Herpes Simplex Virus Encephalitis after Recovery from Coronavirus Disease 2019: A Rare Case Report

Abstract

An 85-year-old woman was diagnosed with coronavirus disease 2019 (COVID-19). The patient was treated with dexamethasone, and the infection was cured. She later developed a low-grade fever and fell unconscious. Positivity for herpes simplex virus deoxyribonucleic acid polymerase chain reaction (HSV-DNA PCR) was detected in the cerebrospinal fluid, so she was diagnosed with HSV encephalitis. The patient was treated with antiviral drugs and recovered from the HSV encephalitis. This case suggests that, in patients with COVID-19 and disorders of consciousness, the possibility of HSV encephalitis should be considered along with COVID-19 encephalitis.

Introduction

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. SARS-CoV-2 can cause severe pneumonia and, in some cases, neurological symptoms including disorders of consciousness, dysosmia, and dysgeusia. In patients with COVID-19, the risk of reactivation of herpes simplex virus (HSV) is significantly higher than in other patients (1,2). Recent studies on HSV reactivation in patients with COVID-19 have reported the presence of exanthema associated with HSV. HSV rarely causes encephalitis, which has a high mortality rate and often leaves neurological sequelae (3,4).

We herein report a patient who developed HSV encephalitis after recovering from COVID-19.

Case Report

An 85-year-old woman with a history of hypertension presented to her family doctor with complaints of a fever and cough. She had smoked 10 cigarettes/day for 30 years since starting smoking at 20 years old and had no history of alcohol consumption. The patient was administered nifedipine (40 mg), carvedilol (7.5 mg), azilsartan (40 mg), and doxazosin (2 mg/day). She tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) and was thus diagnosed with COVID-19.

As the COVID-19 vaccine had not yet been developed, she was unvaccinated. She was referred to our hospital and admitted 12 days after the onset. On an examination, she appeared ill and febrile at 38.0°C. During the same period, she lost her sense of taste and smell but did not suffer from headaches or diarrhea. Her respiratory rate was 20/min with oxygen saturation of 90% on room air. Furthermore, while neurological examination results were normal, fine crackles were present at both lung bases. Laboratory test results on admission revealed a normal white blood cell count (4,000 /μL), no lymphocytopenia (27%), and elevated C-reactive protein (CRP) (2.28 mg/dL) and lactate dehydrogenase (307 U/L) levels.

Chest radiography revealed increasing opacities in both lower lung fields. Chest computed tomography (CT) revealed bronchovascular bundle thickening, interlobular septal thickening, and nonsegmental consolidation in both lower lung lobes (Fig. 1). Overall, her condition corresponded to a moderate COVID-19 infection (stage II based on the COVID-19 Medical Treatment Guide version 3 in Japan).

Figure 1.

Chest computed tomographic scans on admission. Chest computed tomography scans on admission revealed thickening of the bronchovascular bundles, interlobular septal thickening, and non-segmental consolidation in both lower lung lobes, corresponding to COVID-19 pneumonia.

After admission, dexamethasone (6.6 mg) was administered daily for 10 days. On hospital day 9, her body temperature returned to normal, and the opacities on chest X-ray decreased, indicating that she had recovered from COVID-19. However, on hospital day 20, her temperature increased to 38.6°C, and pyuria and bacteriuria were detected. Blood examinations revealed a white blood cell count of 4,600 /μL and CRP levels of 1.91 mg/dL. We diagnosed the patient with a urinary tract infection and administered ceftriaxone 1 g/day. On hospital day 24, laboratory tests revealed a normal white blood cell count of 7,400 /μL, decreased CRP levels (0.71 mg/dL), and no presence of pyuria or bacteriuria. Although we assumed that the urinary tract infection had been cured, a low-grade fever persisted, and she developed indistinct consciousness (Japan Coma Scale II-10). She appeared somnolent, could not track objects with her eyes, and developed speech difficulties. Her neck was supple, and the Babinski reflex was positive on the right side. Hypoglycemia and electrolyte imbalance, which can cause unconsciousness, were not detected.

The opacities on chest radiography improved, and SARS-CoV-2 PCR results of the nasal swab were negative. Therefore, no COVID-19 relapse was observed. A cerebrospinal fluid (CSF) examination revealed the following: a clear appearance, normal opening pressure (13 cmH₂O), elevated cell count of 13 /μL (mononuclear leukocyte, 95%; polymorphonuclear leukocyte, 5%), and mildly high glucose and total protein concentrations (86 mg/dL and 66 mg/dL, respectively). HSV-DNA PCR results for the CSF were positive at 18×10³ copies/mL, SARS-CoV-2 PCR results were negative, bacteria were not detected using Gram staining and culture, and mycobacteria and fungi were not detected using culture. Thus, bacterial and fungal meningitis were ruled out.

An electroencephalogram showed diffuse slowing of background activity and no epileptic waves, indicating disturbance of consciousness. Magnetic resonance diffusion-weighted imaging (MRI-DWI) revealed a high intensity from the anterior left temporal lobe to the left lateral parietal lobe, and no cerebrovascular disease was detected (Fig. 2A). Therefore, she was diagnosed with HSV encephalitis.

Figure 2.

Magnetic resonance imaging-diffusion weighted image (MRI-DWI). A: MRI-DWI on hospital day 24 revealed high intensity from the anterior left temporal lobe to the left lateral parietal lobe, and no cerebrovascular disease was detected (arrow). B: MRI-DWI on hospital day 43 revealed a lower intensity of the lesions and indicates that HSV encephalitis was cured by antiviral drugs (arrow).

On hospital day 27, we administered acyclovir at 500 mg per 12 h. Dose reduction of acyclovir was required, as the patient had renal impairment (creatinine clearance, 26 mL/min). The patient showed improved consciousness and started speaking easy-to-speak words. On hospital day 36, her transaminase levels were elevated (aspartate aminotransferase 117 U/L; alanine aminotransferase, 162 U/L); therefore, acyclovir was switched to vidarabine 600 mg/day. On hospital day 43, her speaking capabilities improved, and MRI-DWI revealed a reduced intensity in the left lobe (Fig. 2B). On hospital days 55 and 62, CSF examinations revealed that HSV-DNA-PCR results were negative, and the cell count was within the normal range; thus, HSV encephalitis was considered cured.

Discussion

HSV enters through the primary infection site, skin surface, or mucosa via direct contact and establishes a latent infection in the nerves that innervate the infection site (5). HSV-specific CD8+ T cells block HSV reactivation from latency, but immunosuppression and physical and psychological stress can impair the T cell function and permit HSV escape latency (5-8). Reactivation of HSV is more likely in patients with COVID-19 than in those with other critical illnesses (2). Shanshal et al. reported that 35% of mild to moderate COVID-19 patients had single or multiple episodes of HSV reactivation during their COVID-19 infection (9). However, their study reported no cases of HSV encephalitis or meningitis.

Recent studies have reported that COVID-19 promotes HSV reactivation through various mechanisms (9-11). COVID-19 is associated with immune dysregulation, T cell cytopenia, decreased interferon-γ (IFN-γ) levels, and overproduction of interleukin-6 (IL-6), which are associated with HSV reactivation. In humans, CD8+ T cells surround HSV-infected neurons within the trigeminal ganglion and regulate HSV reactivation. In addition, CD8+ T cells promote the production of IFN-γ, which has an antiviral effect (6). Depletion of T cells in patients with COVID-19 decreases IFNs levels, whereas a dysregulated IFN response has been associated with a decrease in T cells. Dysregulation of the IFN response may allow latent HSV reactivation in patients with recent COVID-19 infection.

Furthermore, a decrease in IFN levels in patients with COVID-19 may lead to an imbalance between proinflammatory macrophages and macrophages that facilitates repair. High levels of neutralizing antibodies against the spike protein of SARS-CoV-2 have been associated with a marked deficiency of repair-facilitating macrophages and upregulation of proinflammatory macrophages in the lungs of patients with COVID-19. Several reports suggested an association between IL-6 overexpression and HSV reactivation (12-14). IL-6 is a cytokine produced in infections and tissue injuries and induces anti-apoptotic molecules (Bcl-2 and Bcl-xL), inhibiting the destruction of virus-infected cells by virus-specific CD8+ T-cells, thus facilitating the viral survival (15,16). SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor, infects the olfactory epithelium with a high ACE2 receptor expression, and accesses the central nervous system via the olfactory bulb. Another route of viral entry is through the peripheral blood via the lung tissue, which reaches the capillaries of the brain, binds to ACE2 in vascular endothelial cells, and invades the central nervous system (17). COVID-19 also causes significant psychological stress, which increases HSV DNA levels in the blood and impairs T cell surveillance of latently infected neurons, resulting in the activation of the latent virus (7). In addition, the stress hormones epinephrine and corticosterone facilitate the replication of HSV (8). A COVID-19-related fever also facilitates HSV reactivation by directly affecting latently infected neurons and the secretion of IL-6 (9).

Glucocorticoids increase the risk of opportunistic infections. HSV reactivation can occur in patients receiving high-dose glucocorticoids at a cumulative prednisolone equivalent dose of 420 mg every 4 weeks (18). This dose was approximately equivalent to 60 mg of dexamethasone administered every 4 weeks. Therefore, the dose used in the RECOVERY trial, 6 mg dexamethasone per day for 10 days (19), is not sufficient to induce an opportunistic infection and may not facilitate HSV reactivation. However, in COVID-19, various reactivation factors occur simultaneously; thus, even a small dose of dexamethasone may cause HSV reactivation. Gupta et al. reported that, out of eight patients with HSV encephalitis and a history of COVID-19 in the previous six weeks, six received corticosteroid therapy during COVID-19 treatment (11). The report did not specify the daily dose of steroids, but the duration was short (mean 5-6 days; minimum 5 days and maximum 10 days). This suggests that the use of corticosteroids may influence immune dysregulation and the subsequent susceptibility to HSV encephalitis in patients with COVID-19. Furthermore, steroids may facilitate HSV reactivation or improve HSV encephalitis; however, the mechanisms underlying this effect remain unclear. Nevertheless, combination therapy with steroids and acyclovir may improve the HSV encephalitis prognosis (20,21).

A CSF examination is an important test to identify the cause of impaired consciousness. It helps, among other things, differentiate between viral and bacterial meningitis. In the present case, the patient was diagnosed with encephalitis rather than meningitis, based on the low number of cells in the CSF and MRI findings. COVID-19 encephalitis was initially suspected in this case; however, CSF PCR results for SARS-CoV-2 are frequently negative. In addition, COVID-19 encephalitis has been shown to respond to immunotherapy and to be cured quickly. Therefore, the encephalitis in this case may have been sparked by an immune response to SARS-CoV-2, although the possibility of direct viral infiltration cannot be excluded.

SARS-CoV-1, another human coronavirus, causes a respiratory infection pandemic and encephalitis. SARS-CoV-1 was detected in the brain specimens of patients with SARS-CoV-1 encephalitis (22,23), wherein encephalitis was caused by the direct attack of the virus on the nerves, and SARS-CoV-2 in this case, may have caused encephalitis via the same mechanism. Therefore, a diagnosis of COVID-19 encephalitis is necessary. Gupta et al. discovered that electroencephalogram results in patients with HSV encephalitis with a history of COVID-19 showed a wide variety of findings, including periodic lateralized epileptiform discharges; diffuse slowing of background activity; and spike, slow, and normal waves (11). In the present case, the electroencephalogram results showed diffuse slowing of the background activity, which was a nonspecific finding. A French retrospective study on neurological symptoms and MRI findings in 64 COVID-19 patients reported that 38 (56.3%) had brain MRI abnormalities, and 2 with limbic encephalitis had hyperintense signal changes on MRI-DWI (24). The MRI findings of COVID-19 and HSV encephalitis are similar; therefore, differentiating them based on imaging findings is difficult. Recovery from COVID-19 was confirmed using SARS-CoV-2 PCR from nasal swabs, and HSV encephalitis was detected using HSV-PCR in the CSF.

In conclusion, patients with COVID-19 are more likely to have HSV reactivation than patients with other illnesses. Therefore, when patients with COVID-19 present with a disordered consciousness, HSV encephalitis should be considered alongside COVID-19 encephalitis. In the present case, whether or not glucocorticoids for COVID-19-induced HSV reactivation cured HSV encephalitis was unclear. Therefore, the effects of glucocorticoids on patients with COVID-19 and HSV encephalitis should be evaluated in the future.

The authors state that they have no Conflict of Interest (COI).