Clinical Diagnosis of Herpes Zoster in Family Practice

INTRODUCTION

Herpes zoster is a common disease, with a reported incidence varying from 2.2 to 4.8 per 1,000 persons per year.^1–3 It is due to a localized recrudescence of the varicella-zoster virus in sensory ganglia, where the virus has remained dormant since the primary infection (chickenpox). Age and immunity-attenuating diseases are well-known risk factors for herpes zoster.⁴ The most frequent complications of herpes zoster include postherpetic neuralgia and, in cases of ophthalmic herpes zoster, sight-threatening eye problems.

Because the typical unilateral rash helps family physicians diagnose herpes zoster clinically, suspected cases of herpes zoster are rarely investigated serologically or virologically. False-positive diagnosis of herpes zoster, however, is reported to occur in up to 13% of patients^5,6 and may result in unnecessary prescription of antiviral medications, erroneous referral, and unnecessary invasive interventions for the prevention of postherpetic neuralgia.⁷

Serological analysis is one method to confirm the diagnosis of herpes zoster,⁸ but few studies have assessed its value in family practice. Moreover, such analysis in primary care can be fraught with logistic problems. In remote areas laboratory facilities may not be accessed easily, and for research purposes uniform analysis techniques at a central location may be preferred over analyses in different laboratories. To address these problems in resource-limited settings, dried blood spot analysis has been used for the screening and diagnosis of various infectious diseases, including those caused by varicella-zoster virus,⁹ as it greatly facilitates collection and transport of patient material and assures its stability.^10,11

The aims of this study were to determine the positive predictive value of clinical judgment in diagnosing herpes zoster and to assess the logistic appropriateness of dried blood spot analysis in primary care.

METHODS

RESULTS

Paired blood samples of 272 consecutive herpes-zoster patients were received at the laboratory. The median time span between collection of the blood and delivery at the laboratory amounted 4 days (interquartile range: 2 to 6 days). In 12 patients 1 or both samples did not contain sufficient blood for serological analysis. In the remaining 260 patients that were used in the further analyses, at least 6 serological analyses could be performed from each collected blood sample. The median duration of the zoster rash at the enrollment visit was 2 days (interquartile range: 1 to 4 days). The median time between the 2 blood specimens was 7 days (10%–90% range: 7 to 9 days).

DISCUSSION

In this study of herpes zoster in primary care, we found that the clinical diagnosis could be confirmed serologically in 91% of patients with signs and symptoms of herpes zoster. This study therefore shows that family physicians have good clinical judgment with regard to diagnosing herpes zoster, a finding all the more impressive when considering that the percentage of unconfirmed cases could have been lower had an even more sensitive test (ie, polymerase chain reaction for VZV-DNA from vesicle fluid^17,18) been used to confirm the clinical diagnosis.

The diagnosis could not be confirmed serologically in 9% of the patients with clinically diagnosed herpes zoster. This percentage is comparable to results reported by Kalman and Laskin⁵ and Helgason et al.⁶ Our study, however, is the first in which consecutive primary care patients with clinically diagnosed herpes zoster were serologically investigated prospectively, whereas Kalman and Laskin performed viral culture only in a small group of referred herpes-zoster patients (47 patients), and Helgason et al verified the clinical diagnosis of herpes zoster mainly by reviewing the clinical characteristics of patients. In contrast with the Helgason et al study, we found recent herpes simplex virus reactivation in only 1 patient. This finding can be explained by the higher mean age of our study population; in contrast with herpes zoster, the incidence of herpes simplex virus recurrence has been reported to decrease with age.¹⁹

The only independent clinical variables for serologically confirmed herpes zoster were severity and duration of rash at the enrollment visit. Although zoster without rash has been reported (so-called zoster sine herpete),²⁰ the typical appearance of vesicles is a highly distinguishing sign for herpes zoster.

VZV-IgA assay contributed most to the confirmation of the clinical diagnosis of herpes zoster. Because only 57% were positive for VZV-IgA during the first days of the zoster rash, this test is not suitable for identifying acute herpes zoster, ie, at a time when confirmation of the diagnosis may have prompt therapeutical consequences. Combination with a VZV-IgM assay would hardly improve detection (Table 1⇑). A polymerase chain reaction on VZV-DNA from vesicle fluid would be preferred in such a situation.^17,18,21

Of the 272 blood samples, 260 (96%) were suitable for serological analysis, so this diagnostic method proved logistically feasible in primary care, as has previously been described for a variety of infectious diseases, including measles, toxoplasmosis, hepatitis C, and human immunodeficiency virus infection.^16,22–24 Although our study shows that the value of dried blood spot for serological verification of herpes zoster is limited, the logistic advantages of this method, such as ease of collection, transport, and storage, are evident.

Some potential limitations of this study need to be addressed to appreciate the results. First, our aim was to quantify the extent to which a clinical diagnosis of herpes zoster made by the family physician could be confirmed serologically. As a result, we studied only those patients with herpes zoster diagnosed clinically by their physician. We did not aim to determine the value of serologic testing as reference standard for all patients suspected of having herpes zoster. Hence, we could quantify only the positive predictive value of the family physician’s clinical diagnosis, which was 90.8%; we could not assess the corresponding sensitivity, specificity, negative predictive value, and likelihood ratios. Second, because of the inclusion criteria of the randomized clinical trial in which this study was nested, the results apply only to older (older than 50 years) immunocompetent patients with herpes zoster below the C6 dermatome. Because immunosuppression may cause deficient antibody production,²⁵ VZV-serological tests might perform less well in immunocompromised patients. Such patients, however, are at high risk of complications from viral dissemination, and any clinical diagnostic uncertainty should justify prompt referral for specialized care and laboratory investigation. There is no evidence that herpes-zoster patients younger than 50 years or those with cranial (eg, ophthalmic) localization have a diminished serological response to a VZV-reactivation. Finally, patient selection with typical signs and symptoms could have occurred had only patients with typical signs and symptoms of herpes zoster been enrolled in the PINE trial from which this study was derived. The participating family physicians, however, registered the baseline characteristics of all new herpes-zoster patients who visited them during the inclusion period. These data did not differ between enrolled patients and patients who met the inclusion criteria but were not enrolled. We therefore consider the results of this study to be valid for all immunocompetent herpes-zoster patients in family practice.

We conclude that the clinical diagnosis of herpes zoster made by family physicians is correct in more than 90% of cases in which serologic testing was used as a reference standard. Thus, VZV-antibody analysis does not have added value as a routine diagnostic aid in family practice. Our results, however, show that dried blood spot analysis is a logistically convenient method for serological investigation of patients in primary care.