Zoster sine herpete in a patient with lymphoma

Abstract

Zoster sine herpete (ZSH) is an atypical presentation of varicella-zoster virus (VZV) reactivation without characteristic vesicular lesions. Although ZSH presents with neuropathic pain, allodynia, and hyperesthesia in the dermatome distributed by the affected nerve similar to herpes zoster, absence of rash makes diagnosing ZSH challenging. It is necessary to demonstrate laboratory evidence of VZV reactivation to confirm diagnosis. High clinical suspicion is warranted since diagnostic and therapeutic delay can lead to devastating neurological sequelae such as encephalitis, vasculopathy, and postherpetic neuralgia.

Introduction

Zoster sine herpete (ZSH) is an unusual form of varicella-zoster virus (VZV) reactivation characterized by absence of rash when typical dermatomal neuropathic pain occurs. Herpes zoster (HZ)/shingles is a more common manifestation of VZV reactivation. It is marked by vesicular eruption accompanied by neuralgia in the dermatomal distribution of the affected nerve. After primary infection causing chickenpox, VZV establishes latency in the dorsal root, cranial nerve, and autonomic ganglia [1]. VZV can reactivate later following decline of cell-mediated immunity. Triggering factors include immunosuppression, advanced age, chronic diseases, and stress. VZV reactivation can lead to significant neurologic complications, including meningoencephalitis, myelitis, vasculopathy, and postherpetic neuralgia. In the absence of vesicular rash and lack of recognition, ZSH can be easily missed or misdiagnosed. Once ZSH is suspected clinically, empiric antiviral therapy should be initiated and confirmatory laboratory testing to demonstrate VZV reactivation needs to be ordered. The mainstay testing methodology is VZV DNA PCR and VZV IgG/IgM with ELISA. Although widely used, these two methods have their own advantages and disadvantages. Additional CSF analysis for VZV PCR and VZV IgM/IgG should be considered in the diagnosis of ZSH. In this case report, we describe a case of ZSH in an immunocompromised patient with lymphoma.

Case

A 61-year-old female with a past medical history of small bowel T-cell lymphoma complicated by bowel perforation on chemotherapy with CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) presented to the emergency department with right upper quadrant abdominal pain. It started three days before presentation. The pain was worse with deep breathing and sharp in nature. On physical examination, exquisite tenderness was elicited to light tough to right upper quadrant. No rash or erythema was present. Her liver enzymes were normal. A computed tomography (CT) of the abdomen/pelvis prior to presentation had demonstrated pneumoperitoneum associated with bulky mesenteric lymphadenopathy, for which she underwent exploratory laparotomy with small bowel resection. A repeat CT of the abdomen/pelvis in the emergency department showed stranding at the midline of anterior abdominal wall related to scarring and a collection of fluid anterior to the liver. Large amount of stool was observed throughout the colon. The fluid collection was suspicious for seroma. No aspiration was performed. Her abdominal pain was thought to be postoperative. Lidocaine patch and laxatives were started. Herpes zoster preceded by pain was included in the differential, however no vesicular rash ensued. The pain progressively worsened. Day 7 after admission, a suspicion was raised for ZSH based on persistent allodynia, hyperesthesia, and right T5 dermatome sensitivity. In light of severely immunocompromised status and potential disseminated disease process, the patient was started on high dose intravenous acyclovir 10 mg/kg every 8 hours and VZV serology and PCR were sent. Of note, the patient had been on prophylactic oral acyclovir 400 mg twice daily. She did not receive a recombinant zoster vaccine. Over the next 72 hours, the pain significantly improved. VZV IgM/IgG and DNA PCR returned positive. The patient was given acyclovir for 2 weeks. At the completion of therapy, her neuralgia remained subsided without signs or symptoms of developing postherpetic neuralgia. Transitioning to oral antiviral therapy was not necessary.

Discussion

Varicella-zoster virus is a neurotropic herpesvirus specific to humans in the Orthoherpesviridae Family. After primary infection causing varicella/chickenpox, the virus travels retrogradely along sensory nerve neuron fibers and establishes latency in neurons of the dorsal root ganglia, cranial nerve ganglia, and autonomic ganglia, including enteric ganglia [1]. Retrograde axonal transport transmits VZV directly from cutaneous lesions of varicella to neuronal cell bodies. Latency may also be established during viremia [2].

When cell-medicated immunity decreases, the latent virus in the ganglia reactivates and replicates. Following reactivation, the virus travels ante-retrograde from the sensory ganglia to the skin nerve terminals, where it infects and replicates in keratinocytes, and epithelial cells [3]. As a result, a vesicular rash of shingles develops. VZV reactivation can be triggered by multiple factors, including immunosuppressive status, chronic diseases, advanced age, and stress. VZV reactivation can result in significant neurologic and ocular disorders, including meningoencephalitis, vasculopathy, myelitis, Ramsay Hunt syndrome, and necrotizing retinitis. These complications can occur up to 35 % in immunocompromised patients [4].

ZSH is an atypical manifestation of VZV reactivation where dermatomal neuralgia occurs without classic vesicular, erythematous rash. This entity was originally termed " zone fruste " by Widal (1907) and then " zoster sine herpete " by Weber (1916). In 1958, Lewis characterized ZSH in more detail by describing 120 patients presenting with symptoms and signs suggestive of zoster, but without a rash. Two major aspects of the accompanying pain in ZSH were described; sclerotomal pain and dermatomal pain. Sclerotomal pain is associated with a deep boring pain in the muscle and joint with tenderness. Dermatomal pain is associated with a superficial prickling pain with hyperesthesia [5].

Confinement of the reactivated virus to nerve fibers possibly due to variable immune response is the proposed mechanism of ZSH [6], [7]. Instead of migrating to the skin tissue after reactivation in the dorsal root ganglia, the reactivated virus remains confined to the nerve fibers within the affected dermatome, leading to intense pain without visible skin lesions. A study showed that the severity of pain and the prevalence of post-herpetic neuralgia were increased in ZSH compared to herpes zoster (P = 0.0012) [8]. VZV reactivation can also occur in the enteric nervous system, such as the visceral or autonomic nerve, with the virus remaining confined to the nerve fibers, not migrating to the skin surface.

The diagnosis of VZ can be made clinically because the signs and symptoms are characteristic. However, in the case of ZSH, laboratory diagnosis is necessary. The mainstay testing to demonstrate VZV reactivation is VZV DNA PCR and anti-VZV immunoglobulin (IgG and IgM) with enzyme linked immunosorbent assay (ELISA). VZV PCR can be tested broadly for vesicular fluid, scabs from vesicles, skin swabs, throat swabs, cerebrospinal fluid (CSF), tissues from biopsies, blood, and saliva [9]. In addition to serum, VZV IgG/IgM can also be tested for CSF. Importantly, these two testing methods have limitations in terms of efficacy and time window for positivity.

VZV PCR and IgM generally turn positive in the acute phase of reactivation and become negative later. According to studies on VZV myelitis, VZV PCR positivity in the CSF within 7–10 days after the appearance of a rash is 61.5–100 % but decreases to 25–44.4 % thereafter [10], [11], [12], [13]. In the acute phase of VZV reactivation, IgM can be elevated in serum and the CSF. However, the diagnostic use of VZV IgM only to demonstrate VZV reactivation is discouraged. False-negative and false-positive IgM reactions can occur. In a study of patients with ZSH complicated by acute peripheral facial paralysis, only 7/45 patients (15.6 %) were VZV IgM positive [14]. Individuals who developed HZ have invariably detectable levels of VZV IgG. The presence of serum VZV IgG generally indicates past exposure or immunity. Notably, the presence of VZV IgG in the CSF can be used to diagnose ZSH. Intrathecally synthesized VZV IgG might be a better diagnostic indicator compared to VZV PCR in the CSF [15]. Understanding advantages and disadvantages of each method, diagnostic testing for ZSH should include serum VZV IgM/IgG and blood VZV DNA PCR. CSF analysis for VZV PCR and VZV IgM/IgG needs to be considered if those methods are non-diagnostic or neurological complications are present. Our case was diagnosed with ZSH without CSF sampling.

The patient received high-dose intravenous acyclovir with a good outcome. Postherpetic neuralgia did not develop and transitioning to an oral antiviral regimen was not necessary. Despite being on prophylactic oral acyclovir 400 mg twice daily, the patient developed breakthrough VZV reactivation possibly due to malabsorption because of her prior abdominal surgery and chemotherapy. Additionally, the patient did not receive a recombinant zoster vaccine (RZV) due to noncompliance. Vaccine efficacy of RZV against HZ is 97.2 % in immunocompetent adults aged ≥ 50 years [16]. In immunocompromised patients with hematologic malignancies, overall vaccine efficacy is 87.2 % [17].

Conclusions

Zoster sine herpete is a unique manifestation of VZV reactivation. Due to the absence of vesicular eruption and lack of recognition, ZSH ca be easily misdiagnosed. A high index of suspicion is warranted for patients presenting with herpes zoster-like neuralgia without a rash. Once clinically suspected, empiric antiviral treatment should be initiated promptly and laboratory diagnostic testing with VZV PCR and IgM/IgG should be ordered to prevent devastating neurological sequelae.

Author statement

We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.

We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs

CRediT authorship contribution statement

Nguyen Lan: Investigation. Theos Kimberly: Investigation. Shinha Takashi: Writing – original draft, Investigation, Conceptualization.

Declaration of Competing Interest

I have nothing to declare.