Intravenous Vitamin C in the treatment of shingles: Results of a multicenter prospective cohort study

Background

Diagnosis and therapy of herpes zoster (HZ), characterized by dermatomal pain and vesicular rash, frequently involve consultations of general practitioners and hospitalization. Although there are several serious complications of zoster (ophthalmic, splanchnic, cerebral, motor complications), the most common and most feared one in immunocompetent adults is postherpetic neuralgia (PHN). Reported incidences of PHN range between 18% and 33% depending on patient age and assessment time after the infection [1–6]. A recent study reported that 24% of the patients studied had postherpetic neuralgia pain for more than 90 days after rash onset. Median duration of pain was 32.5 days and acute herpes zoster interfered in all health domains, especially sleep quality, enjoyment of life and general activities [1].

Because cellular immunity plays a critical role in reactivation and pathogenesis of varicella zoster virus infection [7], investigating the role of immune-relevant micronutrition is worthwhile from the therapeutic point of view. Vitamin C (ascorbate) is an essential nutrient. It is an important antioxidant [8] and co-factor of various enzymes and involved in the synthesis of collagen, carnitine, neurotransmitters and various neuropeptides and thus critically affects wound healing, energy metabolism, and nervous system function. The highest vitamin C levels are found in immune and nerve cells, reflecting the pivotal role of vitamin C in the function of these tissues [9–11].

Orally administered vitamin C leads to tightly controlled plasma concentration <0.02 mM. Pharmacologic plasma concentrations of vitamin C (>0.2 mM) can be achieved only by parenteral administration [12]. However, pharmacological concentrations are required for the beneficial effects on endothelial function [13], cellular immune function, antioxidative capacity [14], and pain relief [15].

As known from the literature, patients with viral infections exhibit vitamin C deficiencies [16]. This finding was recently confirmed in postherpetic neuralgia patients [17]. These deficient levels seem to play a critical role in the pathogenesis of herpes infections [18] and in the development of postherpetic neuralgia [19].

Low serum levels of vitamin C may be due to increased utilization of vitamin C for the detoxification of reactive oxygen species (ROS) during inflammation. Viral infections produce severe oxidative stress, contributing to cellular damage and disease progression. It was therefore proposed that in the clinical management of viral infections, especially in the early stages, considerable benefits should accrue from anti-oxidant repletion with dosages substantially above recommended daily allowances [20,21].

Studies evaluating the effects of Vitamin C in the treatment of herpes zoster are rare. Werbach compiled 2 experimental studies with intravenously administered 10 g vitamin C, finding beneficial effects on pain and dermatologic symptoms [22]. Such effects were also reported in case reports on herpes and postherpetic neuralgia patients after intravenous administration of vitamin C [23–26] and in a placebo-controlled pilot study [17]. However, there is an ongoing scientific debate on the therapeutic relevance of vitamin C in the treatment of herpes zoster [27].

The rationale of concomitant vitamin C use in acute herpetic and postherpetic neuralgia patients is to combat oxidative stress as a major contributing factor in the pathophysiology of inflammation, neurodegenerative/neuropsychiatric processes, inflammatory skin diseases, and pain [28].

The objective of the observational study presented here was to evaluate the utilization, safety and effects (in terms of reduction of infection-induced complaints) of intravenous (iv) vitamin C administration (Pascorbin® 7.5 g/50 ml) in patients with viral infections, especially shingles, in a primary care practice setting.

Material and Methods

STUDY OBJECTIVES:

Based on our recent investigations [24,25] we hypothesized that intravenously administered vitamin C exerts positive influences on the clinical outcome parameters of HZ, such as acute herpetic neuralgia (AHN) and PHN, and that it reduces dermatologic symptoms and number of affected dermatomes.

STUDY DURATION:

This study was conducted from April 2009 to December 2010.

STUDY DESIGN:

This multicenter, prospective cohort study (observational study) was performed by 16 general practitioners in Germany, who were experienced in the use of Complementary and Alternative Medicine (CAM) in the concomitant treatment of viral infections, especially shingles. The study design and concept, as well as its ethical validity and performance, were based on the actual recommendations of the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (German Federal Institute for Drugs and Medical Devices) and the Paul Ehrlich Institute, in accordance with German laws and the principles of the Declaration of Helsinki and of Good Clinical Practice. The study was registered in Clinical Trials under the trial registration number NCT 00921934. Furthermore, this study followed the actual STROBE guidelines for items to be included in reports on observational studies [29].

STUDY SETTING:

General practitioners recruited by an academic CAM study center received a briefing on the study protocol, the ethical and scientific basis of this observational study, the allocation procedure and the therapy schedule, before the start of the study, in accordance with the study protocol.

Data were collected before the start of vitamin C treatment (visit 1, baseline), after a clinical phase of approx 2 weeks (visit 2), and a follow-up observational phase of approximately a further 12 weeks (Figure 1).

STUDY PARTICIPANTS:

All elective patients of the primary care practices with symptomatic/acute herpes zoster infections were enrolled after their informed written consent and a data privacy policy statement had been obtained. The patients were informed of possible adverse effects and the possibility to withdraw from the study at any time without any curtailment of their treatment. Inclusion and exclusion criteria are shown in (Figure 2). After the return of the completed case report forms (CRFs) it was evident that almost all patients studied had had symptomatic herpes zoster (67 out of 68). We therefore decided to focus this article on HZ but to retain the 1 patient without HZ in all baseline data (age, sex, body weight etc.) because her CRF was correctly completed according to the study design.

A. PRIMARY OUTCOME MEASURES:

The primary outcome measures were:

INTERVENTIONS:

In addition to the standard treatment including analgesics or virostatics at baseline, each patient received acorbic acid (Pascorbin^® 7.5 g/50 ml) in 100 ml NaCL 0.9% as intravenous infusions (2–4 times/week) during the treatment phase of approximately 2 weeks.

DATA SOURCES/MEASUREMENT:

At each admission/visit, the patient’s general condition and the disease-specific previous treatment/medication were recorded. At each medical examination, pain intensity (VAS) was measured. During the first admission the following data were collected and recorded: 1) the patient’s clinical symptoms and complaints due to shingles; 2) location and number of the affected dermatomes; 3) number of single efflorescences; and 4) presence of hemorrhagic lesions.

At admission 2/visit 2 (approximately 2 weeks after the baseline visit) additional parameters (changes in medication and assessment of symptoms) were recorded.

At admission 3/visit 3, approximately 12 weeks after admission visit 1/baseline visit, the following parameters were assessed in addition to the clinical examination: 1) change of medication, 2) assessment of complaints, 3) assessment of vitamin C effects by patient and physician, and 4) possible adverse effects or side effects of vitamin C (Table 1).

POSSIBLE BIAS:

Due to the study design, statistics were maintained only for the primary outcome parameters (VAS, number of affected dermatomes, and presence of hemorrhagic vesicles) and the assessment of efficacy.

SAMPLE SIZE:

In total, 395 case report forms (CRFs) were issued to 63 therapists and 68 correctly and fully completed CRFs of patients with viral infections were returned by 16 general practitioners and were analyzed. In 67 of the 68 subjects, symptomatic herpes zoster was diagnosed.

ASSESSMENT OF PAIN:

At each visit, pain was assessed by means of a 10-point visual analogue scale (VAS) ranging from 0 (=no pain) to 10 (= very severe pain). Changes from baseline were analyzed by means of the One-Sample t-test.

NUMBER OF AFFLICTED DERMATOMES:

At each visit, the number of afflicted dermatomes was assessed by means of the following classification: 0 = none, 1 = 1, 2 = 2, 3 = >2. The frequencies recorded at the baseline visit and the follow-up visits were compared by means of the (exact) Mantel-Haenszel test.

PRESENCE OF HEMORRHAGIC VESICLES:

The presence (or absence) of hemorrhagic vesicles was compared between baseline and follow-up visits by means of Fisher’s exact test.

ASSESSMENT OF EFFICACY:

At baseline, the efficacy of the previous viral infection medication (if applicable) was assessed by means of the following criteria:

The efficacy of ascorbic acid was evaluated and judged by the physician during and at the end of the observation period by means of the same criteria. The assessments of the efficacy of the previous applied viral infection medication and the following concomitant vitamin C therapy were compared by Fisher’s exact test.

All data were checked for plausibility. The data were recorded in an ACCESS database (version 2007) using double data entry. After comparison of the data, they were exported to SPSS Version 19.0 and evaluated. In the context of the descriptive data analysis, the following values were computed, depending on the type of parameter:

Allocation of the concomitant medication and the previous medication was conducted on the basis of the group classifications in the 2010 ”Red List“ [30]. Concomitant diseases were coded according to the ICD-10, German Modification, and classified according to the categories specified there. The focus was set on statistical tests for the main efficacy variables to investigate treatment effects occurring between baseline (visit 1) and the follow-up visits after 2 weeks (visit 2) and 12 weeks (visit 3). Patients could discontinue their participation after visit 2. Therefore, the changes between baseline visit and the last attended visit (visit 2 or visit 3) were also analyzed by applying the Last-Observation Carried Forward (LOCF) principle.

Results

PARTICIPANTS:

In total, 395 case report forms (CRFs) were issued to 63 physicians and 68 correctly and fully CRFs were returned. Sixteen of the 63 initially interested physicians recorded the patient data completely and correctly. The participant rate of the selected physicians was 25.4%. The amount of fully completed CRFs was quite balanced throughout the participating primary care practices (10 physicians returned 5 CRFs each, 5 physicians returned 2, and 1 physician returned 8). Sixty-three (92.6%) patients had shingles, 4 patients had shingles combined with common cold or Epstein-Barr virus infection, and 1 patient had common cold only.

DESCRIPTIVE DATA:

Overall, 42.6% of the participants were men (n=29) and 57.4% were women (n=39); the average age of the patients was 56.3 years (±20.4) and average BMI was 25.8 (±4.6). Thirty-one patients were enrolled immediately after the diagnosis of herpes zoster had been made (within 14 days), 30 patients had herpes zoster-associated complaints for 2 to 6 weeks, and the remaining 7 patients had zoster complaints for more than 6 weeks. The mean amount of vitamin C (in grams) per infusion/application was 9.9±4.6 g. On average, 8 infusions of ascorbic acid were given. At the start of treatment with ascorbic acid, 55.8% of the patients received medications related to the inclusion diagnosis, mainly antibiotics/anti-infectives (45.6%).

In 53 patients (77.9%) concomitant diseases were present; in total 191 diagnoses were reported (most frequently of the ICD group “Diseases of the circulatory system). Twenty-four patients had immunosuppressive disorders. Thirty-five patients (51.5%) used no medications for concomitant diseases; the remaining 33 patients (48.5%) received at least 1 medication (Table 2). At baseline, in the majority of patients the thoracic dermatomes were affected by shingles (43.9%), followed by the cervical (28.8%) and lumbar dermatomes (15.2%).

PAIN: Three patients had no pain at baseline (score value = 0) and were thus excluded from the statistical analysis. The descriptive results per visit are presented in Table 3A. Fifty-nine patients (92.2%) showed an improvement of the VAS value; VAS scores deteriorated in only 1 patient, and 4 patients did not perceive any change in the sensation of pain. The mean VAS score decreases from baseline were statistically significant (p<0.0001) at all visits (Table 3B).

NUMBER OF HZ- AFFECTED DERMATOMES: One patient had no affected dermatomes at baseline and was thus excluded from the statistical analysis. At baseline, 29 patients (43.9%) presented with at least 2 affected dermatomes. At the end of the observation period, only in 5 patients there were still 2 or more affected dermatomes present, while almost 70% of the patients were free from herpes zoster lesions (Table 4). The reduction in number of affected dermatomes was statistically significant at all visits.

PRESENCE (OR ABSENCE) OF HEMORRHAGIC VESICLES: At baseline, hemorrhagic vesicles were present in 32.8% of the patients; at follow-up only 2 patients (3%) had hemorrhagic vesicles; the improvement was statistically significant at all visits (Table 5).

NUMBER OF EFFLORESCENCES/VESICULAR LESIONS:

At visit 1/baseline, in the majority of the participants 1 to 30 vesicles were present. At the end of the observation period the majority of patients (57=86.4%) were free from vesicles (Table 6).

ASSESSMENT OF EFFICACY:

The efficacy of the ascorbic acid treatment was evaluated and judged by the physician during and at the end of the observation period. Only the 37 patients for whom an assessment of the previous medication was available were included in the analysis. Fisher’s exact test yielded a significantly more positive rating for ascorbic acid treatment (Table 7).

COMMON SYMPTOMS - CONCENTRATION IMPAIRMENT AND GENERAL FATIGUE:

At the beginning of the study, 20 patients (29.4%) had moderate or strong concentration impairment. At the end of the observation period, only 4 patients reported moderate or strong complaints and more than 68% patients showed no impairment of concentration (Table 8).

Twenty-five patients (45.5%) reported moderate or strong “general fatigue” at the beginning of the study. At visit 3, moderate complaints were still reported by 2 patients (5%). At the end of the observation period, 61.8% of the patients were free from these symptoms (Table 9). Overall, 78.2% (n=43) of the patients with general fatigue symptoms and 81.8% (n=36) of patients with impaired concentration improved during the whole course of the study (between baseline and the end of the observation period – Table 10).

Adverse effects were observed in 2 study subjects: 1 participant (aged 35 years) had itching and burning sensation on the injection site, followed by paraesthesia; another participant (aged 92 years) exhibited drug-induced urticaria, and according to the protocol the concomitant therapy with ascorbic was stopped. Both patients recovered without sequelae.

Discussion

STRENGTHS AND WEAKNESS OF THE STUDY:

The major strength of our study was the combination of standard pain scores and the assessment of dermatologic symptoms such as the presence of hemorrhagic vesicles and number of efflorescences in the affected dermatome(s) during the study period. Furthermore, for the first time the combination of standard treatment of herpes zoster infection with supraphysiological-dosed intravenous vitamin C within the treatment phase was documented, and the treatment procedure was comparable to that of previous case studies [25]. The participating physicians were to record the numbers of efflorescences and to evaluate the presence of hemorrhagic vesicles at each visit, together with routine pain assessments (VAS). To our knowledge, no study using such a combined assessment of information on dermatological and pain symptoms has been previously published.

The major weakness of our study is the lack of a control group. Furthermore, the low response rate and the low number of patients may have biased the results. Another weakness of the study is that the clinical assessment of the herpes zoster infection without performing confirmatory diagnostic tests might have given rise to study bias, as was reported in other studies [35].

Conclusions

On the basis of our previous preclinical and clinical studies [24,25], and with respect to the fact that low concentrations of vitamin C (≤0.026 mM or 4,6 mg/l) were found to increase independently the PHN risk [17], the study presented here demonstrates that concomitant intravenous administration of ascorbic acid has positive effects on herpes zoster-associated pain and zoster-associated dermatologic findings. Furthermore, common clinical symptoms in patients with shingles, such as general fatigue and impaired concentration, were significantly improved and the risk of developing PHN was reduced.

To confirm our clinical findings, randomized placebo-controlled clinical studies are necessary.