Depression and anxiety, peripheral blood inflammatory factors, and stress levels on therapeutic outcomes in patients with chronic wounds

Abstract

BACKGROUND

The incidence of chronic wounds is rising due to an aging population and lifestyle changes in our country. In addition, as the disease spectrum evolves, chronic wounds have become common clinical issues that seriously threaten health and impose significant social and economic burdens.

AIM

To investigate how depression, anxiety, peripheral blood inflammatory factors, and stress levels affect therapeutic outcomes in patients with chronic wounds.

METHODS

Retrospectively collected clinical data from 110 patients with chronic wounds treated at Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City) between January 2021 and December 2023, categorizing them into effective and ineffective groups based on treatment effects. Differences between both groups were analyzed using univariate analysis, independent risk factors identified via logistic regression, and their predictive value assessed through receiver operating characteristic analysis.

RESULTS

Following treatment, 95 cases were classified as the effective group (cured or improved), while 15 cases with improvement formed the ineffective group. Significant differences between both groups were noted in wound area, infection status, daily bed time, Hamilton Anxiety Rating Scale (HAMA) scores, Hamilton Depression Rating Scale (HAMD) scores, and levels of interleukin-6, tumor necrosis factor-alpha, and superoxide dismutase (P < 0.05). Logistic regression analysis identified a wound area ≥ 7 cm², HAMA ≥ 9 scores, and HAMD ≥ 8 scores were independent risk factors for ineffective treatment in patients with chronic wounds (P < 0.05). The receiver operating characteristic curve analysis revealed that the area under the curve for ineffective treatment based on wound area, HAMA, and HAMD was 0.767, 0.805, and 0.768 respectively.

CONCLUSION

Wound size, anxiety, and depression are significant factors influencing the therapeutic outcomes in patients with chronic wounds that require careful attention, alongside the development of appropriate strategies.

Key Words: Chronic wound; Depression; Anxiety; Inflammatory factors; Stress level; Clinical effect

Core Tip: This study retrospectively analyzed clinical data from 110 patients with chronic wounds to assess the effects of depressive and anxious moods, peripheral blood inflammatory markers, and stress levels on treatment outcomes. The results showed an overall efficacy rate of 86.36%, with independent risk factors identified as wound size and depression/anxiety levels. Additionally, peripheral blood inflammatory markers and stress levels were lower in the effective group than in the ineffective group. Therefore, for patients with chronic wound, it is crucial to address not only the wounds but also their psychological well-being and inflammatory stress status to improve treatment effectiveness.

INTRODUCTION

Chronic wounds are defined as skin tissue damage resulting from various etiologies that fail to heal within a typical timeframe, generally beyond four weeks. These include pressure injury, venous ulcers of the lower extremities, diabetic foot ulcers, radiation ulcers, and postoperative wound complications[1]. Chronic wounds are characterized by high incidence rates, prolonged treatment durations, and substantial healthcare costs. They not only cause physical pain in patients but also interfere with their normal life, increase the economic and psychological burden, and seriously affect the quality of life[2,3]. Therefore, it is of great significance to explore the factors affecting the clinical outcomes of patients with chronic wounds to optimize treatment plans, improve the quality of life of patients, and reduce medical costs. Recently, with the continuous increase in medical research and progress in medical technology, treatment methods for chronic wounds have become increasingly diversified, mainly including drug, physical, surgical, and biological therapies[4]. However, due to the complexity and heterogeneity of chronic wounds, the effectiveness of identical treatments can vary significantly among different patients. Relevant studies have indicated that the onset and progression of chronic wounds are associated with inflammatory response, suggesting that their clinical effectiveness may be influenced by inflammatory factors and stress levels[5,6]. Additionally, other studies have demonstrated that some patients with chronic wounds experience mobility challenges and may require assistance from others for activities such as attending medical appointments or changing dressings[7]. This reliance can lead to emotional burdens characterized by feelings of guilt towards caregivers[7]. Therefore, this study investigates the effects of depression, anxiety, peripheral blood inflammatory factors, and stress levels on the therapeutic outcomes in patients with chronic wounds to provide a theoretical foundation for clinical diagnosis and treatment.

MATERIALS AND METHODS

General information

The clinical data of 110 patients with chronic wounds treated at Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City) from January 2021 to December 2023 were retrospectively collected. Inclusion criteria were as follows: (1) Skin and subcutaneous tissue injuries; (2) Wounds unhealed for more than 4 weeks; and (3) Wound area ≤ 25 cm². Exclusion criteria were: (1) Evident signs of wound infection; (2) Ulcers resulting from diabetic conditions, venous insufficiency, malignancy, or radiation; (3) Concurrent systemic diseases such as hematological disorders, immune system dysfunctions, infections, or malignancies; (4) Vital organ failure including the heart, liver, or kidneys; (5) Presence of mental health disorders; (6) Severe malnutrition or compromised immunity; (7) Incomplete clinical data; and (8) Participants lost to follow-up. The study was reviewed and approved by the Institutional Review Board of Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), approval No. 2024-148-01.

Efficacy criteria

On the 30^th day following the completion of treatment, the patients were asked to review and observe recovery and determine its efficacy. The evaluation criteria for the curative effect were as follows: (1) Cure: Pain disappeared, wound healing, no secretions, and fresh red granulation tissue can be seen; (2) Improvement: The pain is reduced, the area of the wound is reduced, there is a small amount of secretion and fresh red granulation tissue can be seen; and (3) Not healed: The pain is strong, the wound has not healed, and there is a large amount of secretion[8]. The total effective rate = (cured cases + improved cases)/total cases × 100%.

Data collection

General information: Age, sex, education level, wound area, wound type, wound infection, physical exercise, daily bedtime. The Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD) were employed to assess the level of anxiety and depression in patients within one week of treatment. The HAMA comprises 14 items, with scores interpreted as follows: (1) ≤ 7 reflects no anxiety symptoms; (2) 8-13 suggests possible anxiety; (3) 14-20 indicates definite anxiety; (4) 21-28 denotes marked anxiety; and (5) ≥ 29 indicates severe anxiety[9]. The HAMD consists of 17 items, with scores interpreted as follows: (1) ≤ 7 indicates no depressive symptoms; (2) 8-16 suggests possible depression; (3) 17-24 indicates moderate depression; and (4) ≥ 24 signifies severe depression[10]. Levels of inflammatory factors interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) and stress factors [superoxide dismutase (SOD) and malondialdehyde (MDA)] were measured within 24 hours of patient admission. A fasting venous blood sample (5 mL) was collected in the morning, centrifuged at 3000 rpm for 15 minutes to obtain the supernatant, which was stored at -80 °C for subsequent analysis using an enzyme-linked immunosorbent assay.

Statistical analysis

Statistical software (SPSS 27.0) was used to process the data of the 110 patients with chronic wounds. Normally distributed measurement data were expressed as mean ± SD, and comparisons between the two groups were performed using a two-independent sample t test. The ratio of counting data (%) is indicated, and the χ² test was used for intergroup comparisons. P < 0.05 indicated that the difference was statistically significant. Logistic regression analysis was performed on the statistically significant variables identified in the univariate analysis. The enter method was employed to iteratively compute the odds ratio (OR) and 95% confidence interval (95%CI). The receiver operating characteristic (ROC) curve of a single continuous variable was obtained using the MedCalc software, and the area under the curve (AUC) and optimal cut-off value of the continuous variable were calculated.

RESULTS

Clinical efficacy rate in patients with chronic wounds

Following treatment, 53 patients were cured and 42 exhibited an improvement in their condition, classifying them into the effective group. Conversely, 15 patients exhibited no changes and were categorized as the ineffective group. The details of the treatment are presented in Figure 1A.

Figure 1 Patients with chronic wounds. A: Clinical effective rate in patients with chronic wounds; B: Depression and anxiety scores in patients with chronic wounds; C: Level of inflammatory factors in the peripheral blood of patients with chronic wound surfaces; D: Stress levels in patients with chronic wounds; E: The receiver operating characteristic curves of the related variables. ^aP < 0.05 vs ineffective group. HAMD: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; SOD: Superoxide dismutase; MDA: Malondialdehyde.

General data of patients with chronic wounds

Compared with the ineffective group, the effective group had a smaller wound area, a higher incidence of wound infection, and a lower daily bed time (P < 0.05). There were no significant differences between the two groups in terms of age, sex, educational level, wound type, or physical exercise participation (P > 0.05) (Table 1).

Table 1 General data of patients with chronic wounds, n (%).

Index	Effective group (n = 95)	Ineffective group (n = 15)	χ2/t	P value
Age (year), mean ± SD	56.09 ± 13.89	54.20 ± 18.11	0.470	0.639
Sex	/	/	0.322	0.571
Man	56 (58.95)	10 (66.67)	/	/
Woman	39 (41.05)	5 (33.33)	/	/
Educational level	/	/	0.006	0.938
Junior college or below	58 (61.05)	9 (60.00)	/	/
College degree or above	37 (38.95)	6 (40.00)	/	/
Wound area (cm2), mean ± SD	5.29 ± 1.54	7.73 ± 1.79	5.586	< 0.001
Wound type	/	/	0.454	0.978
Pressure ulcer	21 (22.11)	4 (26.67)	/	/
Venous blood ulcer	18 (18.95)	3 (20.00)	/	/
Diabetic foot ulcers	16 (16.84)	3 (20.00)	/	/
Traumatic ulcer	23 (24.21)	3 (20.00)	/	/
Other	17 (17.89)	2 (13.33)	/	/
Wound infection	/	/	11.579	< 0.001
Yes	32 (33.68)	12 (80.00)	/	/
No	63 (66.32)	3 (20.00)	/	/
Participates in physical exercise	/	/	0.750	0.387
Yes	71 (74.74)	5 (33.33)	/	/
No	24 (25.26)	10 (66.67)	/	/
Daily bed time (hour), mean ± SD	11.71 ± 2.36	15.93 ± 2.40	6.431	< 0.001

Depression and anxiety scores of patients with chronic wounds

The HAMA and HAMD scores of the effective group were 6.49 ± 2.18 points and 6.24 ± 2.39 points, respectively. In the ineffective group, the HAMA score was 10.60 ± 2.61, and the HAMD score was 8.33 ± 1.92. Compared to the ineffective treatment group, the HAMA and HAMD scores in the effective group were lower (t = 6.600, P < 0.001 and t = 3.229, P = 0.002, respectively) (Figure 1B).

Levels of inflammatory factors in the peripheral blood of patients with chronic wounds

The levels of IL-6 and TNF-α in the effective group were 16.19 ± 4.01 pg/mL and 56.49 ± 13.36 pg/mL, respectively. In the ineffective group, the levels of IL-6 were 22.67 ± 5.92 pg/mL, and the level of TNF-α was 65.80 ± 12.87 pg/mL. Levels of IL-6 and TNF-α in the effective group were lower than those in the ineffective group (t = 4.089, P = 0.001 and t = 2.520, P = 0.013, respectively) (Figure 1C).

Stress levels of patients with chronic wounds

The SOD and MDA levels in the effective group were 103.72 ± 14.77 nmol/L and 37.23 ± 8.61 nmol/L, respectively. The SOD and MDA levels in the ineffective group were 107.80 ± 12.28 nmol/L and 47.20 ± 9.41 nmol/L, respectively. There was no significant difference in the SOD levels between the two groups (t = 1.016, P = 0.312). The MDA levels in the effective treatment group were lower than those in the ineffective treatment group (t = 4.117, P < 0.001) (Figure 1D).

Multivariate logistic regression analysis

Using clinical efficacy as the dependent variable, wound area, presence of wound infection, daily bed rest duration, HAMA, HAMD, IL-6, TNF-α, and MDA were incorporated as independent variables in the logistic regression model. Continuous variables were assigned using their optimal cut-off values as detailed in Table 2. Logistic analysis showed that wound area ≥ 7 cm² (OR = 16.374, 95%CI: 1.037-258.609), HAMA scores ≥ 9 (OR = 100.709, 95%CI: 2.587-3927.125), and HAMD scores ≥ 8 (OR = 90.937, 95%CI: 2.231-3707.301) were independent risk factors for treatment inefficacy in patients with chronic wounds (P < 0.05) (Table 3).

Table 2 Logistic regression model assignment situation.

Variables	Assignments
Clinical efficacy	1: Ineffective, 0: Effective
Wound area	1: ≥ 7 cm2, 0: < 7 cm2
Wound infection	1: Yes, 0: No
Daily bed time	1: ≥ 14 hours, 0: < 14 hours
HAMA	1: ≥ 9 scores, 0: < 9 scores
HAMD	1: ≥ 8 scores, 0: < 8 scores
IL-6	1: ≥ 19 pg/mL, 0: < 19 pg/mL
TNF-α	1: ≥ 63.88 pg/mL, 0: < 63.88 pg/mL
MDA	1: ≥ 41 nmol/L, 0: < 41 nmol/L

HAMD: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; MDA: Malondialdehyde.

Table 3 Multivariate logistic analysis of factors influencing clinical efficacy in patients with chronic wounds.

Variable	B	SE	Wald χ2	P value	OR	95%CI
Wound area	2.796	1.408	3.943	0.047	16.374	1.037-258.609
Wound infection	0.062	1.343	0.002	0.963	1.064	0.077-14.787
Daily bed time	2.170	1.695	1.640	0.200	8.761	0.316-242.699
HAMA	4.613	1.869	6.094	0.014	100.790	2.587-3927.125
HAMD	4.510	1.892	5.684	0.017	90.937	2.231-3707.301
IL-6	0.917	1.323	0.480	0.488	2.501	0.187-33.450
TNF-α	0.164	1.323	0.015	0.902	1.178	0.088-15.752
MDA	2.934	1.716	2.923	0.087	18.797	0.651-542.754

OR: Odds ratio; CI: Confidence interval; HAMD: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; MDA: Malondialdehyde.

ROC curve analysis of relevant variables

The ROC analysis results showed that the AUC of the wound area, HAMA, and HAMD, were 0.767, 0.805, 0.768, respectively, and the integrated AUC for the three methods is 0.940 (Table 4 and Figure 1E).

Table 4 Receiver operating characteristic curve analysis of the related variables.

Variable	AUC	SE	95%CI	P value
Wound area	0.767	0.063	0.676-0.842	< 0.001
HAMA	0.805	0.057	0.719-0.875	< 0.001
HAMD	0.768	0.058	0.678-0.844	< 0.001
United	0.940	0.0297	0.878-0.976	< 0.001

CI: Confidence interval; HAMD: Hamilton Depression Rating Scale; HAMA: Hamilton Anxiety Rating Scale; AUC: Area under the curve.

DISCUSSION

Chronic wounds represent significant clinical and public health challenges due to their high incidence, complex pathogenesis, and treatment difficulties[11]. Statistics indicate that among patients with diabetes aged > 50 years, the incidence of diabetic foot is as high as 8.1%, the annual mortality rate of diabetic foot ulcers is as high as 11%, and the mortality rate of amputation patients is as high as 22%, with a high overall incidence[12,13]. In addition, patients with chronic wounds often face huge psychological pressure due to long-term disease failure, long treatment cycles, and possible complications, resulting in emotional problems, such as anxiety and depression, which affect clinical efficacy and are not conducive to postoperative recovery. Therefore, it is essential to investigate the factors influencing clinical efficacy in patients with chronic wounds. This study included 110 patients with chronic wounds to evaluate clinical efficacy. The results showed that 95 patients were cured or showed improvement, and the total efficacy rate was 86.36%. Further analysis of the clinical data of 110 patients with chronic wounds showed that the single-factor results such as wound area, wound infection, HAMA, HAMD, IL-6, TNF-α, and MDA influenced poor treatment outcomes in patients with chronic wounds. Multifactor logistic analysis showed that a wound area ≥ 7 cm², HAMA scores ≥ 9, and HAMD scores ≥ 8 are independent risk factors for poor treatment efficacy in patients with chronic wounds.

Oliveira et al[14] pointed out that the wound area is related to growth factors, whereby a larger wound area necessitates an increased supply of nutrients and growth factors to facilitate the healing process. However, patients’ nutritional status and self-repair capabilities are often limited, making it challenging to meet the healing demands of extensive wounds. In addition, large wounds often take longer to heal, and a longer healing process may lead to more complications, such as scarring and dysfunction. Liu et al[15] pointed out that when inflammation occurs in the body, it further damages the wounded tissue and may also affect the normal function of the surrounding healthy tissue, which is not conducive to patient recovery. Pomponio et al[16] found that during wound infection, bacteria, and bacterial metabolites would remain in the patient’s wound, which affects the normal growth of the wound tissue and leads to difficult wound healing. Currently, the main treatment for acute wound infections is antibiotics, however, their inappropriate and excessive use in chronic wound infections not only increases treatment costs but may also prolong recovery time. Moreover, long-term use of antibiotics may lead to an increase in bacterial resistance, making infections more difficult to control[17]. In addition, prolonged bed rest can result in decreased physical activity, compromised blood circulation, and impaired nutrient delivery and waste removal from the wound, all of which are detrimental to the healing process. Alinia-Najjar et al[18] demonstrated that anxiety and depression can reduce patients’ treatment compliance and negatively impact their diet and sleep, indirectly hindering wound healing. Physiologically, these conditions may influence the endocrine and immune systems, further affecting wound repair[19]. For instance, negative emotions can elevate stress hormone levels in patients, impacting inflammatory responses and cellular proliferation in wounds. Additionally, anxiety and depression may also reduce the patient’s immune function, making them more susceptible to infection and delaying wound healing. Schlosser et al[20] found a correlation between anxiety and preoperative comorbidities as well as poor postoperative outcomes. Depression in patients with preoperative wounds is often difficult to heal, which may be related to a reduction in patient self-assessment, self-denial, and psychological factors such as giving up.

IL-6 is an important cytokine produced by the innate immune system during the initial response to injury and infection, promoting the production of acute-phase reactants such as C-reactive protein[21]. In chronic wounds, IL-6 levels may remain persistently elevated due to ongoing inflammation. A study indicated that IL-6 plays a central role in the acute inflammatory response; after infection and inflammation, IL-6 is first generated, and levels rise rapidly, peaking within 2 hours. The higher level is consistent with the severity of inflammation[22]. Excessive IL-6 may lead to an excessive inflammatory response and increase the risk of wound infection, thereby inhibiting wound healing. TNF-α is a key proinflammatory cytokine in skin trauma, which can activate immune cells and promote inflammatory response[23]. Xi et al[24] pointed out that TNF-α can lead to excessive inflammation and poor prognosis, which is consistent with the results of this study. TNF-α can affect the balance of cell proliferation and apoptosis, which may hinder wound healing by promoting cell apoptosis and inhibiting cell proliferation, leading to slow wound tissue repair and poor wound healing. Additionally, TNF-α may negatively affect angiogenesis. Overexpression of TNF-α in chronic wounds may inhibit the proliferation and migration of vascular endothelial cells and reduce the production of vasoactive factors, resulting in impaired wound angiogenesis and further hindering wound healing. Huang et al[25] found that the over-expression of TNF-α and the lack of anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta in diabetic wounds lead to poor wound healing. This observation further supports the negative role of TNF-α in chronic wounds.

MDA is commonly used as an indicator of oxidative damage in the medical field, and increased levels usually indicate that the level of free radicals in the body exceeds the normal range, which may lead to cell damage and an inflammatory response[26]. However, direct studies on the effect of excess MDA on clinical efficacy in patients with chronic wounds are uncommon. The possible mechanisms are as follows. First, chronic wounds are often accompanied by increased oxidative stress. That is, the balance between the antioxidant system and free radicals in the body is destroyed. Increased levels of MDA, a marker of oxidative stress, may reflect the exacerbation of this imbalance[27]. Second, while inflammation is crucial for healing in chronic wounds, excessive inflammatory responses can impede normal healing. Increased MDA levels are generally linked to heightened inflammatory responses[28]. In addition, rising MDA may directly or indirectly affect cellular functions such as proliferation, migration, and differentiation, all of which play important roles in the healing process of chronic wounds[29].

The ROC analysis revealed that wound area, HAMA, and HAMD exhibited high AUC values for predicting poor outcomes in patients with chronic wounds, underscoring their clinical significance. Consequently, for patients with extensive chronic wounds, active debridement should be undertaken to control infection. Negative pressure wound therapy and other advanced techniques should be employed to facilitate healing. Additionally, the patient’s overall nutritional status must be optimized, along with effective management of underlying conditions. For patients experiencing depression and anxiety, psychological evaluation and therapeutic interventions are crucial. Approaches such as psychological counseling, pharmacotherapy, or physical therapy can alleviate emotional distress while enhancing psychological well-being and immune function. However, this study is not without limitations. Firstly, as a retrospective analysis, data collection relies on existing medical records, which may be incomplete or inaccurate, thereby impacting the reliability of the results. Secondly, the sample size is relatively small at 110 patients, which may restrict the generalizability and applicability of the findings; thus, larger prospective studies are warranted for further validation.

CONCLUSION

This study explored the effects of anxiety and depression, inflammatory factors in peripheral blood, and stress levels on clinical efficacy in patients with chronic wounds. The results indicated that patients with larger wound areas and elevated anxiety and depression scores experienced poorer outcomes, identifying these factors as independent risk factors for adverse outcomes in chronic wounds. ROC analysis further corroborated the significance of these factors in predicting unfavorable outcomes. Consequently, healthcare professionals should closely monitor both the wound status and psychological well-being of patients, implementing timely and effective interventions for high-risk individuals to enhance treatment efficacy for chronic wounds.