Risk Factors for Pulmonary Embolism in Patients with Acute Exacerbation of COPD: A Systematic Review and Meta-analysis

Keywords

chronic obstructive pulmonary disease (COPD) - pulmonary embolism - meta-analysis

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by chronic respiratory symptoms due to abnormalities in the airways and alveoli, resulting in persistent and progressive airflow obstruction.[1] COPD is the third leading cause of death globally, after cerebrovascular disease and ischemic heart disease.[2] [3] According to recent studies, the global prevalence of COPD in 2020 was approximately 10.6%, representing 480 million cases. The number of COPD cases is projected to increase by 112 million, reaching a total of 592 million by 2050.[4] Although COPD typically progresses slowly with gradual airflow deterioration, acute exacerbation frequently lead to significant limitations in daily activities due to dyspnea, cough, and fatigue, severely affecting patients' quality of life and survival.[5] [6] Acute exacerbation of COPD is a substantial burden on both patients and healthcare systems.

Recent studies indicate that approximately 30% of acute exacerbations of COPD are unexplained, with some cases potentially linked to concurrent pulmonary embolism (PE).[7] [8] [9] [10] In patients with acute exacerbation of COPD, PE is a significant risk factor for poor prognosis. PE contributes to prolonged hospitalization and an elevated risk of mortality.[8] [11] In cases of exacerbation of COPD, patients often present with symptoms resembling those of acute PE. This similarity can complicate the differentiation between the two conditions and potentially resulting in over- or under-diagnosis of PE.[6] [12] [13] [14] [15] The reported prevalence of PE in patients with acute exacerbation of COPD is 29.1%.[14] The case fatality rate for untreated PE is approximately 30%.[14] [16] Timely detection and intervention for PE in patients with acute exacerbation of COPD significantly reduce the risk of prolonged hospitalization and mortality.[3] [17] Computed tomography pulmonary angiography (CTPA) is widely regarded as the gold standard for diagnosis of PE. However, the widespread use of CTPA in primary hospitals is hindered by the high costs associated with the procedure and the necessary equipment. Additionally, the diagnostic yield of this method for subsegmental thromboembolism, microembolization, and in situ thrombosis is relatively low.[13] [18] [19] [20] Therefore, it is imperative to analyze the risk factors for PE in patients with acute exacerbation of COPD to facilitate early diagnosis.

The present systematic review and meta-analysis aims to identify risk factors associated with the occurrence of PE in patients with acute exacerbation of COPD. Our findings are expected to promote the development of effective prophylactic strategies and diagnostic tools for PE in patients with acute exacerbation of COPD.

Materials and Methods

Search Strategy and Study Selection

Comprehensive systematic literature searches were conducted in the PubMed, Cochrane Library, Embase, and Web of Science databases from inception through November 2024. The search strategy was developed using a combination of Medical Subject Headings (MeSH) terms and free-text keywords. The primary search terms included “pulmonary embolism” AND “chronic obstructive pulmonary disease.” The detailed search strategy, including all search terms and Boolean operators, is provided in [Supplementary Table S1], available in the online version. These search terms were systematically applied across all databases to identify studies relevant to the predefined PICO (Population, Intervention, Comparison, Outcome) framework. Two independent reviewers performed dual screening of titles and abstracts for all identified studies. Potentially eligible studies were selected for full-text retrieval and comprehensive evaluation. Additionally, full-text articles of relevant references were retrieved for further assessment.

Criteria for Considering Studies

The inclusion criteria are established as follows: (1) Original studies investigating risk factors for PE in patients with acute exacerbation of COPD. (2) Eligible study designs included case-control and cohort. (3) The study reported effect measures, including odds ratio (OR), relative risk (RR), hazard ratio (HR), and their 95% confidence interval (CI). (4) The primary outcome was the occurrence of PE for acute exacerbation of COPD. In case-control studies, cases were COPD patients hospitalized for acute exacerbation with PE confirmed by CTPA. Controls were COPD patients hospitalized for acute exacerbation without PE, matched by time period and healthcare facility. (5) PE was diagnosed by CTA or pulmonary angiography, defined as filling defects in the main pulmonary artery or its branches. (6) Studies employing appropriate data collection methods and statistical analyses, and the outcome metrics were subjected to multifactorial logistic regression, and OR and 95% CI were provided. (7) The Newcastle-Ottawa Scale (NOS) score was ≥7 (range 0–9), assessed by two independent reviewers.

Studies were excluded based on the following predefined criteria: (1) Animal studies or non-human research; (2) studies involving non-acute exacerbation of COPD patients; (3) research including abstracts, letters, editorials, expert opinions, reviews, or case reports; (4) duplicate studies or datasets; (5) studies with incomplete data or insufficient information for data extraction; (6) studies demonstrating significant heterogeneity in sensitivity analyses; and (7) studies with unclear definition of study population or outcome measures.

Quality Assessment and Data Extraction

Two independent investigators systematically screened the literature and extracted data. Any discrepancies were resolved through discussion or, when necessary, by consulting a third investigator. The extracted data encompassed: first author, publication year, country of origin, study design, sample size, risk factors, OR, 95% CI, and covariates included in multivariate analyses. The quality of the included studies was assessed using the NOS. The NOS, with a maximum score of 9 points, categorizes studies as low (0–3), moderate (4–6), or high quality (7–9).

Data Synthesis and Statistical Methods

Data from comparable outcomes between COPD patients with and without PE during acute exacerbation were pooled and analyzed using RevMan 5.2. Heterogeneity was assessed using Cochran's Q test and quantified by the I² statistic. A fixed-effects model was used when I² ≤ 50% and p ≥ 0.1; otherwise, a random-effects model was applied. Statistical significance was set at p < 0.05. Publication bias was assessed using funnel plots when ≥10 studies were included. Sensitivity analyses were performed by sequentially excluding individual studies to evaluate potential sources of heterogeneity and result stability.

Results

Study Selection and Quality Assessment

The initial database search identified 7,440 potentially relevant records. After removing 2,316 duplicates, we screened 5,124 unique records. Based on title and abstract screening, we excluded 5,065 records and assessed 59 full-text articles. After full-text assessment, 45 studies were excluded based on predefined criteria. Finally, 14 studies[3] [7] [11] [13] [14] [15] [17] [18] [19] [20] [21] [22] [23] [24] meeting all inclusion criteria were included in the meta-analysis. The study selection process is detailed in the PRISMA flow diagram ([Fig. 1]). All included studies had Newcastle-Ottawa Scale (NOS) scores ≥6, indicating high methodological quality ([Table 1]).

Fig. 1 Flow diagram of study selection.

Table 1 Baseline characteristics and quality assessment of included studies

Author	Year	Study design	Country	Sample size	NOS score
Li[3]	2024	Case-control	China	191	7
Yang[11]	2024	Cohort	China	636	8
Jia[24]	2023	Cohort	China	426	8
Yu[21]	2023	Case-control	China	185	6
Dentali[17]	2020	Cohort	Italy	1043	8
Wang[18]	2020	Case-control	China	125	7
Hassen[7]	2019	cohort	China	361	6
Zhu[13]	2019	Case-control	China	94	6
Li[19]	2016	Case-control	China	522	7
Wang[22]	2016	Cohort	Tunisia	126	6
Akpinar[14]	2014	Cohort	Turkey	172	8
Choi[23]	2013	Cohort	Koreans	103	6
Wang[15]	2012	Case-control	China	208	6
Tillie[20]	2006	Cohort	France	197	7

Abbreviation: NOS, Newcastle-Ottawa Scale.

Characteristics of Included Studies

The meta-analysis 14 included studies (6 case-control[3] [13] [15] [18] [19] [21] and 8 cohort studies[7] [11] [14] [17] [20] [22] [23] [24]) with 10,053 participants was performed. These studies originated from multiple countries: China (n = 9),[3] [7] [11] [13] [15] [18] [19] [21] [24] Italy,[17] Tunisia,[22] France,[20] Korea,[23] and Turkey[14] ([Table 1]).

Outcomes

Nine potential risk factors were identified, each reported in at least two included studies. All eight factors except neutrophil count (NEUT) are the risk factors for PE in patients with acute exacerbation of COPD. The identified risk factors and their statistical significance are presented in [Table 2]. A random-effects model was used when significant heterogeneity was present (I² > 50%); otherwise, a fixed-effects model was applied. Sensitivity analyses were performed by comparing fixed- and random-effects models.

Table 2 Risk factors associated with PE in patients with acute exacerbation of COPD

Risk factors		DVT[12] [26] [18] [16] [25]	Elevated D-dimer levels[12] [14] [19] [20] [22] [23] [24] [26]	Elevated NEUT[11] [21]	Immobilization >3–7 days[16] [20] [25] [27]	Elevated LDH levels[19] [22]	Lower limb asymmetry[15] [16]	PaCO2 < 36 mm Hg[18] [21]	PaO2 < 80 mm Hg[22] [25]
Merger effect measure	Z value	5.19	4.43	1.94	4.05	4.31	4.18	3.24	3.35
	P value	< 0.00001	< 0.0001	0.05	< 0.00001	< 0.0001	< 0.0001	0.001	0.0008
	95% CI	2.83–10.00	1.47–2.73	1.00–1.56	2.57–15.01	1.00–1.01	1.63–3.86	1.24–2.40	1.01–1.05
	OR	5.3	2	1.25	6.21	1.01	2.51	1.73	1.03
Effect model		Random	Random	Random	Random	Fixed	Fixed	Fixed	Fixed
Heterogeneity	P value	0.01	0.0003	< 0.00001	0.03	0.22	0.82	0.36	1.00
	I2 value (%)	69	67	96	66	33	0	0	0
Included studies		5	8	2	4	2	2	2	2

Abbreviations: COPD, chronic obstructive pulmonary disease; DVT, deep vein thrombosis; LDH, lactate dehydrogenase; NEUT, neutrophil; PE, pulmonary embolism.

DVT

Five studies investigated the association between DVT and PE in patients with acute exacerbation of COPD (OR = 5.32, 95% CI: 2.83–10.00; [Fig. 2]). Given the substantial heterogeneity observed (I² = 69%, p < 0.00001), a random-effects model was employed.

Fig. 2 Forest plot for the association between deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD).

Elevated D-dimer Levels

Eight studies, comprising four cohort studies and four case-control studies, demonstrated a significant association between elevated D-dimer levels and PE in patients with acute exacerbation of COPD. The results revealed that acute exacerbation of COPD patients with elevated D-dimer levels had a significantly increased risk of PE (OR = 2.01, 95% CI: 1.47–2.73; [Fig. 3]). Due to considerable heterogeneity (I² = 67%, p < 0.00001), a random-effects model was utilized.

Fig. 3 Forest plot for the association between elevated D-dimer levels and pulmonary embolism (PE) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD).

Elevated NEUT Levels

Our meta-analysis of two studies investigating the relationship between elevated NEUT levels and PE risk in acute exacerbation of COPD revealed substantial heterogeneity (I² = 96%, p = 0.05). The random-effects meta-analysis demonstrated a non-significant association between elevated neutrophil counts and PE (OR = 1.25, 95% CI: 1.00–1.56; [Fig. 4]). Although the p-value reached borderline significance, the 95% CI including the null value (1.00) suggest this association lacks clinical significance.

Fig. 4 Forest plot for the association between elevated neutrophil (NEUT) levels and pulmonary embolism (PE) in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD).

Immobilization for >3 to 7 Days

Four studies, consisting of two prospective cohort studies and two case-control studies, reported the association between immobilization for >3 to 7 days and PE in patients with acute exacerbation of COPD. The results indicated that patients with immobilization for >3 to 7 days had a 6.21-fold higher risk of PE compared with non-immobilized patients (OR = 6.21, 95% CI: 2.57–15.01; [Fig. 5]). A random-effects model was applied due to significant heterogeneity (I² = 66%, p < 0.0001).

Fig. 5 Forest plot for the association between immobilization for >3 to 7 days and pulmonary embolism (PE) in acute exacerbation of chronic obstructive pulmonary disease (COPD).

Elevated LDH Levels

Two included studies investigating elevated lactate dehydrogenase (LDH) levels demonstrated low heterogeneity (I² = 33%, p < 0.0001). Meta-analysis revealed a statistically significant but clinically marginal association (OR = 1.01, 95% CI: 1.00–1.01; [Fig. 6]), with the narrow confidence interval near unity suggesting limited clinical relevance.

Fig. 6 Forest plot for the association between elevated lactate dehydrogenase (LDH) levels and pulmonary embolism (PE) in acute exacerbation of chronic obstructive pulmonary disease (COPD).

Lower Limb Asymmetry

Lower limb asymmetry was significantly associated with PE in patients with acute exacerbation of COPD, as demonstrated by two studies showing no heterogeneity (I² = 0%, p < 0.0001). Patients with this condition had a 2.56-fold increased risk of PE (OR = 2.56, 95% CI: 1.63–3.86; [Fig. 7]).

Fig. 7 Forest plot for the association between lower limb asymmetry and pulmonary embolism (PE) in acute exacerbation of chronic obstructive pulmonary disease (COPD).

PaCO₂ < 36 mm Hg

Two cohort studies investigated the association between PaCO₂ < 36 mm Hg and PE in patients with acute exacerbation of COPD. The results demonstrated that patients with PaCO₂ < 36 mm Hg had a 1.73-fold increased risk of PE compared with those with PaCO₂ < 36 mm Hg (OR = 1.73, 95 % CI: 1.24–2.40; [Fig. 8]). A fixed-effects model was used due to the absence of heterogeneity (I² = 0%, p = 0.001).

Fig. 8 Forest plot for the association between PaCO₂ < 36 mm Hg and pulmonary embolism (PE) in acute exacerbation of chronic obstructive pulmonary disease (COPD).

PaO₂ < 80 mm Hg

Two cohort studies reported the association between PaO₂ < 80 mm Hg and PE. The results revealed a significantly elevated risk of PE in patients with PaO₂ < 80 mm Hg (OR = 1.03, 95% CI: 1.01–1.05; [Fig. 9]). A fixed-effects model was employed as no significant heterogeneity was observed (I² = 0 %, p = 0.0008).

Fig. 9 Forest plot for the association between PaO₂ < 80 mm Hg and pulmonary embolism (PE) in acute exacerbation of chronic obstructive pulmonary disease (COPD).

Sensitivity Analysis and Meta-regression

Low heterogeneity (I² ≤ 50%) was observed for lower limb asymmetry, elevated LDH levels, PaCO₂ < 36 mm Hg, as well as PaO₂ < 80 mm Hg, and a fixed-effects model was applied. Higher heterogeneity was observed for three factors: DVT, elevated D-dimer levels, and immobilization for >3 to 7 days. After the exclusion of certain studies, heterogeneity for DVT, elevated D-dimer levels, and immobilization for >3 to 7 days was significantly reduced, leading to the use of a fixed-effects model ([Table 3]). The corresponding forest plots are presented in [Figs. 2] [3] [4] [5] [6] [7] [8] [9].

Table 3 Sensitivity analysis of risk factors associated with PE in patients with AECOPD

P-Value			<0.001	<0.001	<0.001
After exclusion	Heterogeneity	P value	0.01	<0.001	0.03
		I2 value (%)	69	84	66
	OR		5.32	1.76	6.21
	Effect model		Random	Random	Random
Before exclusion	Heterogeneity	P value	0.01	<0.001	0.03
		I2 value (%)	69	84	66
	OR		5.32	1.76	6.21
	Effect model		Random	Random	Random
excluded documents			1[16]	2[20] [26]	1[20]
Risk factors			DVT	Elevated D-dimer levels	Immobilization >3 to 7 days

Abbreviations: AECOPD, acute exacerbations of COPD; DVT, deep vein thrombosis; PE, pulmonary embolism.

Discussion

Ventilatory dysfunction in COPD has been demonstrated to cause pulmonary edema, ventilation–perfusion mismatch, and decreased lung compliance. These pathophysiological changes result in hypoxemia and compensatory hyperventilation, thereby increasing the risk of PE.[25] Recurrent acute exacerbation of COPD is a significant contributor to increased mortality in COPD patients. Patients with acute exacerbation of COPD exhibit a significantly elevated risk of PE and higher mortality rates, primarily due to acute inflammation, hypoxia, and hypercoagulability.[26] [27] The incidence of PE in acute exacerbation of COPD patients is 3 to 4 times higher than in non-AECOPD patients, and this risk increases with age. PE is a life-threatening complication in AECOPD patients, associated with prolonged hospitalization and higher mortality rates. Identifying risk factors for PE in AECOPD patients is crucial for early intervention and improved outcomes.[1] [28] [29] Therefore, we performed a comprehensive analysis of 14 studies to identify potential risk factors for PE in patients with acute exacerbation of COPD.

In this study, we systematically analyzed the risk factors strongly associated with the occurrence of PE in patients with acute exacerbation of COPD. In line with previous research, we found that elevated D-dimer levels were significantly associated with PE. Moreover, previous studies have demonstrated that plasma D-dimer levels are elevated in patients with COPD during acute exacerbation but decreased substantially during stable disease.[26] Furthermore, elevated plasma D-dimer levels activate coagulation and fibrinolysis pathways during acute thrombosis, thereby promoting PE. The sensitivity of D-dimer testing is inversely correlated with symptom duration, and comorbidities may increase the likelihood of false-positive results.[30] [31] Approximately 80% of PE patients tested positive for D-dimer, while only 6% were affected by DVT. However, the specificity of D-dimer testing decreases with advancing age.[1] [32]

The primary source of thrombi causing PE is DVT in the lower limbs. Thrombosis is characterized by three key factors: vascular endothelial cell damage, altered blood flow, and blood hypercoagulability. An imbalance between the coagulation and fibrinolytic systems underlies the pathogenesis of thrombosis. Prolonged immobilization often leads to impaired venous return and venous stasis in the lower limbs, resulting in tissue ischemia and hypoxemia. Moreover, these conditions promote systemic hypercoagulability, significantly increasing the risk of DVT. When a lower extremity venous thrombus dislodges, it embolizes to the lungs through the bloodstream to the lungs resulting in a PE. Once the embolus has obstructed the pulmonary vasculature, lung tissue remains ventilated but lacks perfusion, often causing breath shortness. This leads to reduced partial pressure of carbon dioxide (PaCO₂), and subsequent hypoxemia. In patients with COPD, hypoxemia typically precedes hypercapnia (carbon dioxide retention). Therefore, pulmonary embolism should be considered in hypercapnic patients whose PaCO₂ decreases or normalizes, particularly when accompanied by breath shortness. A reduction in PaCO₂ during COPD exacerbation may indicate PE, as suggested by several reports.[38] [39]

Patients with COPD often develop secondary erythrocytosis due to chronic hypoxemia, which increases their susceptibility to venous thrombosis, especially during the acute exacerbation of COPD. Therefore, hypoxemia may contribute to elevated red cell distribution width (RDW) levels in patients with acute exacerbation of COPD combined with PE.[18] Severe hypoxemia also leads to hypercapnia (carbon dioxide retention), causing increased pulmonary artery pressure, and potential myocardial damage. Moreover, LDH, an enzyme found in the myocardium, liver, lungs, and other tissues, is released into the bloodstream following tissue damage.[33] As a result, patients with acute exacerbation of COPD combined with PE also exhibit elevated LDH levels to varying degrees. To date, the relationship between RDW and the occurrence of PE in patients with COPD remains poorly understood.

The increased risk of PE in acute exacerbation of COPD is caused by multiple factors, including systemic inflammation, hypoxemia, oxidative stress, and endothelial dysfunction.[18] Elevated levels of inflammatory factors, including serum interleukin-38 (IL-38), stimulate vascular endothelial cells, leading to structural and functional disorders and increasing the risk of thrombosis.[24] Thus, IL-38 exhibits potent anti-inflammatory effects and may improve the thrombotic status in acute exacerbation of COPD patients by suppressing inflammatory responses.[13] [34] [35] [36] [37] Active infection prevention in patients not only slows disease progression but also reduces the risk of PE development.

Elevated levels of NEUT, a key inflammatory cell type, suggest an active inflammatory state. Additionally, several studies have demonstrated that elevated NEUT levels contribute to inflammation and coagulation system activation, thereby promoting thrombosis.[38] [39] Although our current analysis showed no significant association between elevated neutrophil levels and PE, this conclusion is based on only two available studies. More comprehensive data are required for robust verification. Elevated levels of aspartate aminotransferase (AST) may serve as a marker of systemic inflammatory response and multi-organ damage, indirectly indicating a hypercoagulable state and an elevated risk of thrombosis. Patients with acute exacerbation of COPD frequently present with chronic pulmonary heart disease, and right heart insufficiency can result in hepatic stasis, leading to elevated AST levels.[40] [41] A cohort study conducted in a high-altitude region demonstrated that NEUT and AST levels were associated with an increased risk of PE in patients with acute COPD exacerbation.[11] The study also mentions that this association may be attributed to the inflammatory state and activation of coagulation mechanisms, which may promote PE development under hypoxemic conditions at high altitudes. These biomarkers reflect systemic inflammation, multi-organ dysfunction, and hypercoagulability, which are key mechanisms contributing to PE development in this population.

Our systematic analysis confirmed established risk factors with robust literature support, while revealing several under-investigated factors associated with elevated PE risk in acute exacerbation of COPD patients. These factors encompass reduced elevated levels of NEUT, AST, IL-38, and RDW, along with the utilization of mechanical ventilation. However, the pathophysiological mechanisms underlying these associations require clarification through prospective studies to: (a) determine their causal relationships with PE pathogenesis in acute exacerbation of COPD, and (b) evaluate their potential clinical utility for risk stratification.

Through quantitative analysis, this study identified and clarified the primary risk factors associated with PE in patients with acute exacerbation of COPD. For clinical patients with acute COPD exacerbation presenting multiple risk factors, early recognition of PE risk and timely interventions, particularly focused on risk factor management, are essential.

Limitation

This study has several limitations that must be discussed. First, most included studies were conducted in China, which may limit the generalizability of the findings to other populations and introduce geographic bias in the representation of PE risk factors among patients with acute exacerbation of COPD worldwide. Second, although meta-regression analysis was performed to address heterogeneity, substantial residual heterogeneity remained. Third, the meta-analysis included only published studies, potentially introducing publication bias due to the exclusion of unpublished data.

Conclusion

In conclusion, this study systematically summarizes the key risk factors for PE in patients with acute exacerbation of COPD, including DVT, elevated D-dimer levels, immobilization for >3 to 7 days, lower limb asymmetry, elevated LDH levels, PaCO₂ < 36 mm Hg, and PaO₂ < 80 mm Hg. The identification of these risk factors may facilitate early detection of high-risk patients and prevent PE occurrence in acute exacerbation of COPD patients, ultimately improving their survival outcomes.

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