous doppler ultrasonography of bilateral lower extremities within 24 h of admission.

Primary: Prevalence of DVT in 15 patients with AECOPD.

Rutschmann (2007)

Tillie-Leblond (2006)

Switzerland 123 Single-center,

prospective

France 197 Single-center,

prospective

February 2003 –

December 2004

April 1999 –

December 2002

Worsening dyspnea sufficiently severe to warrant an admission to the ED.

Acute deterioration from a stable condition that required hospitalization.

D-dimer was checked on admission. If D-dimer was

>500 ng/mL, both venous doppler ultrasonography of bilateral lower extremities and CTPA were performed in the ED.

All patients underwent both venous doppler ultrasonography of bilateral lower extremities and CTPA within 48 h of admission.

Primary: Prevalence of PE in 21

patients with AECOPD.

Primary: Prevalence of PE in 22

patients with AECOPD due to unknown origin and factors associated with PE.

R. Sato, D. Hasegawa, K. Nishida et al.

Akgun (2006) Turkey 120 Single-center,

prospective

October 2004 –

February 2005

Based on the definition by American Thoracic Society All patients underwent venous doppler ultrasonography

of bilateral lower extremities. CTPA was performed in cases with any suspicion of PE. The timing was not specified.

Primary: Prevalence and clinical 13 characteristics of VTE in

patients with AECOPD (Incidence of PE was also reported).

Erelel (2002) Turkey 56 Single-center,

prospective

Pek (2001) Singapore 33 Single-center,

prospective

Not reported

July 1999 – January 2000

Based on the definition by American Thoracic Society and European Respiratory Society.

Based on the definition by American Thoracic Society, as defined by a history of COPD with increased dyspnea, wheezing, cough or production of sputum.

All patients underwent venous doppler ultrasonography of bilateral lower extremities. Venography was performed if DVT was suspected in venous doppler ultrasonography. Pulmonary perfusion scintigraphy was performed in patients who had sudden chest pain with shortness of breath and/or hypocapnia in arterial blood gas and/or radiological suspicions of PE. The timing of work-up was not specified.

All patients underwent venous doppler ultrasonography

of bilateral lower extremities within 24 h of admission.

Primary: Prevalence of VTE and 9 PE in patients with AECOPD.

Primary: Prevalence of VTE in 15

patients with AECOPD.

Schonhofer (1998)

Germany 196 Single-center,

prospective

January 1995 –

December 1996

Not formally defined. But all patients required admission to the intensive care unit.

All patients underwent venous doppler ultrasonography of bilateral lower extremities. The timing of work-up was not specified.

Primary: Prevalence of VTE in 16

patients with AECOPD.

PE: pulmonary embolism, AECOPD: acute exacerbation of chronic obstructive pulmonary disease, VTE: venous thromboembolism, CTPA: computed tomography pulmonary angiogram, STROBE: strengthening the reporting of observational studies in epidemiology.

611

* was to note that PE was not but VTE was assessed in this study.

American Journal of Emergency Medicine 50 (2021) 606617

Table 2

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American Journal of Emergency Medicine 50 (2021) 606617

612

Characteristics of included patients.

Authors

Age

Mean (SD)

Male

BMI

Mean (SD)

FEV1,%

predicted Mean (SD)

FEV1/FVC, %

Mean (SD)

GOLD

stages

Revised Geneva score

Wells criteria

VTE risk factors

Conturaud (2021)

68.2 (10.9)

63.0%

25.7 (6.7)

58% (96)

53.0% (16.7)

I: 12.7% (86/740)

Low: 18.8%

Prolonged immobilization 18.0% (133/740)

(466/740)

(139/740)

II: 32.3%

Intermediate:

Familial history 9.5% (66/740)

(239/740)

78.9% (584/740)

III: 38.4%

High: 2.3%

Cancer in the past 2 years 8.0% (59/740)

(259/740)

(17/740)

IV: 12.3% (91/740)

Not reported

Previous history of VTE 7.4% (55/740)

Recent surgery 3.3% (24/740)

Recent trauma 2.0% (15/740)

Hassen (2019)

68 (13)

79.4%

Not reported

Not reported

Not reported

Not reported

Not reported

Immobilization for 7 days 29.0% (67/131)

(104/131)

Low: 55.0%

(72/131)

Intermediate:

44.3% (58/131)

high: 0.7% (1/131)

Pang (2018)

72.0 (9.1)

67.3%

23.9 (5.1) in Pts with VTE

42.0% (28.8-59.3) in

48.9% (40.1-59.9) in Pts

Not reported

Not reported

Prolonged immobilization 18.4% (210/1144)

(761/1144)

Pts with VTE

with VTE

Not reported

23.2 (4.3) in Pts without VTE

48.8% (40.4-57.6) in Pts

Family history 0.3% (3/1144)

40.3% (29.0-53.5) in

without VTE

Cancer in the past 2 years 2.3% (26/1144)

Pts without VTE

Previous history of VTE 5.7% (65/1144)

Recent surgery 0.9% (10/1144)

Recent traumatic fracture 0.7% (8/1144)

AbdlHalim

56.2 (11.2)

100%

19.9 (2.0)

Not reported

Not reported

Not reported

Low: 37.3%

(2017)

(83/83)

(31/83)

Intermediate:

50.6% (42/83)

High: 12.0%

(10/83)

Shapira-Rootman

65.5 (43-92)a

71.4%

Not reported

Not reported

Not reported but

Not reported

Not reported

Not reported

Previous history of VTE 0% (0/49)

(2015)

(35/49)

inclusion criteria

Not reported

Recent surgery 0% (0/49)

included

Recent traumatic fracture 0% (0/49)

Akpinar (2014)

71.3 (9.6)

82.6%

BMI >= 30

55.8% (19.4)

FEV1/FVC < 70%

Not reported

I: 7.0% (12/172)

In Pts with PE

Not reported but patients with malignancy, recent

(142/172)

13.9% (24/172)

Low: 18.0% (9/50)

surgery were excluded.

II: 37.2% (64/172)

Intermediate:

64.0% (32/50)

High: 18.0%

(9/50)

III: 35.0%

In Pts with PE

(259/740)

Low: 24.0%

(12/50)

IV: 52.9% (91/740)

Intermediate:

68.0% (34/50)

Choi (2013)

71 (6)

70%

Not reported

50.0% (32-80)a in Pts

51.0% (30-55)a in Pts

Not reported

High: 8.0% (4/50)

Low: 12.9%

Not reported

(70/100)

with PE

57.0% (20-148)a in Pts

with PE

41.0% (20-72)a in Pts

(13/101)

Intermediate:

without PE

without PE

87.1% (88/101)

High: 0% (0/101)

Low: 35.9%

(37/103)

Intermediate:

57.3% (59/103)

High: 6.8%

(7/103)

Kamel (2013)

49.3 (8.4)

100%

Not reported

Not reported

Not reported

Not reported

Unlikely (0-2):

Not reported

(105/105)

65.7% (69/105)

Likely (>=3): 34.4%

(36/105)

Low/intermediate

(0-6): 76.2%

(80/105)

High (>=7): 23.8%

(25/105)

Ristic (2013)

64.0 (in patients

55.0%

Not reported but 14.1% (51/362)

Not reported

Not reported

Not reported

Not reported

In patients with positive d-dimer,

with positive

(199/362)

of patients with positive d-dimer

Not reported

Immobilization 5.2% (19/362)

d-dimer)

had BMI > 30.

Malignancy 6.6% (24/362)

Varicose veins 19.3% (70/362)

Wang (2013)

62 (12)

76.0%

Not reported

Not reported

Not reported

I: 16.3% (34/208)

Not reported

Immobility >=7 days 16.3% (34/208)

(158/208)

II: 21.2% (44/208)

Not reported

Previous VTE 8.7% (18/208)

III: 56.3%

(117/208)

Dutt (2011)

71 (36-84)a

75.0%

Not reported.

Not reported but all

Not reported but all

IV: 6.3% (13/208)

Not reported but

Not reported

Not reported

Gunen (2010)

67.1 (10.1)

(75/100)

79.4%

23.0 (5.0) in Pts with VTE

patients met FEV1,% predicted <80%

38.8% (13.9) in Pts

patients met FEV1/FVC < 70%

Not reported

all patients had stage II to IV.

I: 0% (0/131)

Not reported

Low: 10.7%

Malignancy 5.3% (7/131)

(104/131)

with PE

(14/131)

II: 12.2% (16/131)

Intermediate:

Previous history of VTE 2.3% (3/131)

84.7% (111/131)

25.1 (5.0) in Pts without VTE

39.4% (8.8) in Pts

III: 19.8% (26/131)

High: 4.6%

without PE

IV: 67.9% (89/131)

(6/131)

Low: 54.2%

(71/131)

Intermediate:

40.5% (53/131)

High: 5.3%

(7/131)

Duan (2010)

72 (9)

64.2%

BMI >= 25

Not reported

Not reported

Not reported

Not reported

Prolonged immobilization 14.2% (74/520)

(334/520)

72.1% (31/46) in Pts with VTE

Not reported

Cancer 1.9% (10/520)

65.5% (277/474) in Pts with VTE

Hormone replacement therapy 18.3% (95/520)

Lessiani (2008)

69.8 (8)

61.0%

Weight (kg): 76.1 (13.4)

64.0% (8)

70.0% (10)

Not reported

Not reported

Venous thromboembolism 10.0% (10/100)

(61/100)

Height (m): 1.62 (0.08)

Not reported

Previous history of VTE, or malignancy that affects

coagulation status were excluded.

Rutschmann

71 (8)

68.3%

Not reported

FEV1 (L/s):

Not reported

I: 0% (0/123)

Not reported

Prolonged immobilization 16.3% (20/123)

(2007)

(84/123)

1.42 (0.38) in stage II

II: 22.0% (27/123)

Not reported

0.92 (0.26) in stage III

III: 49.6% (61/123)

Family history 8.9% (11/123)

0.65 (0.15) in stage IV

IV: 28.5% (35/123)

Cancer 4.9% (6/123)

Previous history of VTE 4.1% (5/123)

Recent surgery 1.6% (2/123)

Hormone replacement therapy 4.1% (5/123)

Tillie-Leblond

60.5 (12.1)

78.2%

Not reported but obesity

FEV1 (L/s): 1.56 (0.6)

56.4% (14.8)

GOLD stages not

Low: 47.2%

Prolonged immobilization 6.1% (12/197)

(2006)

(165/211)

(BMI >= 30) was seen in 17.3%

reported

(93/197)

(34/197)

FEV1, % predicated

51-70%: 41.3%

Intermediate:

44.7% (88/197)

Cancer 28.9% (57/197)

(66/160)

High: 8.1%

Previous history of VTE 11.7% (23/197)

(16/197)

35-50%: 41.8%

Not reported.

Recent surgery 2.5% (5/197)

(67/160)

<35%: 16.9%

Recent trauma 0.5% (1/197)

(27/160)

Akgun (2006)

63 (11)

68.3%

Not reported

54.3% (19.1) in Pts

55.5 (14.7) in Pts with

Not reported

Not reported

Patients with risk factors such as recent surgery,

(82/120)

with VTE

VTE

Not reported

previous history of VTE or a history of malignancy

51.9% (22.1) in Pts

56.6 (13.4) in Pts

were excluded from the study.

without VTE

without VTE

(continued on next page)

R. Sato, D. Hasegawa, K. Nishida et al.

American Journal of Emergency Medicine 50 (2021) 606617

613

R. Sato, D. Hasegawa, K. Nishida et al. American Journal of Emergency Medicine 50 (2021) 606617

worthwhile to mention that 3.2% of patients with low suspicion of PE based on these predictive models actually had PE in the study by Couturaud et al. [38]. In another study by Abdel Halim et al., approxi- mately 10% of patients with low probability of PE based on the revised Genova score had PE on imaging [35]. Furthermore, Akpinar et al. re- ported that 18% of patients with low probability of PE based on the re- vised Genova score and 24% of low probability patients based on Wells criteria had PE [33]. Remember that these prediction models were made to assess the pre-test probability of PE or VTE only when cli- nicians suspect PE or VTE based on the history and physical exam. In other words, the Geneva and Wells score were designed to inform fur- ther testing, not to be a test in and of themselves.

VTE risk factors

Not reported but patients with malignancy or other Systemic conditions were excluded.

Not reported but patients with malignancy, left ventricular dysfunction, neurological diseases, or history of VTE were excluded.

Not reported but patients with malignancy, left ventricular dysfunction, neurological diseases, or history of VTE were excluded.

The values were shown as mean with standard deviations or percentages with actual numbers of patients unless specified.

BMI: body mass index, FEV: Forced expiratory volume in the first second of expiration, FVC: forced vital capacity, VTE: venous thromboembolism, GOLD: Global initiative of Chronic Obstructive Lung Disease, Pts: patients.

a Range.

In this meta-analysis, some studies used a D-dimer with a threshold of 500 ug/L to determine whether or not to proceed with CTPA [24,25,29]. The sensitivity of D-dimer, using a threshold of 500 ug/L, was previously reported to be 99.5% [48]. Importantly, Hartmann et al. have suggested that the presence of AECOPD should not affect the diag- nostic performance of D-dimer [49]. While Kamel et al. suggest that the standard paradigm of using D-dimer to rule out PE in patients who are low risk by Wells or Geneva score is valid in the AECOPD population, Wang et al. reported 2.8% of “low risk” patients with PE had D-dimer below the 500 ug/L threshold [30,31], In addition, the prevalence of both PE and VTE was significantly higher in studies that performed CTPA for all patients compared to studies that utilized risk prediction models when determining who to image. These findings raise a concern that CTPA may be underutilized in this population or that common clin- ical risk scores may not be sensitive enough to rule out PE using conven- tional algorithms. Given these discrepancies, the diagnostic value of clinical scoring systems and of D-dimer to exclude PE in patients with AECOPD is ripe for further investigation.

GOLD

stages

Revised Geneva score

Wells criteria

Not reported

Not reported Not reported Not reported Not reported

FEV1 (L/s): 0.91 (0.36)

FVC (L): 2.13 (0.78)

Not reported

Not reported

Not reported Not reported

The most obvious strength of this study is the significant number of patients evaluated compared to the prior meta-analyses [9]. Nonethe- less, there are limitations in this study. There was a significant heteroge- neity among the studies we included. It is worthwhile to note that meta-analyses evaluating prevalence tend to have a higher heterogene- ity than those evaluating other outcomes. One recent article reported that the majority of systematic reviews of disease prevalence had an I2 estimate of 90% or greater [50]. In fact, a prior meta-analysis investigat- ing this topic also reported similar I2 estimate (geater than 92%) [9]. We believe that the vast majority of heterogeneity was related to the method by which PE was diagnosed. As we previously indicated, there was no uniform method for determining which patients should receive CTPA. We attempted to mitigate this by performing a subgroup analysis limited to studies where CTPA was performed in all patients with AECOPD. This analysis showed that the prevalence of PE was actually higher than that of our pooled analysis. Other potential reasons for het- erogeneity include the timing of evaluation of PE or VTE and the severity of included patients. For instance, the study by Pang et al. evaluated 7-10 days after admission while most of studies evaluated PE or VTE in 24-48 h after the admission [36]. Two of included studies only in- cluded patients who required the admission to the intensive care unit [19,37]. We also recognized the potential for heterogeneity between studies conducted on Asian populations versus non-Asian populations as previous studies have shown a lower prevalence of VTE and PE among Asian Americans in the general population regardless of the presence of COPD [10,11]. Asians are also known to require lower doses of warfarin [10,12], suggesting that they may possess antithrom- botic traits. In this meta-analysis, we did not identify any difference in the incidence of PE or VTE between populations. Although other con- founders likely exist, the fact that our study is consistent with prior pub- lished studies suggests the outcomes we observed are clinically relevant.

Table 2 (continued)

Authors

Age

Male

BMI

FEV1,%

predicted

Mean (SD)

FEV1/FVC, %

Mean (SD)

67.5 (10)

Mean (SD)

Mean (SD)

Erelel (2002)

82.1% (46/56) 100% (33/33)

Weight (kg): 63.0 (12.4)

Height (m): 1.61 (0.09) Not reported

FEV1 (L/s): 0.94 (0.28)

52.0% (13)

73.8 (8.8)

41.7% (18.5)

Schonhofer (1998)

66.9 (9.1)

56.1% (110/196)

Weight (kg): 63.5 (12.7)

Height (m): 1.66 (0.08)

FEV1 (L/s): 0.70 (0.20)

38.4% (6.4) in Pts with VTE

39.5% (6.1) in Pts

without VTE

37.0% (6.0)

In conclusion, the prevalence of PE in patients with AECOPD, and the risk of subsequent mortality in this population is high. This finding sug- gests an acute need to reassess the traditional diagnostic strategies we employ to evaluate for PE in this population.

Pek (2001)

614

Table 3

R. Sato, D. Hasegawa, K. Nishida et al.

American Journal of Emergency Medicine 50 (2021) 606617

615

Outcomes.

Authors

Prevalence of PE

Prevalence of VTE

Localization of PE

Hospital length of stay (days)

The mortality

Conturaud (2021)

5.9% (44/740)

7.3% (54/740)

Pulmonary trunk (3/44)

Patients with PE: 9.0 (7.0-14.0)

3-month mortality:

Lobar (14/44)

8.6% (64/740)

Segmental (24/44)

27.3% (12/44) in patients with PE

Subsegmental (3/44)

25.9% (14/54) in patients with VTE

Hassen (2019)

13.7% (18/131)

13.7% (18/131)

Segmental 44% (8/18)

Patients with PE: 9 (4-20)

ICU mortality:

15.3% (20/131)

Patients without PE: 8 (6-12)

44.4% (8/18) in patients with PE

Pang (2018)

2.1% (24/1144)

6.8% (78/1144)

Not reported

Not reported

Not reported

AbdelHalim (2017)

13.3% (11/83)

Not reported

Not reported

Not reported

Not reported

Shapira-Rootman (2015)

18.4% (9/49)

Not reported

Not reported

Not reported

Not reported

Akpinar (2014)

29.1% (50/172)

29.1% (50/172)

Main pulmonary artery (10/50)

Patients with PE: 11.42 (5.69)

3-month mortality:

8.1% (14/172)

Segmental (8/50)

Patients without PE: 8.89 (4.05)

12.0% (6/50) in patients with PE

Choi (2013)

4.9% (5/103)

7.8% (8/103)

Subsegmental (32/50)

Main pulmonary artery (4/5)

Patients with PE: 8 (2-76)a

In-hospital mortality:

Lobar (1/5)

Patients without PE: 7 (0-91)a

5.8% (6/103)

20.0% (1/5) in patients with PE

Kamel (2013)

28.6% (30/105)

31.4% (33/105)

Not reported

Not reported

Not reported

Ristic (2013)

10.8% (68/631)

13.5% (85/631)

Not reported

Not reported

Not reported

Wang (2013)

33.2% (69/208)

41.3% (86/208)

Not reported

Not reported

Not reported

Dutt (2011)

2.0% (2/100)

9.0% (9/100)

Not reported

9 (5-12)a

The mortality (not specified):

2.0% (2/100)

100% (2/2) in patients with PE

Gunen (2010)

13.7% (18/131)

16.0% (21/131)

Centrally located (9/18)

Not reported

In-hospital mortality:

Segmental (5/18)

8.4% (11/131)

Subsegmental (4/18)

27.8% (5/18) in patients with PE

Duan (2010)

Not reported

8.8% (46/520)

Not reported

Patients with VTE: 14 (9-23)

Not reported

Patients without VTE: 11 (8-15)

Lessiani (2008)

Not reported

6.0% (6/100)

Not reported

Not reported

Not reported

Rutschmann (2007)

3.3% (4/123)

3.3% (4/123)

Lobar (3/4)

Not reported

Not reported

Subsegmental (1/4)

Tillie-Leblond (2006)

24.9% (49/197)

Not reported.

Central (20/43)

Not reported

Not reported

Segmental (21/43)

Subsegmental (2/43)

Akgun (2006)

3.3% (4/120)

13.3% (16/120)

Not reported

Patients with VTE: 26.9 (11.4)

Not reported

Patients without VTE: 15.8 (9.6)

Erelel (2002)

8.9% (5/56)

10.7% (6/56)

Not reported

Not reported

Not reported

Pek (2001)

Not reported

0% (0/33)

Not reported

Not reported

In-hospital mortality:

0% (0/33).

Schonhofer (1998)

Not reported

10.7% (21/196)

Not reported

Not reported

Not reported

PE: pulmonary embolism, AECOPD: acute exacerbation of chronic obstructive pulmonary disease, VTE: venous thromboembolism, CTPA: computed tomography pulmonary angiogram. * Patients with deep venous thromboembolism were excluded. Therefore, the number of patients developed pulmonary embolism was unclear.

a Median with range.

R. Sato, D. Hasegawa, K. Nishida et al. American Journal of Emergency Medicine 50 (2021) 606617

Author’s contributions

R.S. is responsible for the conception of the study design, data collec- tion, interpretation of the analysis, writing of the draft, and critical revi- sion of the manuscript. D.H. contributed to data collection and analysis, interpretation of the analysis, writing of the draft, K.N. and K.T. contrib- uted to data analysis and interpretation of the analysis, M.S. contributed substantially to data collection. N.C. supervised the conception of the study design, interpretation of the analysis, drafting and critical revision of the manuscript. All authors approved the submission of the final manuscript.

Credit author statement

Ryota Sato is responsible for the conception of the study design, data collection, interpretation of the analysis, writing of the draft, and critical revision of the manuscript. Daisuke Hasegawa contributed to data col- lection and analysis, interpretation of the analysis, writing of the draft, Kazuki Nishida and Kunihiko Takahashi contributed to data analysis and interpretation of the analysis, Mary Schleicher contributed substan- tially to data collection. Neal Chaisson supervised the conception of the study design, interpretation of the analysis, drafting and critical revision of the manuscript. All authors approved the submission of the final manuscript.

Funding

K.N. was supported by JSPS KAKENHI (Grant # 20K2322) for data analysis.

Conflicts of interest

None.

Acknowledgement

We would like to acknowledge Dr. Abhijit Duggal for advice given on the study design and statistical methods during this study.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2021.09.041.

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