VZV is a kind of human alpha herpes virus. When a person is infected with VZV for the first time, which usually happens in childhood, varicella occurs. Herpeszoster (HZ) is caused by the reactivation of latent VZV in the cranial nerve or dorsal root ganglia in adulthood,1 possibly leading to Postherpetic Neuralgia (PHN). Even after the local skin lesions are repaired, the local skin neuralgia still persists for months or years or even develops into refractory neuralgia that often occurs in middle-aged and elderly people and causes long-lasting pain, especially in elderly women, besides, refractory neuralgia also leads to anorexia, insomnia, and depression, which cast a serious impact on the patient's life. Recent studies have shown that PHN is a kind of neuropathic pain2 and the risk factors of PHN include age, gender, rash precursor symptoms, severe skin damage, severe acute pain, and psychosocial factors.3 The incidence rate of PHN is about 2‒4.6 cases per thousand people per year, and that rate increases greatly to 9.1 cases per thousand people per year in the age group of 50 to 75 years old.4 Studies have shown that the overall incidence rate of PHN in China is 6.64 cases per 1000 people. Besides, there were 99 recurrent episodes in 4313 first episodes from 2015 to 2017. However, the average number of visits of patients exhibiting initial disease onset was significantly lower than the recurrent patients (3.6 vs. 6.7 per patient), and the average hospitalization time for recurrent attacks is longer than the first attack. About 9%‒34% of patients will develop PHN, and the rates of incidence and prevalence increase gradually with age.5

Despite such harms brought by PHN, the mechanism of the disease remains unclear in China. Currently, effective biomarkers to predict PHN remain unavailable, which makes it difficult for PHN prevention and successful PHN treatment. By observing the changes in serum cytokine levels in patients with postherpetic neuralgia, the relationship between cytokine levels and the pain degrees in PHN patients was investigated to find out the immunological factors affecting the onset of PHN, thereby establishing the foundation for early clinical intervention.

A total of 80 patients with PHN and 80 healthy volunteers were enrolled in this study. The characteristics of patients and volunteers were shown in Table 1.

There were no marked differences between patients with PHN and volunteers in variables, including age, gender, TNF-α, TC, TG, IL10 and LDL-C (p > 0.05, respectively).

There was a significant difference in serum IL6 levels between mild PHN and severe PHN groups, and patients in the severe PHN group had higher serum IL6 levels than those in the mild PHN group (10.41 ± 4.97 vs. 6.65 ± 2.25, p < 0.05). And patients with severe or mild PHN had higher serum IL6 levels than healthy volunteers p < 0.05 (Fig. 1), Serum IL6 levels in patients with PHN were higher than those in volunteers (7.35 ± 2.15 vs. 3.27 ± 1.02, p = 0.00) (Fig. 2).

Figure 1.

Serum IL6 levels in mild PHN, severe PHN and healthy volunteers’ groups (*p < 0.05).

(0.09MB).

Figure 2.

Serum IL6 levels in Postherpetic Neuralgia (PHN) and healthy volunteers’ groups (*p < 0.05).

(0.06MB).

The ROC curve of IL6 levels for PHN was shown in Fig. 3. The AUC value was 0.896 (95% Confidence Interval: 0.85‒0.95, p < 0.0001). According to the ROC curve, the cut-off value of serum IL6 levels for PHN was 4.95 pg/mL, with 80% sensitivity and 86.2% specificity.

Figure 3.

Receiver operator curve of IL6 for postherpetic neuralgia. The area under the curve values was 0.896 (95% CI 0.85‒0.95, p < 0.0001).

(0.13MB).

In the PHN group, an appropriate dose of gabapentin was given orally based on the patient's conditions, and Mecobalamin was given via intramuscular injections at a daily dose of one. After the 14th treatment, all patients with PHN were assessed by a Likert scale score. The results were shown in Table 2. Serum IL6 levels at admission were associated with a Likert scale score and on the 14th day after treatment (p < 0.05).

Postherpetic neuralgia is a kind of refractory neuropathic pain. In recent years, studies have shown that PHN could be associated with several nervous system damage.7 PHN can have a variety of systemic symptoms, including chronic fatigue, anorexia, weight loss, lack of activity, and insomnia, accompanied by emotional or psychological changes, such as anxiety, depression, inattention, etc. some patients have suicidal tendencies.8 In China, it has been reported that about 45% of patients suffered moderate to severe emotional interference, 40% of patients with postherpetic neuralgia suffered moderate to severe interference in their daily living activities, more than 40% of patients were accompanied by moderate to severe sleep disorders and 59.68% of patients had or often had suicidal thoughts.9 It is also reported in foreign literature the more severe the pain, the more serious the impact on patients' energy, sleep, and overall quality of life. In addition, it can have a moderate to severe impact on family members' lives, causing them to experience fatigue, stress, insomnia, and emotional distress.10

A variety of inflammatory substances has been revealed to involve neuropathic pain.11 Specifically, cytokines are capable of regulating a variety of cellular physiological functions. They are polypeptides with small molecular weights that are synthesized and secreted by all kinds of cells in the body, playing an important role in the stress processes of trauma, pain, and infection.12 At present, numerous types of cytokines have been discovered, including Interleukin (IL), Interferon (IFN), Colony Stimulating Factor (CSF), Tumor Necrosis Factor (TNF), Nerve Growth Factor (NGF), and Transforming Growth Factor (TGF). They are found to engage in the regulation of homeostasis in the immune system, and if excessive stress occurs, pathological reactions will happen. Earlier studies have shown that cytokines can be categorized as pro-inflammatory or anti-inflammatory.13 The former includes IL-6, IL-1, IL-8, and TNF, while the latter involves IL-4, IL-10, soluble Interleukin-2 receptor antagonist (IL-2), and tumor necrosis factor. Under normal physiological conditions, these two types of cytokines keep a fine balance with the help of neuroendocrine and humoral regulations.14 It is noteworthy that IL-6 is a multi-effector cytokine produced by Th2 cells, monocyte macrophages, and endothelial cells. It is a crucial molecule in immune response, acute phase response, and hematopoietic regulation. Besides, as a differentiation and growth factor of B-cells, T-cells, and endothelial cells, IL-6 can activate target genes, participate in humoral immunity, induce megakaryocyte maturation, and act on the growth, differentiation, regeneration, and degradation of nerve cells in both peripheral and central nervous systems. Under normal physiological conditions, the IL-6 content secreted by macrophages, mast cells, lymphocytes, neurons, and glial cells is at a low level, which facilitates the normal development and repair of the nervous system, while a high level of IL-6 content can cause damage to the nervous system. Researchers also found that the level of IL-6 in PHN or posterior neuralgia patients was positively correlated with sensory loss and loss of cold sensation in the area of pain.15–19

Under peripheral nerve injury, the expression of IL-6 and IL-6 receptors in the spinal cord is up-regulated. In animal experiments, IL-6 injections into normal rats can inhibit their responses to thermal and mechanical stimulation. Even when the pain responses caused by mechanical stimulation were preserved, IL-6 injections could still inhibit the pain responses caused by thermal stimulation. Therefore, IL-6 has been verified to play an important role in the persistent pain resulting from peripheral and central nerve injury.20,21 In addition Arruda et al.22 conducted several animal experiments, in which IL-6 antibodies or allogeneic IgG were applied to treat rats with persistent hyperalgesia due to peripheral nerve injury.

In the present study, it was found that the serum IL-6 level was positively correlated with the Likert scale score, suggesting the role of IL-6 in the pathological progression of PHN. Some cytokines such as IFN-gamma, IL-6, and IL-8 were slightly raised in the zoster group compared with a group of normal healthy subjects of similar age distribution, these differences only verged on significance.23 It was partially consistent with the present study, but this study further confirmed that IL6 was closely related to PHN through stratified grouping. In the present study, the level of serum IL-6 in patients with severe PHN was significantly higher than that in patients with mild PHN or the healthy control group, and they were higher in patients with severe PHN than those in patients with mild PHN. Suggesting that PHN patients with high IL-6 levels were more likely to develop PHN.

In the present study, the serum IL-6 level showed a statistically significant difference between PHN patients before and after treatment. Saxena et al. studied the treatment process of herpes zoster neuralgia and used Cognitive Behavioral Therapy (CBT) along with pregabalin. The pain relief effect is remarkable, a significant downregulation of mRNA expression of IL-6 was observed.24 Confirming consistent results in East Asian and West Asian populations, however, it is not shown that IL6 level is closely related to PHN prognosis. This study found that serum IL6 levels in patients with PHN in admission are correlated to the Likert scale score on the 14th day after diagnosis. It is indicated that serum IL6 levels in patients with PHN in admission may be a predictive factor for short-term prognosis.

Serum IL6 may be a diagnostic indicator of PHN with 85% sensitivity and 87.5% specificity. The possibility of herpes zoster developing into PHN can be judged early by the level of IL6. Early intervention and regular treatment of patients with elevated IL-6 levels could help alleviate their pain and improve their quality of life.

To sum up, the level of serum interleukin-6 is related to the degree of postherpetic neuralgia and may be a useful diagnostic biomarker in such cases.

Zhejiang Provincial Health Science and Technology Project 2022KY977.

Ding Lin: Data collection, analysis, and interpretation.

Changyang Zhong: Approval of the final version of the manuscript; critical literature review; manuscript critical review.

Quanlong Jiang: Effective participation in research orientation.

Aihua Huang: Intellectual participation in propaedeutic and/or therapeutic management of studied cases.

Yuan Liu: Preparation and writing of the manuscript; statistical analysis.

Yan Zhang: Study conception and planning.

None declared.