Varicella-zoster virus encephalitis in an elderly patient with influenza A infection

Abstract

Varicella-zoster virus (VZV) encephalitis is a rare but severe condition associated with significant morbidity and mortality. Its clinical presentation is often nonspecific and may overlap with other neurological conditions, including complications of influenza infection. We report a case of a 76-year-old man with confirmed influenza A infection who developed progressive neurological deterioration. Notably, no cutaneous manifestations suggestive of herpes zoster were observed. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis, and polymerase chain reaction confirmed the presence of VZV DNA. The patient was treated with intravenous acyclovir, resulting in clinical improvement and full neurological recovery. This case highlights the diagnostic challenges of acute neurological manifestations during influenza infection, where symptoms may be attributed to influenza-related complications. It underscores the importance of considering VZV reactivation, particularly in elderly patients, even in the absence of typical cutaneous manifestations, to ensure timely diagnosis, appropriate antiviral treatment, and improved clinical outcomes.

Introduction

Varicella-zoster virus (VZV) encephalitis is a rare condition with an estimated annual incidence of approximately 2–5 cases per 1,000,000 and is associated with a high mortality rate up to 20% [[1], [2], [3], [4], [5]]. Early diagnosis and prompt initiation of antiviral therapy are essential for improving clinical outcomes [3,6].

The clinical presentation is heterogeneous and often nonspecific, overlapping with a wide range of infectious and noninfectious neurological conditions, including central nervous system (CNS) complications of influenza infection. Consequently, delayed diagnosis may occur, particularly during the influenza season.

The diagnosis is confirmed by detection of VZV DNA in the cerebrospinal fluid (CSF) using polymerase chain reaction (PCR).

Here, we present a clinical case of VZV encephalitis in the absence of a typical rash in a patient with influenza A infection. The case highlights the importance of considering not only influenza-associated encephalitis/encephalopathy but also other CNS infections, particularly VZV CNS infection, in the differential diagnosis of acute neurological deterioration during influenza infection, especially in patients with risk factors for VZV reactivation, such as advanced age and diabetes mellitus.

Case presentation

A 76-year-old man presented to the Emergency Department during the influenza season with a 2-day history of progressive weakness, loss of appetite, and fever up to 37.7°C. One day prior to hospital admission, he developed confusion and difficulties with drinking and speech.

His past medical history included hypertension, type 2 diabetes mellitus treated with oral antidiabetic therapy, and prior coronary stenting.

At the time of admission, the patient was in impaired general condition, oriented to time and place, and febrile (38.8°C). No skin rash was observed. Lung auscultation revealed mild crackles at the base of the left lung, and oxygen saturation was 91% on room air. Heart rate was within normal limits, and blood pressure was 140/90 mmHg. There was no neck stiffness or other signs of meningeal irritation. The Glasgow Coma Scale (GCS) score was 15 (E4, V5, M6). No focal neurological deficits or seizure activity were observed.

Initial laboratory investigations revealed a mild leukocytosis (10.76 × 10⁹/L, reference range 3.5–10.5 × 10⁹/L) with elevated granulocyte count (7.77 × 10⁹/L, reference range 3.5–5.5 × 10⁹/L), hemoglobin 130 g/L (reference range 140–180 g/L), normal C-reactive protein (0.8 mg/L, reference range <6 mg/L), and elevated serum glucose (12.95 mmol/L, reference range 2.8–6.4 mmol/L). Other hematological and biochemical parameters, including platelet count, AST, ALT, GGT, serum creatinine, fibrinogen, sodium, and potassium, were within normal limits.

A rapid antigen test performed on a nasopharyngeal swab was positive for influenza A.

Chest computed tomography (CT) performed on the day of admission showed no evidence of infiltrates or consolidation. Brain CT on the same day demonstrated diffuse hypodense areas consistent with multi-infarct encephalopathy (Fig. 1), which were unchanged compared with those observed on a previous outpatient brain CT performed ten months earlier.

Fig. 1.

Brain computed tomography showing diffuse hypodense areas consistent with multi-infarct encephalopathy.

The patient was started on oral oseltamivir (75 mg twice daily) and symptomatic therapy.

On the second day of hospitalization, the patient’s level of consciousness progressively deteriorated, he became somnolent, unable to establish verbal contact, and exhibited psychomotor agitation (GCS 9, E2, V2, M5). No focal neurological deficits or seizure activity were observed during the hospitalization. A lumbar puncture was subsequently performed. The results of the CSF analysis are shown in Table 1. At the time of lumbar puncture, serum glucose was 6.4 mmol/L, corresponding to a CSF/serum glucose ratio of 0.6.

Table 1.

CSF analysis results.

Parameter	Result	Reference ranges
WBC (mm3)	74 85% Lymphocytes 15% Monocytes	0–5
Protein (g/L)	2.9	0.15–0.45
Glucose (mmol/L)	3.95	4.5–8.0 (2/3 of serum glucose)

CSF culture was negative. Qualitative PCR testing using a multiplex panel for neuroinfections detected VZV DNA, while all other tested pathogens were negative, including Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Escherichia coli K1, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, enterovirus, herpes simplex virus 1 and 2, human herpesvirus 6, human parechovirus, Cryptococcus neoformans/gattii, and Streptococcus pyogenes.

Based on these findings, intravenous acyclovir was initiated at a dose of 10 mg/kg every 8 h.

On the third day of acyclovir treatment, oliguria developed, with a urine output of 400 mL, accompanied by an increase in serum creatinine to 526 μmol/L, urea to 26.9 mmol/L. Serum potassium was 5.5 mmol/L. The acyclovir dose was adjusted to 5 mg/kg every 24 h according to the patient’s renal function. Urine output, fluid balance, serum creatinine, urea and electrolytes, blood pressure, heart rate, and pulmonary findings were closely monitored. Pulmonary auscultation revealed crackles, consistent with volume overload, which was managed with intravenous furosemide.

Within 72 h, renal function began to improve, with recovery of urine output, a negative fluid balance, and progressive normalization of serum creatinine and urea levels. Renal function normalized within 6 days of the onset of acute kidney injury, without the need for hemodialysis. The acute kidney injury was considered likely multifactorial, with a possible contribution from acyclovir-associated nephrotoxicity.

On the sixth day of hospitalization, pulmonary auscultation revealed crackles, and repeat chest CT demonstrated findings of pulmonary congestion, in the setting of which inflammatory changes could not be excluded. Inflammatory markers also increased, including C-reactive protein (113.3 mg/L), leukocyte count (12.58 × 10⁹/L), and granulocyte count (10.21 × 10⁹/L). Empirical antimicrobial therapy with ceftriaxone was initiated while awaiting the results of blood and urine cultures, which were subsequently negative.

Acyclovir was administered for 15 days at appropriate doses. The patient’s condition gradually improved, with full recovery of consciousness and no residual focal neurological deficits. Inflammatory markers returned to within normal limits. Follow-up CSF analysis performed on day 15 of antiviral treatment was normal. The patient was discharged in stable condition with preserved neurological function and remained neurologically intact during one month of clinical follow-up.

Discussion

Varicella-zoster virus (VZV) belongs to the Herpesviridae family. Primary infection typically occurs in unvaccinated children and manifests as varicella (chickenpox). Following primary infection, the virus persists in a latent state in the cranial nerve and dorsal root ganglia [7,8]. Viral reactivation, known as herpes zoster, may occur years or even decades after the initial infection.

The incidence of herpes zoster is associated with multiple factors. It increases with advancing age, which was described by Hope Simpson more than 60 years ago [9]. It is estimated that the risk rises to 50% among individuals living to 85 years [10,11]. In addition to age, immunosuppression represents a major risk factor. This includes immunocompromised states due to solid organ or stem cell transplantation, hematologic malignancies, rheumatic disorders, chronic pulmonary or kidney diseases, and acquired immunodeficiency [[10], [11], [12]].

Herpes zoster typically presents with a painful herpetic rash with a dermatomal distribution. However, reactivation of the virus may also occur without the presence of a rash, a condition known as zoster sine herpete, which is estimated to account for approximately one-third to one-half of VZV CNS infections [8,[13], [14], [15]]. In both presentations, viral reactivation may lead to complications involving the central nervous system, such as encephalitis and meningoencephalitis. These complications occur most commonly in immunocompromised and elderly individuals.

VZV encephalitis is a rare condition with an estimated annual incidence of approximately 2–5 cases per 1,000,000 inhabitants [[1], [2], [3], [4], [5]]. Despite this relatively low incidence, VZV represents one of the leading etiological agents of viral encephalitis [3,4,14]. The reported incidence has increased in recent years, largely due to improved detection of viral DNA using polymerase chain reaction (PCR) methods.

The condition is associated with a high mortality rate up to 20% [1,3]. Different factors have been identified as predictors of poor outcome, most notably a prolonged interval between disease onset and initiation of antiviral therapy, advanced age, and underlying immunosuppression [3,4,6,11,13].

The clinical presentation is heterogeneous and nonspecific, most commonly including headache, fever, dizziness, focal neurological deficits, altered mental status, and seizures [[1], [2], [3], [4], [5],14,16]. These manifestations may overlap with numerous noninfectious and infectious neurological conditions, including influenza-associated central nervous system complications. Consequently, delayed diagnosis of VZV encephalitis may occur, particularly during the epidemiological season of influenza.

Influenza is an acute viral illness characterized by seasonal outbreaks during the autumn–winter period in the Northern Hemisphere. It affects individuals across all age groups. The clinical presentation most commonly includes constitutional, catarrhal, and respiratory symptoms such as fever, malaise, weakness, headache, rhinitis, conjunctivitis, sore throat, and cough. However, atypical or nonspecific manifestations may also occur. Influenza is generally a self-limiting infection, but it can lead to serious complications. Central nervous system involvement is a rare but potentially severe complication in adult patients [[17], [18], [19]]. Its reported incidence is approximately 1.5 per 1000 cases [17,18], with encephalitis or encephalopathy representing the most frequently described neurological manifestations [[17], [18], [19]].

Consideration of influenza in patients presenting with fever and neurological symptoms, particularly during the epidemiological season, is essential to ensure timely diagnosis, initiation of appropriate therapy, and improved outcomes.

In addition, influenza may predispose to secondary infections, including those caused by reactivated bacterial, fungal, and viral pathogens, as a result of influenza-mediated dysfunction of the host immune system. It has been well documented that influenza infection can induce transient immunosuppression and impair innate and adaptive immune responses [20,21].

However, whether influenza A infection contributed to VZV reactivation in the present case cannot be established. The patient’s advanced age and type 2 diabetes mellitus are themselves recognized risk factors for VZV reactivation and provide alternative explanations for the development of VZV central nervous system infection [[10], [11], [12]]. Therefore, the coexistence of influenza A infection and VZV encephalitis in this patient should be regarded as a temporal association rather than evidence of a causal relationship. From a clinical perspective, influenza infection does not exclude other CNS infections, and neurological symptoms should not automatically be attributed to influenza-associated encephalitis or encephalopathy. This case highlights the possibility of VZV CNS infection coexisting with influenza infection, even in the absence of cutaneous manifestations.

From an educational perspective, this case illustrates the importance of considering alternative causes when new neurological symptoms develop during a viral infection. When neurological deterioration occurs during influenza infection, other CNS infections should remain in the differential diagnosis, including VZV infection even in the absence of a typical rash. Recognition of this possibility may prompt appropriate CSF investigation and facilitate timely initiation of specific antiviral therapy.

Conclusions

VZV infection should be considered in the differential diagnosis of patients presenting with acute neurological symptoms, even in the absence of cutaneous manifestations and when another infection with CNS involvement is present, particularly in individuals with risk factors for VZV reactivation. Early diagnosis and prompt initiation of antiviral therapy are critical for improving clinical outcomes. Confirmation of the diagnosis relies on detection of VZV DNA in the cerebrospinal fluid (CSF) using polymerase chain reaction (PCR).

CRediT authorship contribution statement

Ralitsa Yordanova: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Ethics declaration

Written informed consent to take part in the study and to publish the article has been obtained from all participants or their legal representatives. The privacy rights of participants have been observed.

This study was performed in compliance with relevant laws, regulatory frameworks and guidelines where the research took place. Ethics committee approval was not required under relevant laws and institutional guidelines. Ethical approval was not required for this case report in accordance with institutional and national guidelines.

This research follows the CARE guidelines and the CARE checklist.

Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the author used ChatGPT (OpenAI) for language editing. The author reviewed and edited the content as needed and takes full responsibility for the content of the manuscript.

Funding

No specific funding was received for this work.

Conflicts of interest

The author declares no conflicts of interest.

Declaration of Competing Interest

The author declares that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.