Influence of systemic immune and cytokine responses during the acute phase of zoster on the development of postherpetic neuralgia

Influence of systemic immune and cytokine responses during the acute phase of zoster on the development of postherpetic neuralgia 1 first-author 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:sx169y@163.com †E-mail:sx169y@163.com sx169y@163.com 2 1 Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Department of Anesthesiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Department of Anesthesiology, the Second People’s Hospital, Jiaxing 314000, China Department of Anesthesiology, the Second People’s Hospital, Jiaxing 314000, China Postherpetic neuralgia (PHN) is a severe sequela of herpes zoster (HZ). Until now, only age and pain severity were considered predisposing factors for the development of PHN. We evaluated 49 patients with acute phase HZ, 10 of whom developed PHN (Group A) and 39 of whom did not develop PHN (Group B). Twenty-five healthy volunteers similar in age and gender distribution to the study group were recruited as controls (Group C). Numbers of serum CD3 + (pan-T lymphocytes), CD4 + (helper/inducer), and CD8 + (suppressor/cytotoxic) lymphocytes were decreased significantly in Groups A and B relative to the control group, but there were no statistical differences between Groups A and B. Interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, IL-8, and IL-10 were significantly elevated in Groups A and B relative to Group C. IL-6 was significantly higher in Group A than in Group B, and was significantly positively correlated with pain severity scored on a visual analog scale. Therefore, we suggest that the inflammatory response, especially that of IL-6, in the acute phase of HZ may be associated with hyperalgesia and the development of PHN. T lymphocyte Cytokines Postherpetic neuralgia (PHN) Herpes zoster (HZ) INTRODUCTION 1 Herpes zoster (HZ) is an often painful disease caused by varicella-zoster virus (VZV) infection. Its incidence is about 3.0 per 1000 patients who visit hospitals each year and increases with age, especially in persons over the age of 50 years (Donahue et al., 1995 1995 ; Galil et al., 1997 1997 ; Kost and Straus, 1996 1996 ). Patients with HZ complain of painful, vesicular rashes with erythema, which usually take 3~4 weeks to heal (Opstelten et al., 2002 2002 ). T cells (CD4 + and CD8 + ) are induced when the patients are first infected with VZV. In the memory CD4 + T cell response to VZV, T helper-1 (Th1) cells predominate, with production of pro-inflammatory cytokines including interleukin (IL)-6. It has been reported that there is reduced VZV-specific lymphocyte-mediated immunity in response to secondary challenges by the virus; however, the facts surrounding the reactivation of VZV are not well-understood (Wilson et al., 1992 1992 ). It has also been reported that a series of Th1-like cytokines such as IL-4 and interferon (IFN)-γ are involved (Zhang et al., 1994 1994 ). However, Webster et al.( 1989 1989 ) reported that HZ does not present in patients with a decreased T cell immunity. Postherpetic neuralgia (PHN) is pain lasting over four weeks after the rashes of HZ have healed. Age is recognized as an important factor predicting the development of PHN (Helgason et al., 2000 2000 ). Pain on presentation and the severity of prodromal pain are recognized as high-risk factors (Decroix et al., 2000 2000 ). Although it has been shown that persistence of VZV in mononuclear cells following infection may be associated with PHN, the mechanism involved in the development of PHN remains unknown (Mahalingam et al., 1995 1995 ). Zak-Prelich et al.( 2003 2003 ) demonstrated that although there was slight elevation of some cytokines, such as IL-6 and IL-8, in their zoster group, they found no significant differences between the group that developed PHN and the group that did not. The aim of the present study was to investigate relationships between systemic immune and cytokine responses in the acute phase of HZ and the development of PHN by examining pain severity and serum level changes in T lymphocyte subsets and a series of cytokines in patients with acute HZ. MATERIALS AND METHODS 1 Patients 2 The study was approved by the institutional ethics committee of Zhejiang University and informed written consent was obtained from all patients before they were enrolled in the study. Forty-nine patients (28 males, 21 females; 50~79 years of age, mean (65±6) years old) who visited the pain clinic were enrolled in the study group. All of the patients with HZ received intravenous acyclovir at 500 mg once per day for 5 d and then were switched to oral acyclovir, 800 mg once per day for 7 d. The clinical presentations of the patients were monitored for about 6 months from the acute HZ occurrence. The patients were divided into two subgroups, Group A and Group B, according to whether they developed postherpetic neuralgia (PHN) or not, respectively. Exclusion criteria were no pain during the acute phase, recent history of immunosuppressive drug or hormone therapy, other diseases of the immune system, and serious infection or complications of the central nervous system. The control group (Group C) was composed of 25 healthy volunteers (17 males, 8 females; 50~76 years of age, mean (63±7) years old) with a similar age range and gender distribution as the patient group. Blood samples were collected via venipuncture on the patients’ first visit to the hospital, within 4 d of the first presentation of zoster; blood samples were also collected from Group C via venipuncture. Subgroups of T lymphocytes (CD3 + , CD4 + , CD8 + , and the ratio of CD4 + /CD8 + ) were determined by fluorescence-activated cell sorter analysis (Cytomics FC500, Beckman Coulter, USA) within 6 h of sampling. Monoclonal antibodies (mouse anti-human immunoglobulin G (IgG); Tritest CD4/CD8/CD3) for CD3, CD4, and CD8 determination were purchased from Becton Dickinson Ltd. (USA). Serum for cytokine analysis was collected and stored at −20 °C immediately after sampling. Analyses of serum IL-1β, IL-6, TNF-α, IL-8, and IL-10 were done by cytometric bead array assay using kits from Bender Medsystems (FlowCytomix Human Th1/Th2 Kits, Bender Medsystems, Austria). Statistical analysis 2 All data except visual analogue scale (VAS) scores are presented as mean± SD . VAS scores are presented as median and quartile [ M ( Q )]. The statistical significances of differences between groups were determined by one-way analysis of variance (ANOVA) followed by Dunnet’s test for multiple comparisons. Mann-Whitney and χ 2 tests were used to evaluate differences in sex and age between the patient and control groups. The Wilcoxon test was used to evaluate differences in VAS scores between Groups A and B; Spearman rank correlation analysis was used to analyze VAS scores as a function of plasma cytokine concentrations. Pearson correlation analysis was used to evaluate correlations between cytokine levels and T lymphocyte subsets. P < 0.05 was considered statistically significant. Statistical evaluations were performed using SPSS 13.0. RESULTS 1 Clinical features 2 Demographic data and VAS pain scores are presented in Table 1 1 . There were no significant differences in gender or age between the groups. The mean VAS score for Group A was significantly higher than that for Group B ( P < 0.05). Of the 49 patients with HZ, 10 developed PHN (20.4%). Three of these 10 patients had rashes on the face and 7 had rashes on the trunk. The mean age of the HZ patients with PHN was (67±5) years and that of the HZ patients without PHN was (65±6) years; this difference was not significant ( P > 0.05). Group A: patients with herpes zoster (HZ) who developed postherpetic neuralgia; Group B: HZ patients who did not develop postherpetic neuralgia; Group C: healthy controls. Age is reported and mean± SD ; VAS scores are presented as M ( Q ) P < 0.05 as compared with Group A Age (year) Sex, F/M VAS Group A 67±5 6/4 9 (8) Group B 65±6 15/24 6 (5) * * Group C 63±7 8/17 0 T lymphocyte subgroup and cytokine analysis 2 The results of T lymphocyte subset (CD3 + , CD4 + , and CD8 + lymphocytes) analysis and the concentrations of tumor necrosis factor (TNF)-α, IL-1β, IL-6, IL-8, and IL-10 are shown in Table 2 2 . The percentages of CD3 + (pan-T lymphocytes), CD4 + (helper/inducer), and CD8 + (suppressor/cytotoxic) lymphocytes were significantly lower in Groups A and B than in Group C ( P < 0.05), but there were no statistical differences between Groups A and B ( P > 0.05). Data are reported as mean± SD . Group A: patients with herpes zoster (HZ) who developed postherpetic neuralgia; Group B: HZ patients who did not develop postherpetic neuralgia; Group C: healthy controls P < 0.05 as compared with Group C P < 0.05 as compared with Group B IL-6 TNF-α IL-1β IL-10 IL-8 CD3 + CD4 + CD8 + Group A 76.65±22.83 * * ∇ ∇ 227.72±149.15 * * 53.05±10.43 * * 109.80±40.19 * * 833.75±462.23 * * 52.24±10.00 * * 29.25±5.08 * * 21.08±6.48 * * Group B 57.13±15.98 * * 191.89±137.85 62.04±22.06 * * 102.80±40.10 * * 602.16±277.99 * * 56.13±11.00 * * 33.41±8.38 * * 20.46±5.82 * * Group C 45.34±10.08 * * 93.64±53.05 * * 44.69±13.33 * * 72.45±26.66 * * 217.76±63.33 * * 67.72±7.80 37.94±7.29 28.03±4.59 Although the levels of pro-inflammatory TNF-α, IL-1β, IL-6, and IL-8 and that of anti-inflammatory IL-10 were higher in Groups A and B than in Group C, there was only a significant difference in the concentration of IL-6 between Groups A and B ( P < 0.05). There was a significant positive correlation between the serum levels of IL-6 and VAS scores in Group A ( r =0.8110, P < 0.05); there were no significant relationships between the levels of any other cytokines and VAS scores for Groups A and B ( P > 0.05; Table 3 3 ) and between cytokine levels and T cell subset populations ( P > 0.05; Table 4 4 ). Group A: patients with herpes zoster (HZ) who developed postherpetic neuralgia; Group B: HZ patients who did not develop postherpetic neuralgia Significant correlation ( P < 0.05) 2 Cytokine 2 r Group A Group B  TNF-α 0.2575 −0.131  IL-6 0.8110 * * −0.350  IL-1β 0.5598 −0.136  IL-10 0.1730 −0.158  IL-8 0.2805 0.115 Group A: patients with herpes zoster (HZ) who developed postherpetic neuralgia; Group B: HZ patients who did not develop postherpetic neuralgia 3 Cytokine 6 r 3 Group A 3 Group B CD3 + CD4 + CD8 + CD3 + CD4 + CD8 + TNF-α −0.233 −0.187 −0.247 −0.037 −0.235 −0.077 IL-6 −0.051 0.188 −0.159 −0.063 −0.116 0.027 IL-1β −0.148 −0.161 −0.065 −0.096 −0.145 −0.151 IL-10 −0.140 −0.410 −0.137 −0.253 0.050 −0.073 IL-8 0.250 0.164 0.391 0.031 −0.029 −0.184 DISCUSSION 1 Previous reports have shown that the prevalence of PHN exceeds 50% in HZ patients older than 60 years of age, suggesting that age is a risk factor for PHN (Helgason et al., 2000 2000 ). In the present investigation, we enrolled only patients who were older than 60 years of age. In the present study, the populations of T lymphocyte subsets and serum levels of specific cytokines were evaluated in patients with acute phase HZ to determine whether alterations in these factors were associated with the development of PHN. We collected blood samples from patients when they visited the hospital within 4 d of HZ onset. While it might be desirable to collect the samples as soon as possible after HZ presents, this is usually impractical. T lymphocyte subset populations and the development of PHN 2 Previous studies have reported different results concerning T lymphocyte subset populations in patients with HZ. Patients with deficiencies in both CD4 + and CD8 + lymphocytes are at high risk for VZV infection, and therefore at higher risk for PHN (Cauda et al., 1987 1987 ; Higa et al., 1992 1992 ; von Seidlein et al., 1996 1996 ; Domingo et al., 2001 2001 ). The presentation of serum VZV-specific CD4 + lymphocytes reduces with age, putting aging people at elevated risk for developing PHN (Asanuma et al., 2000 2000 ). However, a previous study detected increases in the percentages of CD4 + and CD8 + lymphocytes, not CD3 + lymphocytes, in the acute phase of HZ, resulting in marked decreases in CD4 + /CD8 + ratios (Higa et al., 1992 1992 ). Differences in the study populations and the specific timing of the studies could have contributed to the differences in the results among the various studies. In present study, there were significant decreases in the percentages of CD3 + , CD4 + , and CD8 + lymphocytes in all patients with HZ relative to patients without HZ, suggesting that depression of cell-mediated immunity in the acute HZ period was associated with development of HZ. There were no differences in T lymphocyte subset populations between Groups A and B, suggesting that changes in T lymphocyte subsets are not predictive of PHN. Influence of cytokine production on the development of PHN 2 Although the populations of certain T lymphocyte subsets decreased in patients with HZ, the concentrations of five specific cytokines were elevated significantly in patients with HZ relative to those without. Furthermore, the concentrations of IL-6 in patients with PHN were higher than those in HZ patients without PHN, and there was a positive correlation between the level of IL-6 and the VAS pain score in patients with PHN, suggesting that patients with severe pain and high levels of IL-6 had a higher risk of developing PHN. Zak-Prelich et al.( 2003 2003 ) reported only slight elevations of several cytokines, such as IL-6, and no significant differences in serum cytokine concentrations between HZ patients with and without PHN. Fewer cases (only 30 patients were included) and a broader age range (14~65 years) could be the bases of the differences between Zak-Prelich’s results and ours. This discrepancy should be addressed in future studies with larger sample sizes. TNF-α is a pro-inflammatory cytokine produced by several types of cells, including inflammatory cells and some non-immune cells (Vilcek and Lee, 1991 1991 ; Vassalli, 1992 1992 ). TNF-α has been shown to produce hyperalgesia and to upregulate other cytokines like IL-6, IL-8, and IL-1β, but serum levels did not correlate with the severity of HZ. IL-1β is also a pro-inflammatory cytokine that can upregulate expression of substance P and nerve growth factor in the spinal cord or inhibit glutamate clearance between synapses by glia (Laughlin et al., 2000 2000 ). TNF-α may have an important role in nocioception and induce mechanical hyperalgesia (Yabuuchi et al., 1996 1996 ). Application of an IL-1 receptor antibody attenuated formalin-induced hyperalgesia and capsaicin-induced hyperalgesia by blocking IL-1β activation (Watkins et al., 1997 1997 ; Davis and Perkins, 1996 1996 ). It has been reported that IL-8 levels in cerebrospinal fluid, not in serum, at full crusting of herpetic rash can also predict the development of PHN (Kotani et al., 2004 2004 ). However, in the present study, the serum concentrations of TNF-α, IL-1β, and IL-8 did not differ between the group with PHN and the group without PHN, indicating that these cytokines were involved in the development of HZ but not of PHN. IL-6 is a pro-inflammatory cytokine and is considered a sensitive and early marker of tissue damage that is involved in series of functions, including modulation of the immune and nervous systems. This cytokine plays an important role in allodynia and hyperalgesia after peripheral nerve injury in rodents (Arruda et al., 2000 2000 ). In the present study, only serum concentrations of IL-6 differed between the PHN group and the non-PHN group, and IL-6 levels correlated well with the VAS pain score, indicating that possible nerve injury or an excessive inflammatory response to VZV was involved in the development of PHN. It is possible that IL-6 could predict the occurrence of PHN, but the mechanisms involved need further investigation. IL-10 is produced by Th2 cells and is recognized as an anti-inflammatory cytokine with analgesic properties. Gene expression of IL-10 increases immediately after nerve injury and presents a second peak in 45 d. These changes in IL-10 may play an important role in nerve regeneration and the attenuation of neuralgia (Üçeyler et al., 2007 2007 ). Similarly, the application of IL-10 reduces pain behavior in different kinds of pain models (Üçeyler et al., 2007 2007 ). The induction of VZV-specific T lymphocytes was shown to be accompanied by transient increases in IL-10 production, suggesting that parallel increases in IL-10 may predominate in the induction of immunity to some viral pathogens (Jenkins et al., 1998 1998 ). In the current study, serum concentrations of IL-10 in the PHN group were higher than those in controls, but did not differ from concentrations in the non-PHN group, indicating an auto-regulation of immune responses to VZV infection but also indicating that this anti-inflammatory reaction is not sufficient to prevent a patient with HZ from developing PHN. The inflammatory response of T lymphocyte subsets and cytokines in the acute phase of HZ may result in hyperalgesia and induce limited anti-inflammatory responses, but it cannot effectively restrain the VZV and prevent damage to the skin, resulting in persistent neuralgia. 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