Herpes simplex encephalitis associated with infliximab therapy for ulcerative colitis: A case report

Abstract

BACKGROUND

Infliximab, an inhibitor of tumor necrosis factor alpha, is effective for inducing clinical remission in moderate to severe ulcerative colitis (UC). While generally safe, infliximab carries a risk of viral and bacterial reactivation, such as tuberculosis and hepatitis B virus. Reactivation of herpes simplex virus (HSV) leading to encephalitis remains incompletely characterized.

CASE SUMMARY

A 54-year-old female with UC exacerbation was transitioned to infliximab therapy after a partial response to corticosteroids. Three days post-infusion, she developed acute neurological symptoms, including confusion, aphasia, and respiratory distress, necessitating intubation. Initial computed tomography imaging was unremarkable. Magnetic resonance imaging demonstrated bilateral medial temporal lobe edema and limbic involvement. Cerebrospinal fluid analysis revealed mildly elevated white blood cells and glucose. PCR testing confirmed HSV-1 encephalitis. The patient was treated with intravenous acyclovir, resulting in gradual clinical improvement, although persistent neurological deficits remained.

CONCLUSION

HSV encephalitis, although rare, is a potential complication of infliximab. Early suspicion, diagnosis, and initiation of empirical acyclovir are essential to improve outcomes.

Key Words: Herpes simplex encephalitis; Tumor necrosis factor inhibitor; Ulcerative colitis; Encephalitis; Herpes simplex virus; Case report

Core Tip: Herpes simplex encephalitis is a rare but potentially fatal complication of tumor necrosis factor alpha (TNF-α) inhibitor therapy. This case presents a rare instance of herpes simplex virus type 1 encephalitis, which developed only a few days after starting infliximab treatment for ulcerative colitis. Published literature provides evidence that TNF-α functions as a vital factor that protects against viral infections in the nervous system. Inhibition of TNF-α action allows viruses to reactivate and enter the brain. The treatment of herpes simplex encephalitis requires early recognition and an immediate cerebrospinal fluid PCR sample and initiation of antiviral medication to achieve better neurological results.

INTRODUCTION

Infliximab is a monoclonal antibody targeting tumor necrosis factor alpha (TNF-α). It has revolutionized the management of moderate to severe ulcerative colitis (UC). It is effective in inducing disease remission; controlling symptoms such as diarrhea, rectal bleeding, and abdominal pain; and achieving mucosal healing[1]. While infliximab therapy is generally considered safe, it has a risk of latent infection reactivation, such as tuberculosis and hepatitis B virus[2]. For this reason, it is recommended to screen for latent infections before initiating therapy.

In rare cases, herpes simplex virus (HSV) reactivation has been reported, with some leading to serious events including HSV encephalitis. We present an unusual instance where HSV-1 encephalitis developed as a complication of infliximab treatment in a patients with UC.

CASE PRESENTATION

Chief complaints

A 54-year-old female with a history of UC presented with severe abdominal pain and bloody diarrhea, consistent with an acute disease flare.

History of present illness

The patient was admitted for management of a UC exacerbation. Prior to admission, she had been maintained on mesalamine 2.4 g daily without previous exposure to biologic therapy. She was initially treated with intravenous corticosteroids, which showed only partial clinical improvement. She received methylprednisolone 40 mg twice daily for 9 days. Due to inadequate response, infliximab therapy (5 mg/kg; 500 mg) was initiated for disease control while she remained on systemic corticosteroid therapy.

Three days after receiving the first dose of infliximab, the patient developed sudden-onset vomiting, confusion, aphasia, and brief pauses on cardiac telemetry, rapidly followed by respiratory distress requiring intubation.

History of past illness

The patient had a known diagnosis of UC but no prior history of neurological disease, HSV infection, or central nervous system (CNS) infection.

Personal and family history

The patient had no personal or family history of neurological disorders, autoimmune diseases other than UC, or immunodeficiency.

Physical examination

On physical examination, the patient’s vital signs were as follows: Body temperature, 37.3 °C; blood pressure, 110/73; heart rate, 90 beats per minute; respiratory rate, 20. The patient was conscious, alert, and oriented. Abdominal examination revealed a soft abdomen with moderate tenderness in the lower abdomen.

Laboratory examinations

Lumbar puncture revealed clear cerebrospinal fluid (CSF) with 13 white blood cells (× 10⁶/L) and a glucose level of 82 mg/dL. The CSF was tested for viral pathogens, and PCR confirmed the presence of HSV-1 DNA.

Imaging examinations

On the day of neurological deterioration, a non-contrast computed tomography (CT) scan of the brain and CT angiography were negative for acute stroke, hemorrhage, or large vessel occlusion. A magnetic resonance imaging (MRI) performed the following day showed no acute intracranial abnormality. On Day 5 after clinical deterioration, repeat MRI demonstrated restricted diffusion on diffusion weighted imaging sequences with corresponding T2/fluid-attenuated inversion recovery hyperintensity involving the bilateral insular cortex and medial temporal lobes, consistent with evolving herpes simplex encephalitis.

FINAL DIAGNOSIS

The final diagnosis was herpes simplex virus type 1 encephalitis following initiation of infliximab therapy for UC.

TREATMENT

The patient was treated with intravenous acyclovir at a dose of 10 mg/kg every 8 hours, calculated based on adjusted body weight, for a total duration of 21 days.

OUTCOME AND FOLLOW-UP

The patient showed gradual but slow clinical improvement, with persistence of neurological deficits. Follow-up imaging and CSF analysis demonstrated negative PCR consistent with recovery. However, repeated MRI showed persistent cerebral edema.

DISCUSSION

Reactivation of HSV during TNF-α inhibitor therapy is rare, but it has been reported in the literature. While most cases involve adalimumab and etanercept, evidence also connects reactivation to infliximab[3]. TNF-α plays an important role in the immune response to HSV infection by activating inflammatory pathways and recruiting immune cells to suppress viral replication[4,5]. Inhibition of TNF-α disrupts this defense and makes patients more susceptible to viral reactivation. The main symptoms of HSV encephalitis include fever, headache, and altered mental status, as well as specific neurological problems in particular areas of the body. The presentation may be atypical or delayed in patients who are taking TNF-α inhibitors, resulting in poor outcomes. The MRI findings include temporal lobe edema, together with CSF analysis results indicating lymphocytic pleocytosis, but HSV DNA detection through CSF PCR is required to confirm the diagnosis[3,4]. As summarized in Table 1, only a limited number of studies have described HSV encephalitis in patients treated with TNF-α inhibitors. The onset of symptoms occurs at different times after starting treatment, which requires staying alert throughout the entire treatment period.

Table 1 Summary of reported cases of herpes virus infections associated with tumor necrosis factor alpha inhibitors.

Ref.	Medication	Treated condition	Timing of symptoms	Virus type
Nicolai et al[6], 2016	Etanercept	Juvenile idiopathic arthritis	Not specified	Varicella-Zoster
Bradford et al[3], 2009	Adalimumab, infliximab	Rheumatoid arthritis	15 months, 24 months	HSV-1
Schepers et al[7], 2014	Adalimumab	Psoriasis	24 months	HSV-1
Crusio et al[8], 2014	Etanercept	Psoriatic arthritis	Not specified	HSV-1

HSV-1: Herpes simplex virus 1; TNF-α: Tumor necrosis factor-alpha.

TNF-α plays an important role in the innate immune response against HSV-1. The pathway inhibition mechanism allows viruses to become active again while they spread toward the CNS. Research experiments on mice have shown that TNF-α and cytokine interleukin 1 beta (IL-1β) function as vital cytokines that help the brain establish its initial defense mechanism against viral pathogens[5]. In the C57BL/6 knockout mouse model showed that TNF-α and IL-1β deficient mice had weak microglial activation while the virus spread freely through the pons and medulla, which caused fatal HSV-1 encephalitis[5]. In contrast, wild-type mice mounted a good innate inflammatory response, and 85% survived the infection[5]. These findings show TNF-α to be an important mediator of early antiviral neuroimmune defense. Clinically, patients who are treated with TNF-α are more susceptible to herpes virus infection, as it places the patient in a vulnerable state. Pediatric patients who are treated with etanercept for juvenile idiopathic arthritis have a higher rate of recurrent herpes labialis. This suggests an increased chance of reactivating HSV-1 during active treatment with TNF-α blockade[6]. Collectively, both experimental and clinical studies suggest that TNF-α inhibition increases the risk of HSV-1 reactivation, predisposing these patients to encephalitis. It is important to acknowledge that the patient remained on systemic corticosteroid therapy at the time infliximab was initiated. Corticosteroids are independently associated with impaired cellular immunity and have been reported as risk factors for HSV reactivation. Therefore, the development of HSV encephalitis in this case may reflect the combined immunosuppressive effects of corticosteroids and TNF-α inhibition rather than infliximab alone.

The literature contains only a few cases of HSV encephalitis linked to TNF-α inhibitors. These cases show common patterns in their clinical presentation, including multiple agents (adalimumab, infliximab, and etanercept) and occurrence in various underlying conditions, such as rheumatoid arthritis, psoriasis, and psoriatic arthritis[3,6-8]. Most patients show their first signs of neurologic deterioration a year after beginning therapy.

Some of these cases have atypical disease courses: For example, a patient receiving long-term adalimumab for psoriasis had progressive temporal lobe involvement and was resistant to standard antiviral therapy[7]. In a case series of patients who received TNF-α inhibitors (infliximab and adalimumab) and developed HSV temporal lobe encephalitis, early radiological progression was shown despite standard dose acyclovir; however, all patients eventually improved with continued therapy[3]. Moreover, a patient who had been on ipilimumab and corticosteroids and who had started infliximab for immune-related colitis developed fatal HSV-1 encephalitis, which demonstrated that combined immune system suppression is a risk factor for fatal HSV infections[9]. Additional reports of HSV-1 encephalitis during etanercept therapy highlight that this complication is not isolated to a single TNF-α inhibitor[6,8]. These cases show that HSV encephalitis that develops in patients receiving TNF-α blockade medication results in disease manifestation with intense symptoms, with delayed improvement or failure to improve through conventional antiviral therapy.

The early onset of neurological symptoms within three days of infliximab administration raises important mechanistic considerations. Although classical models of HSV reactivation suggest a longer time to reactivation, experimental mouse models demonstrate that TNF-α plays a critical role in early CNS viral containment[5]. In these models, TNF-α deficiency is associated with progression to HSV encephalitis within days[5]. It is therefore plausible that subclinical viral replication during corticosteroid therapy, followed by TNF-α inhibition, impaired early neuroimmune control and facilitated rapid CNS invasion. These findings support a multifactorial pathogenesis in immunocompromised hosts.

The present case study offers important insight into HSV encephalitis, which affects patients who receive TNF-α inhibitors, cases of which are scarce in the literature. Unlike most of the published articles related to HSV-1 encephalitis after prolonged biologic medication exposure, our case occurred within a few days of starting infliximab for UC. It is one of the earliest documented cases of HSV-1 encephalitis and one of the first for UC. The short duration between the appearance of symptoms and the start of infliximab shows that recent corticosteroid use, along with TNF-α inhibitors, has made HSV more likely to reactivate or invade the CNS. Further case reporting is required to establish risk factors and causality, as well as long-term outcomes.

CONCLUSION

HSV encephalitis, although rare, should be considered in patients receiving TNF-α inhibitors who develop acute neurological symptoms. Prompt clinical evaluation and appropriate diagnostic workup are essential when suspicion arises. Early initiation of empiric acyclovir should be considered in cases with concerning clinical and radiologic features suggestive of herpes viral encephalitis. This case highlights the importance of maintaining clinical vigilance in immunocompromised patients.