Introduction
The world has been fighting the COVID-19 pandemic for the past few years. Like other viruses, the SARS-CoV-2 virus underwent mutations, leading to new variants. Despite the availability of a vaccine, in January 2022, the COVID-19 virus managed to resurge, with global reports indicating 23.5 million cases per week. Subsequently, in December 2022 and January 2023, the prevalence of COVID-19 surged once more, peaking at 44.2 million cases per week globally. This condition emphasizes the need to continuously expand our understanding of the disease’s pathogenesis to ensure effective case management [
1,
2].
One significant aspect of this virus’s pathogenesis is strongly associated with the overproduction of pro-inflammatory cytokines. COVID-19 patients exhibit markedly increased levels of inflammatory cytokines (interleukin [IL]-6 and tumor necrosis factor [TNF]-α), fibrinogen, D-dimer, factor VIII, and von Willebrand factor (vWF), along with decreased antithrombin levels, leading to a prothrombotic milieu. It is proposed that this phenomenon occurs due to the entry of SARS-CoV-2 into pneumocytes, where it binds to the angiotensin-converting enzyme (ACE-2), resulting in the depletion of available ACE-2. This enzyme acts on degrading angiotensin-II (Ang-II); hence, its depletion leads to an excess of Ang-II. Excess Ang-II then binds to angiotensin receptor-1, exacerbating the hypercoagulable state by increasing cytokine levels and inducing the expression of plasminogen activator inhibitor 1 (PAI-1) on endothelial cells. This state of hypercoagulability plays a key role in the induction or exacerbation of peripheral artery disease (PAD) [
1-
4].
PAD is a circulatory problem resulting from stenosis and occlusion of medium- to large-sized arteries outside the heart and brain, accounting for coronary artery disease and cerebrovascular disease, respectively. PAD most commonly affects the lower extremities, manifesting as thigh or calf pain during walking or exertion (intermittent claudication) [
5, 6]. Statistics corroborate the relevance of COVID-19 and PAD by demonstrating an increase in PAD cases in tandem with the progression of the COVID-19 pandemic [
4]. Regarding the outcomes, comorbidities that induce a hypercoagulable state, such as hypertension and diabetes, are believed to worsen the prognosis. Individuals with these conditions often exhibit reduced ACE-2 expression, further contributing to elevated Ang-II levels [
3,
7].
Despite the pandemic having subsided, comprehending this aspect remains crucial for enhancing the management of COVID-19 patients with PAD, particularly in light of the potential emergence of new COVID-19 variants and coagulation problems in patients with long COVID-19 syndrome [
8]. Furthermore, while COVID-19’s association with hypercoagulable conditions is well-established, the interconnections of COVID-19, PAD clinical outcomes, and associated comorbidities have not been clearly explained. Most available studies have relied solely on case reports and case series, with several yielding inconsistent results. Hence, we intend to assess clinical outcomes in COVID-19 patients with PAD and identify significantly associated comorbidities.
Materials and Methods
We conducted our systematic review following the guidelines outlined in the Cochrane handbook for systematic reviews of interventions version 6.2 and adhered to the reporting standards of the PRISMA (preferred reporting items for systematic review and meta-analysis) [
9]. Additionally, we have registered this study with an ID of CRD42023405758 in the international prospective register of systematic reviews (PROSPERO) in compliance with international research ethics regulations.
Search strategy
Four independent reviewers conducted an extensive literature search across multiple electronic databases, including PubMed, Scopus, Cochrane, Embase, Wiley, and ProQuest, up to July 22, 2023. Keywords that matched the MeSH browser, such as PAD, acute limb ischemia, critical limb ischemia, intermittent claudication, COVID-19, diabetes mellitus, hypertension, and comorbidities, were employed in the search. Additionally, we utilized Google Scholar as a search engine to point out additional articles that could be found in the several databases included but are being overlooked due to the keywords. Advanced search techniques were employed as applicable and available to refine the search results according to the extra category available in each database.
Study eligibility criteria
Studies were screened based on inclusion and exclusion criteria. The inclusion criteria were observational studies such as cohort prospective and retrospective, PAD patients with COVID-19 with or without comorbidities (with PAD as all arterial diseases outside coronary and brain vascular) defined, and qualitative and quantitative outcomes. The exclusion criteria were PAD patients without COVID-19, uncompleted studies, studies in a language other than English, and irretrievable full-text. The planned procedure is shown in
Figure 1.
Data extraction
We predetermined the outcome sheet in tabular form (MS Excel® for Mac; Microsoft Corporation, Redmond, WA, 2018) to include the following extracted data: author and year of publication; study characteristics, including the design, location, and length of study; study population, including sample size, subject types, range or mean age, gender, BMI, and comorbidities; and study outcomes. Our study outcomes are re-thrombosis, amputation, limb salvage, and mortality rate. In this data extraction, all authors extracted both qualitative and quantitative characteristics. In addition, all authors rechecked the accuracy of the extracted data while performing statistical analysis. All the disagreements between authors were resolved by the majority of opinions.
Risk of bias in assessment
Critical appraisal was performed following the Newcastle-Ottawa quality assessment scale for cohort studies to assess the bias of the included studies qualitatively [
10]. The score is converted to Agency for Healthcare Research and Quality (AHRQ) standards, divided into >6: Good; 4-6: Fair; and 4: Poor. Four reviewers did the quality assessment blind to each other’s scores, then discussed until a consensus was reached [
11].
Statistical analysis
We conducted the statistical analysis using Review Manager version 5.4 from The Nordic Cochrane Center, the Cochrane Collaboration in Copenhagen. We extracted the studies’ odds ratios and prevalence percentages and interpreted the combined effects. To account for potential heterogeneity among the studies, we applied the DerSimonian-Laird random-effects model as sug- gested by Riley et al. We assessed heterogeneity using the estimated effect (I2) statistics, following Cochrane thresholds, where values of 0%, 25%, 50%, and 75% in- dicate insignificant, low, moderate, and high heteroge- neity, respectively [
12].
Results
Study selection and characteristics
A total of 8886 studies were identified through seven databases, with details listed in
Appendix 1.
After re- moving 7860 duplicates, 987 were removed based on their relevant “titles” and “abstracts.” Also, 5 full texts were not retrieved, and 14 full texts were excluded based on the exclusion criteria. Finally, 21 studies were included for qualitative and quantitative analysis (
Figure 1). The characteristics of the included studies are listed in
Appendix 2.
Quality assessment
Each study was assessed for its selection, comparability, and outcomes using the Newcastle Ottawa scale (NOS) for cohort studies (
Appendixes 3 and
4) [
13-
33].
Overall, the studies were rated as high quality with a low risk of bias. According to the AHRQ, only five studies were deemed “poor quality.”
Clinical outcomes
The clinical outcomes of PAD were compared between the control and COVID-19 groups (
Figure 2).
COVID-19 patients were associated with significantly worse outcomes compared to control, evidenced by a higher mortality rate (OR: 3.82 [95% CI, 1.10%, 13.22%]; P=0.03; I2=30%) and higher re-thrombolysis rate (OR: 3.09 [95% CI, 1.31%, 7.28%]; P=0.1; I2=10%), with insignificant to low heterogeneity. However, there is no significant difference between the two groups in amputation rate (OR: 2.99 [95% CI, 0.9%, 9.89%]; P=0.07; I2=27%) and limb salvage rate (OR: 0.58 [95% CI, 0.06%, 5.60%]; P=0.64; I2=82%). Low to high heterogeneity was found in these insignificant results.
The associated comorbidities rate in COVID-19 patients is shown in
Figure 3.
Hypertension was the most common comorbidity (67.0%; 95% CI, 0.54%, 0.80%), followed by diabetes mellitus (DM) (50.0%; 95% CI, 0.37%, 0.62%), hyperlipidemia (47.0%; 95% CI, 0.30%, 0.64%), heart diseases (28.0%; 95% CI, 0.14%, 0.41%), and atrial fibrillation (16.0%; 95% CI, 0.06%, 0.25%) in COVID-19 patients with PAD. However, all these results were correlated with high heterogeneity.
Discussion
In COVID-19 patients, a prothrombotic state and various thrombotic events are prevalent. Compared to other respiratory illnesses like acute influenza or other viral infections, SARS-CoV-2 infection significantly increases the incidence of thrombotic events. These events often manifest with severe clinical symptoms attributed to hypercoagulability induced by cytokine production. While the exact cause of this hypercoagulable state in COVID-19 has remained uncertain, several theories have been proposed, including endothelial dysfunction, coagulation abnormalities, hypoxia-induced endothelial changes, and conventional risk factors. These factors collectively heighten susceptibility to PAD in COVID-19 patients [
34].
Our systematic review and meta-analysis consistently revealed that COVID-19 patients with PAD are associated with higher rates of re-thrombosis (OR=3.09; 95% CI, 1.31%, 7.28%; P=0.01), mortality (OR=3.82; 95% CI, 1.10%, 13.22%; P=0.03), amputations (OR=2.99; 95% CI, 0.90%, 9.89%; P=0.07), and limb salvage (OR=0.58; 95% CI, 0.06%, 5.60%; P=0.64). Despite the relatively lower statistical significance in the amputation and limb salvage groups, they are included in our analysis due to their substantial relevance to overall prognosis and complications in COVID-19 patients [
4]. Our findings related to the mortality rate were in line with systematic review and meta-analysis by Zuin et al. (2022) which found that COVID-19 patients with PAD correlated significantly with higher mortality risk compared to control (OR 2.78 [95% CI, 2.37%, 3.27%]) [
35]. Besides, another study by Ren et al. (2023) also supported these results with a pooled OR of 1.29 (95% CI, 1.1%, 1.5%) [
36]. The need for amputations was significantly increased in the COVID-19 period, related to patients with PAD up to three times, as reported from a review by Pride et al. (2023) [
37]. These findings may also be explained by the indirect impact of COVID-19, which affected healthcare delivery, especially for vulnerable populations.
In accordance with the results of our research, Goldman et al. underscored the impact of COVID-19-induced prothrombotic states on thrombus prevalence in large and medium arteries [
17]. This condition contributes to worse outcomes, including amputation and mortality in COVID-19 patients with PAD. Bellosta et al.’s cohort study further substantiates this, revealing a significant mortality rate (40%) in patients with COVID-19 pneumonia presenting acute lower-extremity ischemia symptoms [
16].
Concerning comorbidities, worse prognoses in COVID-19 patients are often observed when comorbidities are present. Our study aims to identify the most common comorbidities in COVID-19 patients with PAD, with hypertension (67%), DM (50%), hyperlipidemia (47%), heart disease (28%), and atrial fibrillation (16%) emerging as the most prevalent. These findings were similar to other systematic reviews by Rostagi et al. (2021), which found that hypertension, diabetes, and hypercholesterolemia were the most frequent comorbidities in order of occurrences in COVID-19 patients with PAD [
3]. Hypertension, in particular, stands out due to its association with an activated innate immune response and chronic inflammation, which weaken initial immunity against SARS-CoV-2 infection. Hypertensive and diabetic patients also exhibit pre-existing endothelial dysfunction, increasing their susceptibility to PAD [
38]. Rastogi et al. (2021) also revealed that COVID-19 patients with comorbidities of diabetes or hypertension presented with a higher risk of lower limb complications and, therefore, might require anti-coagulation [
3]. These findings underscore the importance of evaluating comorbidities in COVID-19 patients with PAD to guide treatment decisions and improve prognosis.
This systematic review and meta-analysis had several limitations. The clinical outcomes of PAD in COVID-19 patients were presented with a small number of studies and subjects included in the analysis. Due to the small number of studies and subjects, we could not perform adequate subgroup analysis. High heterogeneity results were found, especially in COVID-19-associated comorbidities, using proportional meta-analysis. Besides, according to the NOS scale, some included studies were of poor quality.
Our study provides valuable insights for future research, potentially informing approaches to reduce mortality risk and enhance patient prognosis in patients with PAD. Furthermore, gaining a deeper understanding of PAD enables us to better inform vulnerable individuals about the importance of disease screening, progression, and prevention more effectively, especially in other comorbidities that may worsen the prognosis. It is important to emphasize that despite the pandemic having subsided, these findings retain their significance and may be helpful in patients with similar conditions. Besides, the COVID-19 pandemic has shown us both direct (such as hypercoagulability) and indirect effects (such as impacts on healthcare delivery). Therefore, better disease-related strategies must be prepared for the future.
Ethical Considerations
Compliance with ethical guidelines
This article is a meta-analysis with no human or animal sample.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Authors contributions
Conceptualization, methodology, and investigation: Theresia Feline Husen; Data curation: Theresia Feline Husen, and Kelvin Kohar; Software and formal analysis: Kelvin Kohar; Validation and supervision: Nathanael Nathanael; Resources: Theresia Feline Husen, Ilona Nathania, and Kelvin Kohar; Visualization, and the original draft preparation: Theresia Feline Husen, Ilona Nathania, Kelvin Kohar, and Ruth Angelica; Review, and editing: Theresia Feline Husen, Ilona Nathania, and Kelvin Kohar; Final approval: All authors.
Conflict of interest
The authors declared no conflict of interest.
Acknowledgements
The authors would like to thank all those who contributed to this study’s conceptualization, production, and publication.
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