Introduction

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder among women of reproductive age [1,2], and is characterized by hyperandrogenism, ovulatory dysfunction, and the presence of multiple ovarian cysts [3,4]. PCOS is associated with autoimmune responses and is defined as a polygenic, multifactorial, systemic, and inflammatory disease involving imbalanced steroid levels, which suggests a connection to unhealthy lifestyle factors [5]. Research has implicated elevated insulin levels and insulin resistance among the primary conditions linked to this syndrome [6]. This disorder triggers an increase in free androgens by decreasing sex hormone-binding globulin and promoting androgen production, in turn contributing to metabolic and reproductive dysfunctions [7]. Steroidogenesis is regulated by gonadotropins, namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Increased LH secretion from the pituitary and heightened sensitivity of theca cells to gonadotropin stimulation result in excessive androgen production [8]. When LH concentrations rise disproportionately compared to FSH, the ovaries preferentially amplify androgen production. In women with hyperandrogenism, elevated levels of insulin and insulin-like growth factor (IGF) lead to increased LH activity. Furthermore, PCOS can disrupt ovarian steroidogenesis and folliculogenesis, leading to the development of polycystic or irregular ovaries and anovulation, as well as an increased oxidative stress index [9].

A disrupted lipid profile has been reported to affect 70% of women with PCOS [10]. Oxidative stress is considered a potential factor influencing the pathogenesis of the condition. The regulation of insulin, growth factor, and interactions among androgens in PCOS are primarily affected by the PI3K/AKT/mTOR signaling pathway [11]. Furthermore, DNA mutation induced by oxidative stress contributes to cancer pathogenesis, tumor survival, angiogenesis, and invasion. Consequently, an increased risk of cancer has been reported in women with PCOS [12]. The underlying causes of oxidative stress in these women are not fully understood [13]. Oxidative stress impairs glucose uptake from muscles and adipose tissue and diminishes insulin secretion from the beta cells of the pancreas [14]. Along with a reduction in antioxidants, such oxidative stress may lead to an increased risk of cardiovascular diseases, insulin resistance, high blood pressure, central obesity, and dyslipidemia in individuals with PCOS [15]. Increased malondialdehyde (MDA) levels are indicative of lipid peroxidation in the context of PCOS. Studies suggest a negative correlation between total antioxidant capacity (TAC) and the homeostatic model assessment for insulin resistance (HOMA-IR) [16]. In patients with PCOS, serum paraoxonase-1 (PON-1) levels are positively associated with TAC and inversely associated with HOMA-IR, testosterone, and MDA [17]. Therefore, dietary intake of antioxidants may have beneficial effects in mitigating metabolic complications associated with PCOS [18]. Consequently, herbal medicine has recently been introduced as a complementary therapy in the management and control of this disease [19]. Nowadays, due to the numerous complications caused by various diseases and the influence of diet, the use of dietary supplements to reduce morbidities and complications has garnered considerable global attention [20].

Green coffee contains chlorogenic acid, a bioactive substance [21] that combats oxidative stress [22]. This compound not only possesses antioxidant and anti-inflammatory properties but also plays a key role in the regulation of glucose and fat metabolism in various disorders, including diabetes [23], cardiovascular diseases [24], obesity [25], cancer [26], and liver steatosis [21]. Chlorogenic acid has been shown to reduce the risk of heart disease by lowering low-density lipoprotein (LDL) oxidation, cholesterol, and MDA levels [27]. PON-1 is an esterase produced in the liver and transported by high-density lipoprotein (HDL) [28], leading to its recognition as an antioxidant component of HDL. Studies have indicated that PON-1 inhibits the peroxidation of LDL and the production of oxidized LDL, as well as the hydrolysis of homocysteine, all of which are potent factors in the promotion of cardiovascular disease. Furthermore, PON-1 has been observed to detach from HDL under high-glucose conditions, an issue noted in diabetes [29,30]. Research has shown that chlorogenic acid can increase PON-1 activity [31]. However, a knowledge gap persists concerning the effects of chlorogenic acid on oxidative stress in patients with PCOS.

The study was designed to investigate the effects of green coffee supplementation on PON-1 activity and MDA levels in women with PCOS.

Materials and Methods

Study Design

This study was conducted at the Nutrition Faculty Laboratory of Tehran University of Medical Sciences. We included patients diagnosed with PCOS based on the Rotterdam criteria. These criteria include clinical and/or biochemical signs of hyperandrogenism, ovulation abnormalities, and the presence of enlarged and/or polycystic ovaries on ultrasound images (featuring 12 or more small follicles arranged peripherally and/or an ovarian volume greater than 10 mL). A diagnosis of PCOS is established when 2 or more of these criteria are met [32]. The patients were recruited by a gynecologist.

Inclusion and Exclusion Criteria

The inclusion criteria encompassed women aged 20 to 40 years with PCOS who were referred from a gynecology clinic and expressed willingness to participate. The exclusion criteria were as follows: women who intended to become pregnant during the study period; those with allergies or intolerance to green coffee; those diagnosed with thyroid or kidney disorders or any type of acute disorder; and those on nutritional supplements, including zinc, or high-protein, high-carbohydrate, or high-fat diets. Additionally, participants who became pregnant, did not complete their supplement regimen, or developed other diseases (such as cancer or hormonal, autoimmune, inflammatory, or infectious diseases) after enrollment were also excluded from the study.

Intervention

The green coffee supplement comprised 400 mg of supplement-grade green coffee bean extract powder, including both raw and roasted forms, and contained 50% chlorogenic acid. Additionally, it included a small amount of lactose and less than 2% caffeine (Bonyan Salamat Kasra). The dosage of green coffee used in this study was lower than the level recommended by the manufacturer. By administering a reduced dose of 400 mg/d—compared to the 800 mg/d suggested by the manufacturer—we aimed to prevent minor side effects associated with green coffee consumption, such as sleep disruption. Furthermore, we sought to assess the viability of recommending the long-term consumption of green coffee tablets at this lower dosage. The placebo tablets were composed of starch filler and were designed to be indistinguishable from the green coffee supplements in terms of size, shape, weight, and color.

Study Outcomes

The primary outcomes of this trial included changes in PON-1, MDA, HDL, LDL, cholesterol, triglyceride, HOMA-IR, insulin, and fasting blood sugar (FBS). The secondary outcomes involved changes in body mass index (BMI), waist circumference (WC), and hip circumference (HC).

Study Procedure

The participants were randomly allocated to either the intervention or control group using a randomized block design method. Both researchers and patients were blinded to the supplement type (placebo or green coffee), with the allocation codes held by an independent third party not involved with the research team. Laboratory evaluations were conducted using a blind coding system. Individuals in the intervention group received 1 tablet of green coffee supplement daily, whereas the control group was given a placebo capsule that appeared visually similar to the green coffee supplement. This regimen was followed for 6 weeks. Before and after the intervention, a registered nurse collected a 7-mL blood sample from each participant after 12 hours of fasting. These samples were centrifuged, and the resulting sera were stored at −70 °C until analysis.

Dietary Intake and Physical Activity

Daily dietary intake, based on 24-hour recall for 2 weekdays and 1 weekend day [33,34], and physical activity levels were assessed at the beginning and end of the intervention period. To evaluate physical activity, the International Physical Activity Questionnaire [35] was used in interviews, with results reported in metabolic equivalent hours per day [36,37]. The daily dietary intake of nutrients was calculated using Nutritionist IV software (First Databank Division, The Hearst Corporation) [38].

Measurement of Biochemical Parameters

Before and after the intervention period, 7 mL of blood samples were collected following 12 hours of fasting. These samples were centrifuged, and the sera were stored at −70 °C until analysis. The concentrations of PON-1 and MDA were determined using a commercial enzyme-linked immunosorbent assay kit (Bioassay Technology Laboratory), following the manufacturer’s instructions. FBS and lipid profile components (triglyceride, cholesterol, LDL, and HDL) were measured with specific enzymatic kits (Pars Azmoon), and the results were compared before and after the intervention. HOMA-IR was calculated using the following equation: fasting glucose (mmol/L)×fasting insulin (µIU/mL)/22.5.

Anthropometrics and Appetite Assessment

Anthropometric indices and appetite levels were assessed before and after a 6-week intervention. Participants were weighed without shoes and in light clothing to the nearest 0.1 kg using a digital scale (SECA). Height was also measured without shoes, following standard procedures, to the nearest 0.1 cm with a tape measure. WC and HC were determined using a flexible measuring tape. WC was measured to the nearest 0.5 cm at the midpoint between the last rib and the iliac crest, while HC was measured at the maximum circumference over the buttocks. To assess appetite, the Simplified Nutritional Appetite Questionnaire was administered [39]. This questionnaire comprises 4 questions, each with 5 possible answers. Scores are assigned on a scale of 1 to 5 points for options 1 through 5, respectively. The total appetite score is then calculated, with a score ranging from 4 to 14 indicating low appetite and scores from 15 to 20 indicating normal appetite [40].

Randomization

This study was a double-blind controlled randomized clinical trial (RCT). Patients were randomly assigned to either the intervention group or the control group using a randomized block design. The sealed envelope method was employed to ensure randomization, and the study participants were unaware of the randomization details, such as block sizes. Both the researchers and the patients were blinded to the nature of the supplement (placebo or green coffee). The codes for the supplements were maintained by an independent third party not involved with the research team. Laboratory evaluations were also conducted using a blind coding system.

Sample Size

The sample size for the current study was calculated to detect a change of 3.5 pg/mL in PON-1 levels between the intervention and control groups, with a power of 90% and a 95% confidence interval. A mean difference of 12 pg/mL was considered significant. Based on a standard deviation of 13.5 pg/mL for each group, we determined that 22 samples per group were needed.

Statistical Analysis

The assumptions of analysis of covariance (ANCOVA) were evaluated, revealing that the residuals were not normally distributed. Given the non-normal distribution of the groups, we employed Quade ANCOVA. This method tests for equality of residuals across groups, which are derived from the linear regression of both the ranked response variable and the ranked covariate. Furthermore, Quade ANCOVA differs from standard parametric ANCOVA analyses in that it treats covariates as random rather than fixed effects. Data analysis was conducted using IBM SPSS for Windows ver. 26.0 (IBM Corp.). A p-value of less than 0.05 was considered to indicate statistical significance.

Ethical Consideration

This study was a double-blind RCT conducted with the approval of the Ethics Committee of the Faculty of Medical Sciences and Technologies of the Islamic Azad University, Science and Technology Branch (IR.IAU.SRB.REC.1398.045). The RCT was registered with the Iranian Registry of Clinical Trials (IRCT20191129045540N1). Patients provided their signed consent by completing the form approved by the Ethics Committee.

Results

In this study, of the 44 individuals with PCOS initially enrolled, 10 participants were withdrawn. Consequently, 34 participants (17 in the intervention group and 17 in the control group) completed the study protocol. The general characteristics of the patients are presented in Table 1 and Figure 1. The necessary assumptions for conducting covariance analysis were not satisfied; therefore, we employed Quade nonparametric ANCOVA.

Anthropometric Measurements, Physical Activity, and Appetite Score

No significant changes were observed in weight, BMI, HC, WC, or waist-to-hip ratio (WHR) following the intervention. Additionally, the level of physical activity was unchanged from baseline to the end of the study period (Table 2). The p-values obtained indicate that green coffee supplementation did not significantly impact the aforementioned variables. Furthermore, the McNemar test showed that green coffee supplementation had no significant impact on appetite. In the investigation into the effects of green coffee consumption on appetite, no change in appetite was apparent among the control group, and the condition of the participants remained unchanged. In the treatment group that consumed green coffee, only 1 out of 14 individuals with a low appetite reached a normal appetite level.

Dietary Intake

The dietary intake of macronutrients and vitamin E, as well as daily energy intake, were evaluated as potential confounding factors influencing PON-1 levels [41]. These variables remained consistent between baseline and after the intervention. Consequently, they were not considered confounding variables (Table 3).

Glycemic Indices and Lipid Profile

No significant changes were noted in FBS (p=0.986), insulin level (p=0.201), or HOMA-IR (p=0.173) following the intervention. Furthermore, neither LDL cholesterol (LDL-C, p=0.520) nor HDL cholesterol (HDL-C, p=0.518) levels changed significantly. However, Quade ANCOVA analysis revealed that green coffee supplementation significantly reduced total cholesterol by 18.8 units (p=0.013) and triglyceride by 6.1 units (p=0.054). Thus, green coffee supplementation led to a notable decrease in total cholesterol and triglyceride levels, without significantly impacting LDL or HDL levels (Table 4).

MDA and PON-1 Activity

The findings indicated that supplementation with green coffee significantly raised the PON-1 level by 3.5 units (p=0.038). However, no significant change was observed in MDA levels (p=0.314) (Table 4).

Discussion

The results of this study revealed that green coffee consumption significantly elevated PON-1 activity and reduced triglyceride and cholesterol levels. Conversely, no meaningful changes were observed in MDA levels, anthropometric measurements, glycemic indices, or appetite levels as a result of green coffee intake.

In PCOS, the usual cyclic change in gonadotropin-releasing hormone (GnRH) is predominantly absent, leading to a constant high-frequency drive that alters gonadotropin levels—specifically, an increase in LH and a decrease in FSH—contributing to hyperandrogenism and ovulatory disruption [42]. Clinical and preclinical studies have shown that, despite the negative feedback from estradiol and progesterone, a high LH pulse frequency persists. Moreover, even exogenous progesterone does not suppress the LH pulse frequency, indicating a relative resistance to negative feedback [43]. Hyperandrogenemia may be responsible for the resistance to the negative feedback inhibition of the GnRH pulse, as the normalization of the negative feedback response was observed with the blockade of androgen receptors [42]. A study of adult women with PCOS demonstrated that flutamide, an androgen-receptor antagonist, normalized the sensitivity of GnRH to negative feedback following pretreatment with combined progesterone/estradiol, although the baseline pulse frequency remained unchanged [44].

Effects of Green Coffee Supplementation on Glycemic Indices

The present study found no significant differences in glycemic indices between the groups after green coffee supplementation. Hyperinsulinemia, as demonstrated in patients with PCOS, results in the overproduction of androgens in the adrenal glands and ovaries through several mechanisms: (1) elevation of LH secretion, (2) increased adrenocorticotropic hormone level, (3) increased theca cell sensitivity to LH, (4) reduction in IGF-1 binding protein level, (5) upregulation of IGF-1 receptors in the ovaries, and (6) inhibition of sex hormone-binding globulin production in the liver [45]. In recent years, several articles have indicated that chlorogenic acid inhibits alpha-glycosidase activity in the pancreas in vitro [46,47]. Zuniga et al. [48] conducted a study examining the effect of chlorogenic acid administration on glycemic control, insulin secretion, and insulin sensitivity in patients with glucose intolerance. When 400 mg of chlorogenic acid was administered 3 times a day for 12 weeks, a significant decrease in fasting glucose and a significant increase in insulin sensitivity were observed in the intervention group. A meta-analysis revealed that chlorogenic acid reduces blood glucose when consumed for more than 8 weeks [49]. Another clinical trial aimed to evaluate the effectiveness of 2 supplements—caffeine and caffeine with chlorogenic acid—on fasting glucose and insulin levels in patients with type 2 diabetes and fatty liver. This study suggested that, except for the increased insulin levels associated with chlorogenic acid plus caffeine, none of these parameters changed significantly after the 6-month intervention compared to the control group [50].

In line with our study, Khalili-Moghadam et al. [51] examined the effect of green coffee supplementation on glycemic indices in patients with type 2 diabetes. Patients received green coffee extract (GCE) containing 400 mg of chlorogenic acid twice a day for 10 weeks. The findings demonstrated a significant decrease in FBS, while insulin and HOMA-IR did not change significantly. Conversely, Roshan et al. [52] showed that 800 mg/d of GCE for 8 weeks can decrease blood glucose and insulin resistance in patients with metabolic syndrome. Similarly, an animal study indicated that a high-fat diet plus 0.5% w/w GCE in mice with metabolic syndrome does not affect insulin resistance after 12 weeks [53]. Additionally, a meta-analysis revealed that GCE can decrease FBS, while it showed no effect on insulin or HOMA-IR [54]. Chlorogenic acid has been proposed to modify FBS by activating AMP-activated protein kinase, which promotes glucose uptake through the fusion of glucose transporter 4 with the plasma membrane [48]. Furthermore, GCE activates hepatic proliferation-activated receptor α (PPAR-α), facilitating lipid elimination from the liver and reducing insulin resistance. Chlorogenic acid also inhibits glucose 6-phosphatase enzyme activity, leading to reduced glucose production through glycogenolysis and gluconeogenesis [51]. Notably, contradictory findings are available. In this study, we evaluated the effect of green coffee supplementation on PCOS, while other studies have focused on different populations. Additionally, differences in baseline FBS and insulin levels can yield varying results.

Effects of Green Coffee Supplementation on Lipid Profile

The results of the present study suggest that green coffee can lower triglyceride and total serum cholesterol levels without affecting HDL-C and LDL-C concentrations. Roshan et al. [52] conducted a study that paralleled ours, with the goal of assessing the effects of green coffee supplementation on glycemic and lipid indices. In their study, patients received 400 mg of green coffee twice daily for 12 weeks. Their findings indicated no significant differences in lipid profiles. Additionally, a meta-analysis revealed that chlorogenic acid effectively lowers LDL concentrations only in women with normal LDL levels who receive supplementation for more than 8 weeks. Similarly, an increase in HDL levels was noted only in women who had low HDL levels and took supplements for over 8 weeks [49]. The influence of green coffee on the lipid profile is mediated by several potential mechanisms. Chlorogenic acid, a key component of green coffee, inhibits the intestinal absorption, transfer, and hepatic biosynthesis of lipids and cholesterol, resulting in reduced cholesterol levels in the serum or liver [55]. Experimental studies have also shown that chlorogenic acid can modulate specific genes involved in lipid metabolism by upregulating PPAR-α expression [56]. A meta-analysis of 17 RCTs demonstrated that green coffee supplementation significantly reduced LDL and cholesterol levels, although triglyceride levels remained unchanged. The analysis also revealed an improvement in HDL levels. Furthermore, a dose-response meta-analysis indicated no significant relationship between the dose and duration of green coffee supplementation and the lipid marker profile [57]. A recent RCT found that supplementing with green coffee twice daily can decrease triglyceride levels and increase HDL levels in patients with type 2 diabetes. However, no significant changes were observed in LDL or cholesterol concentrations [51]. These conflicting results may be attributed to the characteristics of the participants and the specifics of the supplementation regimen. It has been observed that some RCTs report an increase in LDL levels and a decrease in HDL levels following green coffee supplementation [58,59]. Overall, the findings suggest that factors such as oxidation and degradation, which produce structural changes in chlorogenic acid, may contribute to the varying effects on lipid marker metabolism [57].

Effects of Green Coffee Supplementation on Anthropometric Measurements

The results of this study did not indicate a significant difference in anthropometric parameters. In contrast, Vinson et al. [60] demonstrated that supplementation with chlorogenic acid (both 1,050 mg and 750 mg) for 6 weeks led to reductions in body weight, body fat percentage, and BMI. In a separate study involving individuals with overweight, for 12 weeks the intervention group received 360 mg of chlorogenic acid, while the control group received 35 mg. After the intervention, the intervention group exhibited significantly decreased abdominal fat, weight, and WC [61]. Consistent with our findings, an RCT showed that taking 400 mg of green coffee for 8 weeks did not significantly alter BMI in patients with metabolic syndrome, although WC decreased significantly [52]. Furthermore, a study aimed at assessing the impact of roasted green coffee consumption on body fat percentage and WC in individuals with metabolic syndrome found that green coffee consumption reduced body fat percentage in both participants with and without hypercholesterolemia. However, WC reduction was only observed in individuals with normal cholesterol levels, with no such reduction in the hypercholesterolemic group [62]. In agreement with our study, a recent RCT indicated that supplementation with 400 mg of decaffeinated GCE for 12 weeks had no significant effects on anthropometric parameters in breast cancer survivors [63]. Additionally, a meta-analysis revealed that green coffee supplementation significantly reduced BMI and WC, but not WHR. In a dose-response analysis, this meta-analysis also indicated no significant relationship between the dosage of chlorogenic acid and changes in anthropometric indices [64]. Subgroup analysis from an umbrella meta-analysis suggested that green coffee supplementation at dosages ≤600 mg/d and interventions lasting longer than 7 weeks were particularly likely to reduce body weight [65]. Considering the varying results from clinical trials and meta-analyses, one may conclude that factors such as participant characteristics and baseline anthropometric parameters may influence changes in anthropometric indices. To clarify the effects of supplementation, more clinical trials with larger populations are warranted.

Effects of Green Coffee Supplementation on Antioxidant Levels and Oxidative Stress

In the present study, a significant increase was observed in PON-1 activity, while MDA levels did not change significantly. Polyunsaturated fatty acid peroxidation generates reactive oxygen species (ROS) through oxidative stress. Excessive ROS can lead to increased tissue damage in the ovary [66]. Additionally, ROS production can disrupt the mitochondrial membrane, resulting in the liberation of cytochrome c, which is involved in the apoptotic process. Pro-apoptotic proteins can cause DNA damage and trigger apoptosis. Antioxidant agents have been shown to improve antioxidant status and reduce potential consequent injury [67]. In an interventional and crossover study that evaluated the effects of consuming 6 g/d of green and roasted coffee in beverage form, Martinez-Lopez et al. [68] found that the antioxidant capacity, as measured by oxygen radical absorbance capacity and ferric reducing antioxidant power, increased significantly. However, no change was noted in antioxidant status, as assessed by 2,2′-azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid). Oxidative damage to serum lipids and proteins, indicated by MDA and carbonyl group levels, decreased significantly [68].

Another study showed that chlorogenic acid isomers mitigated oxidative stress in human gut Caco-2 cells treated with inflammatory proteins by activating the NrF2/keap1-Are signaling pathway. Chlorogenic acid also reduced cellular oxidative stress by scavenging ROS and increasing glutathione (GSH) activity [69]. Furthermore, Feng et al. [70] investigated the effects of liposomal chlorogenic acid on the livers of rats and found that GSH and superoxide dismutase activities significantly increased in the treatment group. Additionally, they observed a significant reduction in MDA levels and an increase in TAC compared to the control group. In an RCT, Fasihi et al. [71] observed that supplementation with 400 mg of green coffee twice daily in patients with metabolic syndrome was associated with a decrease in MDA level. Notably, the dosage used in our study was lower than that in the Fasihi study. Additionally, the target populations in the studies differed. Consistent with our findings, a recent RCT reported that 400 mg of green coffee supplementation twice weekly for 10 weeks in patients with diabetes had no significant impact on MDA level [51]. In another RCT, supplementation with 800 mg/d of green coffee for 8 weeks in patients with dyslipidemia significantly increased TAC and decreased oxidized LDL-C [72]. The composition of raw versus roasted coffee can influence polyphenol activity, potentially explaining these inconsistent results; thus, further clinical studies are warranted.

The present study had certain limitations. First, the small sample size was due to financial constraints that limited our ability to involve multiple centers in the recruitment process. Second, budgetary restrictions prevented us from assessing the impact of green coffee consumption on endothelial factors that could influence other parameters in patients with PCOS. A strength of our trial is that, to our knowledge, it is the first RCT to investigate the effects of green coffee supplementation on PON-1 and MDA markers in patients with PCOS.

According to observed changes and information regarding loss to follow-up, the power of the study was 82% for the sample size of 34, which is considered acceptable. Although the sample size in this study was small, we obtained acceptable and meaningful results. We suggest that future studies investigate the same effect in a larger population to validate our findings.

Conclusion

The results of this study indicate that green coffee supplements can increase PON-1 levels and alter lipid profiles, including serum triglyceride and cholesterol levels, in women with PCOS. However, no significant changes were observed in glycemic indices or oxidative markers. Consequently, further research in this area is warranted.

HIGHLIGHTS

• Polycystic ovary syndrome is a prevalent endocrine disorder among women of reproductive age.

• Oxidative stress is considered a potential factor in the pathogenesis of polycystic ovary syndrome.

• Green coffee contains chlorogenic acid, a bioactive substance known for its antioxidant and anti-inflammatory properties.

• Supplementation with green coffee may increase paraoxonase-1 activity and alter cholesterol and triglyceride levels. However, it has no significant impact on malondialdehyde levels or glycemic indices.

Article information

Ethics Approval

The study received approval from the Ethics Committee of the Faculty of Medical Sciences and Technologies of the Islamic Azad University, Science and Technology Branch, under the reference number IR.IAU.SRB.REC.1398.045. It was conducted in accordance with the principles set forth in the Declaration of Helsinki. The RCT was registered with the Iranian Registry of Clinical Trials (IRCT20191129045540N1). Patients provided their signed consent by completing the form approved by the Ethics Committee.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding

None.

Availability of Data

The datasets are not publicly available but can be obtained from the corresponding author upon reasonable request.

Authors’ Contributions

Conceptualization: AS; Data curation: MM, AM, AI; Formal analysis: MY, MGH; Investigation: AI, MM, AM; Methodology: AI, MM, AM; Software: MY, MGH; Resources: MVD; Writing–original draft: AI, MVD, MG, AM, MM, MY; Writing–review & editing: all authors. All authors read and approved the final manuscript.

Acknowledgements

We would like to express our gratitude to the numerous officers and managers, including the Commissioner of the Korea Disease Control and Prevention Agency (KDCA), for their invaluable support during the COVID-19 response. We also extend our thanks to all those who contributed to this work and participated in the process of risk assessment.

Figure 1.

Flowchart of samples.

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