Accelerated recovery and alleviated pain by oral whey protein in herpes zoster patients: a randomized controlled trial

Abstract

Background

Herpes zoster is usually caused by varicella-zoster virus reactivation, particularly in the aged. It imposes postherpetic neuralgia and impacts life quality, which may be improved by nutritional interventions.

Objective

This study aimed to evaluate the efficacy and mechanism of oral whey protein supplementation in the recovery, pain, and life quality of herpes zoster patients.

Methods

Forty herpes zoster patients were recruited in Shanghai Dermatology Hospital and randomly divided into the treatment group (n = 20) and the control group (n = 20), with normal therapy. Whey protein was orally administrated 20 g per time, twice per day. The recovery time, pain scores (VAS), dermatology life quality index (DLQI), nutritional status (PG-SGA), oxidative stress markers, and immune parameters were investigated.

Results

Whey protein supplementation significantly reduced the recovery time and scabbing time compared to controls. Pain scores were decreased, and DLQI was improved. Nutritional status (PG-SGA scores) was improved, with increased serum prealbumin. Total protein and albumin were not changed. Oral whey protein increased the GSH content and GSH-PX activity, but the SOD activity, MDA content, and NO content were not altered. The serum contents of IL-6, IFN-γ, IgG, and IgA were increased, while TNF-α, C3, C4, CRP, IgE, and IgM, were not statistically changed.

Conclusions

Oral whey protein adjuvant to standard therapy accelerated recovery, reduced pain, and improved quality of life in herpes zoster patients, probably by improving the nutritional status, enhancing the antioxidant system, and supporting the immune system, which highlighted the application of whey protein in herpes zoster therapy.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12937-026-01372-0.

Introduction

Herpes zoster is an acute infectious dermatological disease resulting from the reactivation of the varicella-zoster virus (VZV) in the spinal ganglia. The immune functions tend to fade with the increase in age, facilitating the VZV reactivation. Consequently, the incidence of herpes zoster significantly rises among individuals aged over 50 years [1, 2]. Globally, the burden of herpes zoster is substantial and continues to rise. Recent data from the Global Burden of Disease study indicate that the combined annual incidence of varicella and herpes zoster worldwide has reached approximately 86.7 million cases [3]. The incidence of herpes zoster is progressively increasing due to the demographic shift towards an aging population. In China, recent meta-analyses estimate that the annual number of new herpes zoster cases currently exceeds 6 million [4]. Similarly, approximately 1 million cases of herpes zoster are diagnosed annually in the United States (Clinical Overview of Shingles (Herpes Zoster), Centers for Disease Control and Prevention (CDC)). The most common serious complication of herpes zoster is postherpetic neuralgia, which can last for months or years in severe patients. Pain and psychological burden may cause loss of appetite, malnutrition, and metabolic changes, leading to decreased quality of life and the occurrence or aggravation of herpes zoster. Hence, the treatment for herpes zoster patients to alleviate pain and increase life quality is intensively pursued.

Nutritional support plays a critical role in the management and treatment of various diseases. It is essential for maintaining overall health, supporting the immune system, promoting healing, and improving prognosis. In infectious diseases, malnutrition can weaken immunity, increasing susceptibility to infections and delaying recovery [5, 6]. Adequate nutrition strengthens the immune system, as some key nutrients like vitamins, zinc, selenium, and omega-3 fatty acids support the function of many immune cell types [7–10]. In addition, nutritional support is crucial for tissue repair and wound healing. Proteins, amino acids, and micronutrients (vitamin C, zinc) are essential for collagen synthesis and tissue regeneration [11]. Although the nutritional status may affect the anti-virus immunity and skin lesion/repair in herpes zoster, nutritional treatment for herpes zoster patients is not documented. More interestingly, a cross-sectional study showed that malnutrition is a risk factor for postherpetic neuralgia [12]. Whether supplemental nutrition is beneficial to support herpes zoster therapy and alleviate postherpetic neuralgia deserves to be explored.

In the present study, we used the oral supplement of whey protein in addition to the clinical therapy to observe the effects on recovery, pain, and life quality in herpes zoster patients. The changes in nutritional status after treatment were also verified. We also investigated the impacts of nutritional treatment on systemic immunity and the redox system. These results would provide the clinical evidence for using nutritional support in herpes zoster to accelerate recovery and alleviate pain.

Methods

Patient recruitment

This study was approved by the Medical Ethics Committee of Shanghai Dermatology Hospital (approval number: 2022-30). It was officially registered in the “Medical Research Registration and Filing Information System” of the National Healthcare Security Information Platform of China (MR-31-25-032097). Clinical trial number: not applicable. The study was conducted under the principles of the Declaration of Helsinki. Written informed consent, including consent for the use of biological samples for research purposes, was obtained from all participants before any study procedures commenced. Inclusion criteria: (1) Patients aged 40 to 70 years old; (2) Patients diagnosed with herpes zoster for the first time; (3) No hormone drugs were used; (4) Patients were conscious and could communicate; (5) Patients could clearly express their willingness to participate in this study and sign the informed consent; (6) Patients could accept oral nutritional support. Exclusion criteria: (1) Patients aged < 40 or > 70 years old; (2) Patients with mental or cognitive impairment, unable to communicate, unable to answer questions; (3) Clinical treatment drugs included hormones; (4) Unwillingness to participate in the study; (5) Protein allergy or corn starch allergy; (6) Pregnant women; (7) Severe immune system diseases, kidney diseases, other malignant tumors; (8) Other situations not suitable for protein supplementation. A total of 40 patients with herpes zoster in Shanghai Dermatology Hospital from December 2022 to November 2023 were recruited. They were randomly divided into the control group and treatment group, 20 patients in each group (Fig. 1, the participant flow chart). There was no significant difference in baseline data between the two groups (Table 1, p > 0.05).

Fig. 1.

The participant flow chart and the main outcome of the study

Table 1.

The baseline data of herpes zoster patients

Patients	Control	Treatment	p value
	20	20
Age (years)	61.50 ± 7.30	60.45 ± 8.53	0.68
Gender
Male	7	7
Female	13	13
BMI (kg/m2)	24.23 ± 2.71	23.09 ± 3.44	0.25
Smoker (%)	None	None
Alcohol (%)	None	None
Blood test
White blood cell (109/L)	5.89 ± 1.27	5.18 ± 1.34	0.10
Neutrophil Percentage (%)	53.16 ± 10.56	49.02 ± 10.65	0.22
Lymphocyte Percentage (%)	34.46 ± 9.62	37.24 ± 10.67	0.39
Monocyte Percentage (%)	9.08 ± 2.59	10.62 ± 3.24	0.11
Eosinophil Percentage (%)	2.61 ± 2.38	2.57 ± 2.31	0.96
Basophil Percentage (%)	0.71 ± 0.28	0.57 ± 0.19	0.09
C-Reactive Protein (mg/L)	4.15 ± 5.47	5.14 ± 5.40	0.73
Globulin (g/L)	25.81 ± 2.89	25.47 ± 3.57	0.74
Albumin/Globulin (g/L)	1.62 ± 0.17	1.60 ± 0.25	0.77
Alanine Aminotransferase (U/L)	27.35 ± 19.21	21.30 ± 17.10	0.30
Alkaline Phosphatase (U/L)	73.26 ± 17.62	69.44 ± 13.81	0.47
Aspartate Aminotransferase (U/L)	21.75 ± 9.01	17.35 ± 6.25	0.08
Gamma-Glutamyl Transferase (U/L)	33.30 ± 21.41	31.4 ± 25.25	0.80
Lactate Dehydrogenase (U/L)	164.45 ± 35.03	153.1 ± 21.06	0.22
Blood Glucose (mmol/L)	5.43 ± 0.97	5.11 ± 0.65	0.23
Triglycerides (mmol/L)	1.35 ± 0.30	1.30 ± 0.43	0.66

Clinical therapy and nutritional support

All patients received normal clinical therapy for herpes zoster, including Acyclovir for antiviral therapy, Mecobalamin for the nervous system, and Pregabalin for relieving nerve pain. A 7-day, double-blind trial was performed. Patients in the treatment group received oral whey protein (supplied by MarryHealth^® ABD Bioactives) after breakfast and lunch, 20 g per time, 40 g per day. The whey protein was extracted from milk, consisting of β-lactoglobulin (56%), α-lactobumin (11%), serum albumin (10%), immunoglobulin (22%), and lactoferrin (0.8%). Patients in the control group received an equal amount of dextrin. Although there were significant differences in taste, smell, texture, and chewing sensation between the whey protein and dextrin, patients were not aware during the actual intervention which one they were taking - the whey protein or dextrin, since they had no prior exposure to these two products. The status of skin lesions was daily recorded, including the time of herpes recovery and the time of skin scab formation. The recovery time and pain scores (VAS) were defined as the strictly pre-specified primary endpoints of this study.

Pain score

The patients’ feeling of postherpetic neuralgia was evaluated by the visual analogue scales (VAS scale, Supplementary File 1). There were 10 degrees of pain, and the patients were asked to choose the most suitable degree of pain before and after nutritional treatment. The VAS scale used was a standard 10 cm horizontal line labeled “No pain” at one end and “Worst pain imaginable” at the other. The VAS pain scale is a commonly used scale for evaluating pain in herpes zoster [13].

Life quality score

The Dermatology Life Quality Index (DLQI) was used to evaluate the life quality of patients in the two groups before and after the nutritional treatment (Supplementary File 2). The score was 0–30, and the higher the score, the greater the impact of herpes zoster on the quality of life of patients.

Nutritional assessment

The nutritional status of patients was assessed by the patient-generated subjective global assessment (PG-SGA) before and after the nutritional treatment (Supplementary File 3). Patients were divided into three grades according to the score: 0–3: good nutritional status, 4–8: moderate or suspected malnutrition, and ≥ 9: severe malnutrition. PG-SGA is a commonly used nutritional assessment scale in nutrition studies. It was initially designed for cancer patients, but its application scope has now been expanded to various diseases.

Biochemical determinations

The serum of patients before and after the intervention was collected for biochemical determination [14]. The levels of total protein (g/L), albumin (g/L), and prealbumin (mg/L) were detected by an automatic biochemical analyzer (BS-240, Mindray, China) [15]. The immune biochemical indicators, including immune globulin (A, G, M, E), complement factors (C3, C4), and C-reactive protein (CRP), were also determined. The serum glutathione (GSH, µmol/L) was measured by a reduced glutathione (GSH) assay kit (Cat. A006-2-1, Nanjing Jiancheng Bioengineering Institute, China) [16]. The serum glutathione peroxidase activity was measured by a glutathione peroxidase (GSH-PX) assay kit (Cat. A005-1-2, Nanjing Jiancheng Bioengineering Institute, China). The serum MDA was measured by a microscale Malondialdehyde (MDA) assay kit (Cat. A003-2-2, Nanjing Jiancheng Bioengineering Institute, China) [17]. The serum SOD was measured by a superoxide dismutase (SOD) assay kit (Cat. A001-3-2, Nanjing Jiancheng Bioengineering Institute, China).

Enzyme-linked immunosorbent assay

The serum contents of immune cytokines IFN-γ, IL-6, and TNF-α were measured by commercial ELISA kits following the protocols (Cat. E-HSEL-H0007; E-EL-H6156; E-EL-H0109, Elabscience, China) [18]. Briefly, 100 µl serum samples were added to the antibody-coated 96-well plate, and the standards were added at the same time. After incubating at 37℃ for 1 h, the primary antibody was added and incubated for 1 h to form a double-antibody sandwich. Then the secondary antibody was added and incubated for 0.5 h, followed by the addition of TMB substrate for detection at 450 nm by a plate reader (Synergy2, Biotek, USA) [19].

Statistics

Sample size and statistical power were calculated by G*Power as before [18]. Primary endpoints included recovery time and pain score, with Cohen’s d values of 1.60 and 0.71, respectively. The statistical power was > 0.99 for the recovery time and 0.72 for the pain score. Data were presented as mean ± SD. The count data was tested by the chi-square test. The unpaired t-test was used for two-group comparisons, with evaluation of Cohen’s d. All continuous data involving pre- and post-intervention measurements across the two groups were tested by two-way repeated-measures ANOVA, with evaluation of Partial Eta Squared (η_p²). For multiple comparisons, the Bonferroni correction was used to strictly control Type I errors. The difference was set at p < 0.05.

Results

1. Oral administration of whey protein decreased the recovery time and pain score in herpes zoster patients.

As shown in the participant flow chart, 40 recruited herpes zoster patients were randomly divided into 2 groups (Fig. 1). The baseline data showed no statistical difference between 2 groups (Table 1). Then the patients in the control group received normal therapy and equal-energy dextrin, while the patients in the treatment group received normal therapy plus oral administration of whey protein (Fig. 1). After 7 days of intervention, the patients in the treatment group recovered better than the control group (Fig. 2A). The scabs were decreased by oral whey protein, and the scabbing time was decreased during the treatment period (4.48 ± 0.83 vs. 3.35 ± 0.93 days; mean difference: 1.13 days, 95% CI: 0.57 to 1.69; p < 0.001, Cohen’s d = 1.28) (Fig. 2B and C). The recovering time of herpes zoster patients was decreased by oral whey protein treatment (6.43 ± 0.88 vs. 4.88 ± 1.05 days; mean difference: 1.55 days, 95% CI: 0.93 to 2.17; p < 0.001, Cohen’s d = 1.60) (Fig. 2D and E). Importantly, chronic pain (5.05 ± 1.73 vs. 3.95 ± 1.36; mean difference: 1.10, 95% CI: 0.10 to 2.10; p = 0.03, Cohen’s d = 0.71) (Fig. 2F) and the impact on life quality (7.55 ± 3.86 vs. 4.20 ± 2.46; mean difference: 3.35, 95% CI: 1.28 to 5.42; p = 0.002, Cohen’s d = 1.04) (Fig. 2G) are the main disturbances of herpes zoster, which were effectively alleviated by oral whey protein treatment.

Fig. 2.

The effects of oral whey protein on (A) skin lesions, (B & C) scabbing time, (D & E) recovering time, (F) pain scores, and (G) DLQI scores. *, p < 0.05; **, p < 0.01; ***, p < 0.001; tested by unpaired independent t-test and repeated-measures ANOVA, n = 20

• 2.Oral administration of whey protein improved the nutritional status in herpes zoster patients.

To determine the reasons for oral whey protein’s effects, we first used the PG-SGA scale to observe the nutritional status of patients. Two-way repeated-measures ANOVA revealed a highly significant group-by-time interaction effect for the PG-SGA scores. While both groups showed decreased scores over time, the oral whey protein treatment led to a significantly greater reduction in PG-SGA scores compared to the control group (mean reduction of 4.00 ± 1.69 vs. 2.35 ± 1.53 points; mean difference in reduction: 1.65, 95% CI: 0.62 to 2.68; interaction p = 0.002, partial η² = 0.217), indicating a robust improvement in the symptom-driven nutritional status (Fig. 3A). The percentage of severe malnutrition was also decreased (Fig. 3B). However, the serum contents of total protein (Fig. 3C) and albumin (Fig. 3D) were not increased. In contrast, a highly significant group-by-time interaction effect was observed for the serum content of pre-albumin (Fig. 3E). While the control group exhibited only a marginal increase (226.7 ± 44.97 to 233.0 ± 36.43 mg/L), the oral whey protein treatment led to a robust and significantly greater elevation in pre-albumin levels (222.2 ± 44.64 to 268.0 ± 47.08 mg/L; net difference in increase: 41.50 mg/L, 95% CI: 18.00 to 65.00 mg/L; interaction p = 0.001, partial η² = 0.251).

Fig. 3.

The effects of oral whey protein on PG-SGA scores (A), nutritional status (B), and serum contents of total protein (TP) (C), albumin (D), and prealbumin (E). *, p < 0.05; **, p < 0.01; ***, p < 0.001; tested by repeated-measures ANOVA, n = 20

• 3.Oral administration of whey protein enhanced the GPX-GSH antioxidant system in herpes zoster patients.

Because whey protein is rich in cysteine, a precursor of glutathione (GSH), we investigated its potential exploratory role in modulating the redox system. Two-way repeated-measures ANOVA revealed significant group-by-time interaction effects for specific antioxidant markers. While the serum GSH content was increased over time by normal therapy itself (80.94 ± 12.63 to 125.7 ± 14.49 µmol/L), the oral whey protein intervention was associated with a significantly greater elevation (78.27 ± 13.46 to 140.2 ± 14.16 µmol/L; net difference in increase: 17.17, 95% CI: 8.39 to 25.95; interaction p < 0.001, partial η² = 0.291) (Fig. 4A). Strikingly, the activity of glutathione peroxidase (GSH-PX) exhibited an interaction effect. While GSH-PX slightly decreased in the control group (37.65 ± 14.46 to 31.30 ± 14.31 U/mL), it substantially increased in the whey protein group (22.50 ± 13.58 to 60.90 ± 21.12 U/mL; net difference in change: 44.75, 95% CI: 34.15 to 55.35; interaction p < 0.001, partial η² = 0.657) (Fig. 4B). These results suggested that oral whey protein was associated with an augmented GPX-GSH antioxidant response. However, no significant interaction effects were observed for other oxidative stress markers. The superoxide dismutase (SOD) activity was decreased similarly in both groups without a significant interaction effect (interaction p > 0.05) (Fig. 4C). Furthermore, the serum contents of malonaldehyde (MDA) (Fig. 4D; interaction p > 0.05) and nitric oxide (NO) (Fig. 4E; interaction p > 0.05) were unaffected by the oral whey protein, as their change trajectories did not significantly differ between the two groups.

Fig. 4.

The effects of oral whey protein on serum content of GSH (A), GSH-PX activity (B), SOD activity (C), MDA content (D), and NO content (E). *, p < 0.05; **, p < 0.01; ***, p < 0.001; tested by repeated-measures ANOVA, n = 20

• 4.Oral administration of whey protein promoted the anti-virus immunity in herpes zoster patients.

To explore potential immunological factors associated with the clinical recovery of herpes zoster patients, we also investigated the immune cytokines and immune proteins in the serum of herpes zoster patients. Meaningfully, oral whey protein increased the serum contents of IL-6 and IFN-γ (Fig. 5A, Control-Before: 6.376 ± 1.139; Control-After: 6.433 ± 1.022; Treatment-Before: 5.961 ± 0.7485; Treatment-After: 6.987 ± 1.075, net difference in increase: 0.97 pg/mL, 95% CI: 0.32 to 1.62; interaction p < 0.01, partial η² = 0.192) (Fig. 5C, Control-Before: 30.52 ± 14.88; Control-After: 30.15 ± 14.46; Treatment-Before: 25.05 ± 11.63; Treatment-After: 34.38 ± 12.24, net difference in change: 9.70 pg/mL, 95% CI: 1.14 to 18.26; interaction p < 0.05, partial η² = 0.121). However, the intervention did not significantly affect TNF-α (Fig. 5B; interaction p > 0.05). Furthermore, the complement factors C3, C4, and CRP were not significantly altered by the oral whey protein, showing no meaningful interaction effects (Fig. 5D and F; all interaction p > 0.05).

Fig. 5.

The effects of oral whey protein on serum contents of IL-6 (A), TNF-α (B), IFN-γ (C), C3 (D), C4 (E), CRP (F), IgG (G), IgA (H), IgE (I), IgM (J). *, p < 0.05; **, p < 0.01; ***, p < 0.001; tested by repeated-measures ANOVA, n = 20

Regarding immunoglobulins, exploratory analyses showed statistically significant interaction effects for IgG and IgA. The immunoglobin IgG and IgA were increased (Fig. 5G, Control-Before: 12.78 ± 3.911; Control-After: 13.19 ± 4.022; Treatment-Before: 12.67 ± 2.732; Treatment-After: 15.41 ± 3.728, net difference: 2.33 g/L, 95% CI: 0.23 to 4.43; interaction p < 0.05, partial η² = 0.116) (Fig. 5H, Control-Before: 2.639 ± 0.9952; Control-After: 3.089 ± 1.344; Treatment-Before: 2.475 ± 0.8740; Treatment-After: 3.653 ± 1.477, net difference: 0.73 g/L, 95% CI: 0.01 to 1.45; interaction p < 0.05, partial η² = 0.098), while IgE and IgM were not significantly changed (Fig. 5I and J; interaction p > 0.05). These exploratory observations suggest that oral whey protein supplementation was associated with selective alterations in cytokine and immunoglobulin profiles. Due to the short intervention period, these immunological findings remain hypothesis-generating and require further validation to determine their precise clinical relevance.

Discussion

This randomized controlled trial aimed to evaluate the adjuvant efficacy of oral whey protein in herpes zoster patients. Our study was constructed based on the null hypothesis (H0) that oral whey protein, when combined with standard clinical therapy, would provide no additional benefit regarding the time to skin lesion resolution or pain alleviation compared to standard therapy plus a placebo. The alternative hypothesis (H1) posited that whey protein supplementation would significantly accelerate recovery and alleviate pain, potentially by improving nutritional status and modulating systemic redox and immune responses. Our findings provided statistical evidence to reject the null hypothesis for our primary endpoints, as the treatment group demonstrated a significantly shorter recovery time and reduced pain severity compared to the control group (interaction p < 0.001). These results suggested that the adjunct nutritional support might exert a clinical benefit during the acute phase of herpes zoster. Furthermore, our secondary immunological and antioxidant findings provided a preliminary mechanistic understanding that warranted further hypothesis-driven verification in larger, adequately powered clinical trials.

It is generally believed that weak immune function is one of the important risk factors for herpes zoster, whereas malnutrition can lower immunity. Our study reported that 85% of the patients in both control and treatment groups were malnourished. This high rate might be attributed to the fact that herpes zoster patients were 40–70 years old. The advanced age and poor nutritional status, along with weakened immunity, made them prone to contracting herpes zoster. That means the varicella-zoster virus was easily reactivated in malnourished and aged people, causing the high rate of malnutrition. Besides, the PG-SGA score is sensitive to recent weight loss and disease-related symptoms (like pain and loss of appetite, common in herpes zoster), which may classify patients as “moderately or suspected malnourished” even in the absence of severe, chronic undernutrition. At present, there are no studies on whey protein in the treatment of herpes zoster. We first reported that the nutritional status of the herpes zoster patients was significantly better after whey protein supplements, which in turn supported the recovery of herpes zoster. Studies have found that whey protein, as a high-quality nitrogen source, can improve the negative nitrogen balance of patients with malignant tumors, stimulate the synthesis of muscle protein, and maintain body weight to avoid or slow the development of cachexia and adverse reactions [20]. For patients with herpes zoster, active whey protein provided the essential amino acids and improved the nutritional status of patients. Although the albumin and total protein levels were not increased, the prealbumin level was significantly higher after nutritional intervention. A possible reason was the short duration of the nutritional intervention.

GSH is the main endogenous antioxidant, which can quickly neutralize a large number of free radicals produced in the inflammatory response and minimize the damage of inflammation to normal tissues [16, 17]. The reactivation of the varicella-zoster virus and the subsequent neural inflammation and cutaneous eruption are known to induce significant oxidative stress [21]. This state is characterized by an overproduction of reactive oxygen species (ROS), which can damage lipids, proteins, and DNA, potentially exacerbating tissue damage, impairing wound healing, and contributing to the persistence of pain, including postherpetic neuralgia [22]. For instance, a study by Oskay et al. demonstrated altered levels of antioxidant and inflammatory biomarkers in herpes zoster patients, supporting the involvement of oxidative stress in its pathophysiology [23]. In the context of skin inflammation in herpes zoster, activated leukocytes infiltrating the lesions generate a substantial amount of peroxides, which can damage surrounding healthy tissues and cells, thereby prolonging recovery [23]. However, our findings demonstrated that whey protein supplementation significantly increased serum GSH content and enhanced the activity of glutathione peroxidase (GSH-PX). This enhancement of the GPX-GSH antioxidant axis is a plausible mechanism contributing to the observed clinical improvements. Whey protein is a rich source of cysteine, a rate-limiting precursor for the de novo synthesis of GSH [24]. By providing abundant substrate, whey protein supplementation could support the body’s capacity to maintain an adequate GSH pool under conditions of oxidative stress. The increased GSH-PX activity further indicated an enhanced ability to neutralize hydrogen peroxide and organic hydroperoxides, thereby reducing oxidative damage and potentially creating a more favorable environment for tissue repair and resolution of inflammation [25]. This was particularly relevant in herpes zoster, where managing the inflammatory cascade is crucial for recovery. While the activities of superoxide dismutase (SOD) and levels of malondialdehyde (MDA) and nitric oxide (NO) were not significantly altered in our short-term intervention, the specific boosting of the GSH system highlights a targeted effect. The 7-day duration may have been sufficient to modulate the highly dynamic GSH system, but insufficient to induce detectable changes in other parameters with different turnover rates or larger body pools. This aligns with existing literature on nutritional support in conditions of acute stress, where rapid modulation of GSH is recognized as a critical defense mechanism [26].

The whey protein can also provide substrates for immune cells to synthesize cytokines, antibodies, and immunoglobulins, improving the immune function of the body, which are essential for the treatment of herpes zoster patients. It should be noted that a full, de novo synthesis of immunoglobulins and cytokines typically takes longer than the 7 days of treatment [27]. However, the timepoint we supplemented the whey protein to patients is not the beginning of reactivation of the varicella-zoster virus. This meant the synthesis of immunoglobulins and cytokines had already begun, and the whey protein treatments probably accelerated this synthetic process. Besides, whey protein is a source of pre-formed immunoglobulins and contains bioactive molecules that may acutely modulate immune cell activity [28]. Given the poor compliance of patients after discharge from the hospital, we provided intervention only during the 7 days of hospitalization and increased the intervention dosage to 40 g of whey protein daily. The results showed that the short-term improvement in the patients’ disease and nutritional status could be achieved through high-dose supplementation. Inflammatory cytokines are changed in herpes zoster patients [29]. In the present study, we observed the increases in IL-6, IFN-γ, IgG, and IgA. It has been reported that IL-6 is closely related to the pain degree and the time of symptom remission and subsidence in patients with herpes zoster [30]. Also, the deficiency in IFN-γ was correlated to herpes zoster [31], while the immune inhibitor against IFN-γ increased the risks of herpes zoster [32]. The IgG and IgA could neutralize the virus to function in herpes zoster [33, 34]. Hence, the oral whey protein might enhance the immune system to accelerate herpes zoster recovery. The increase in IL-6 and IFN-γ within a 7-day period was noteworthy. This rapid response might be related to the bioactive components in whey protein, such as immunoglobulins and lactoferrin [28], which might provide a direct immunomodulatory stimulus rather than solely acting through slow, de novo protein synthesis. Further mechanistic studies, such as molecular biology experiments and animal experiments, to explore this potential rapid-acting effect are highlighted.

Limitations

While the sample size was evaluated for the primary clinical endpoints, it was highly likely underpowered for the numerous secondary exploratory endpoints, increasing the risk of overestimating treatment effects or Type I errors. Given our small sample size (n = 20 per group) and the multiplicity of endpoints, the remarkably large effect sizes observed in clinical recovery times might be significantly overestimated. Therefore, these clinical benefits must be interpreted with extreme caution until replicated in larger, adequately powered multicenter trials. Because whey protein and dextrin were indeed organoleptically distinct, and the formal blinding validation was absent, the partial unblinding was a highly probable risk, which inherently introduces expectation bias into subjective outcomes like VAS, DLQI, and PG-SGA. The accuracy and validity of the tools employed in this study, specifically the visual analogue scale (VAS) for pain and the Dermatology Life Quality Index (DLQI), warrant careful interpretation. Future studies should incorporate validated neuropathic pain scales, such as the Douleur Neuropathique 4 (DN4) questionnaire, to more precisely characterize the pain response. Similarly, while the DLQI is widely validated for chronic skin conditions, its application in acute herpes zoster captures the acute patient burden rather than chronic dermatological morbidity. The remarkably high rate of malnutrition (85%) was identified in our study using the PG-SGA. The PG-SGA was highly sensitive to recent weight changes and symptoms affecting food intake. Herpes zoster caused severe acute pain and discomfort, which frequently led to a transient but significant loss of appetite. Therefore, the high PG-SGA scores in our cohort likely reflect the acute illness burden and immediate symptom-driven nutritional risk, rather than chronic, severe physiological undernutrition. Furthermore, because the PG-SGA is primarily validated for cancer and chronic illnesses, its application in acute herpes zoster represents an exploratory approach.

In conclusion, the oral active whey protein adjuvant to normal clinical therapy could significantly promote herpes zoster recovery and alleviate pain. The probable reasons tend to be the improved nutritional status, enhanced antioxidant system, and the synthesis of immunoglobulins and cytokines for the anti-virus system. A larger number of participants to be tested and the specific mechanism to be investigated are needed for promoting the application of whey protein in herpes zoster patients.

Authors' contributions

Xiaowen Niu: Conceptualization, Methodology, Investigation, Data curation. Hua Ni: Methodology, Investigation. Linyun Shen: Validation. Bei Zhu: Resources. Huan Shi: Resources, Supervision. Qingqiong Luo: Resources. Jianxin Yang: Investigation. Hui Shen: Resources. Dongyao Wang: Resources, Methodology. Sha Dai: Conceptualization, Writing- Original draft preparation, Project administration. Yuxiao Tang: Formal analysis; Writing - Original Draft; Funding acquisition; Visualization; Writing - Review & Editing.

Funding

This work was supported by the National Natural Science Foundation of China (81903306), Shanghai Natural Science Foundation (23ZR1477600), Y.T is supported by the Young Elite Scientists Sponsorship Program by CAST (2022QNRC001).

Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committee of Shanghai Dermatology Hospital (approval number: 2022-30). Clinical trial registration: Medical Research Registration and Filing Information System of China (MR-31-25-032097). Clinical trial number: not applicable. The study was conducted under the principles of the Declaration of Helsinki. Written informed consent, including consent for the use of biological samples for research purposes, was obtained from all participants before any study procedures commenced.

Competing interests

The authors declare no competing interests.