Recurrence of acyclovir-resistant herpes encephalitis in an immunocompromised patient: A case report

Abstract

BACKGROUND

Acyclovir (ACV)-resistant herpes simplex virus (HSV) strains have emerged and gradually increased in number. Prolonged treatment, such as for immunocompromised patients, has been observed on many occasions to lead to the development of resistance. Additionally, some strains of HSV exist that are ACV resistant, and they can cause severe complications that may be impossible to treat with current therapies. We report the first case of ACV-resistant herpes encephalitis (ARHE) recurring in an immunocompromised adult patient without neurosurgical intervention.

CASE SUMMARY

A 58-year-old man with a fever of 38°C had tremors. Evaluation revealed 14 points on the Glasgow Coma Scale with 39°C fever but unremarkable physical examination. Diagnosis was infection of unknown origin; fever continued, and the Glasgow Coma Scale worsened to 8. Imaging showing a high-intensity area between the left temporal lobe and insular cortex suggested herpes encephalitis. ACV was started. Cerebrospinal fluid (CSF) was positive for HSV DNA, confirming the diagnosis. However, unresolved symptoms suggested ARHE; therefore, we initiated vidarabine treatment. Later testing confirmed ARHE. Foscarnet was started based on a hospital day 25 blood test revealing pancytopenia, possibly from vidarabine. Consciousness improved, and the patient moved to rehabilitation. However, symptoms worsened, suggesting recurrence. Diffusion-weighted magnetic resonance imaging revealed a high high-intensity area around the right temporal lobe; CSF was positive for HSV DNA, confirming recurrent herpes encephalitis. ACV and foscarnet were initiated. Fever decreased, consciousness improved, and HSV DNA on hospital days 78 and 93 was CSF negative. Treatment was terminated on hospital day 86.

CONCLUSION

ARHE recurred in the patient following remission; therefore, it is necessary to discuss the length of the treatment period.

Key Words: Acyclovir-resistant herpes encephalitis; Recurrence; Immunocompromised status; Neurosurgical interventions; Treatment; Case report

Core Tip: Acyclovir (ACV)-resistant herpes simplex virus strains have emerged and gradually increased in number. We report the first case of ACV-resistant herpes encephalitis (ARHE) recurring in an immunocompromised adult patient without neurosurgical interventions. Clinicians should recognize this condition because treatment for ARHE is limited, and it often develops into severe herpes disease that is refractory to antiviral drug therapy. In addition, ARHE recurred in the patient following remission; therefore, it is necessary to discuss the length of the treatment period. There is no established standard treatment for recurrence cases; therefore, accumulation of evidence is needed.

INTRODUCTION

Globally, herpes simplex virus (HSV) is the most common double-stranded DNA virus, representing serious dangers to human health through sporadic focal encephalitis, meningitis, genital herpes, cold sores, herpes stromal keratitis, and cancer[1-5]. Millions globally are affected by diseases caused by HSV HSV-1 and HSV-2[2,6]. Estimates put the prevalence of HSV-1 infection worldwide at ~67%, although estimates can be as low as 49% or as high as 87%[4,7]. For HSV-2, estimates suggest that it has infected 20%–25% of the general adult population, and most commonly causes only mild symptoms[2,4,8]. However, depending on immunological state, HSV-1 and HSV-2 can potentially cause severe conditions and systemic infections[8].

HSV makes up nearly 50% of all confirmed encephalitis cases, making it the most common infectious encephalitis pathogen[9]. Encephalitis is more commonly caused by HSV-1 than by HSV-2; while HSV-1 can be the cause of cases of herpes simplex encephalitis (HSE) posing a risk to patients’ lives, there is also a significant amount of overlap[10,11]. HSV-1 is primarily the cause of HSE, which accounts for 5%–15% of both pediatric and adult infectious encephalitis[12]. HSE is a reactivation of a latent herpes virus, enabling the virus to directly lead to viral neurotoxicity[13]. Recurring infections are another characteristic trait[14]. The characteristic course of HSE is short and monophasic, but patients may also experience, a few weeks later, neurological relapses or deficit worsening, after terminating viral therapy and when there is apparent stabilization of the signs and symptoms of damage to the central nervous system[15].

Acyclovir (ACV) arrived on the market in 1977 as the first drug specifically to treat HSV[4,5]. Viral thymidine kinase (TK) phosphorylates it, forming ACV monophosphate, which is in turn phosphorylated by cellular kinases, taking on its active form of ACV triphosphate[4,5]. ACV-triphosphate serves as a competitive inhibitor of viral DNA polymerase[5]. It is the predominant therapeutic drug used for suppressing HSV-1 in clinical interventions, and ACV analogs serve as the reference drugs for herpetic infections[4,8]. ACV is the exclusive antiviral medication used for treating the rarely seen, yet potentially fatal, viral infection HSE[5,16,17]. Indeed, widespread adoption of ACV led to a decrease in HSE-related mortality[5]. HSV DNA polymerase is selectively inhibited by the first- and second-line antiviral drugs used for treating HSV infections (ACV and related compounds), and by foscarnet and cidofovir[14]. However, there has been an emergence of ACV-resistant strains of HSV, which are gradually increasing[4,5,8]. The incidence rate of ACV-resistant HSV has been reported as ~0.5% in immunocompetent patients, and 3.5%–10% in immunocompromised patients[5,18]. Prolonged treatment, such as for immunocompromised patients, has been observed on many occasions to lead to the development of resistance[17]. Additionally, some strains of HSV exist that are ACV resistant, and they can develop into severe complications that can be impossible to treat with therapies that exist today[19]. Here, we report the first case of ACV-resistant herpes encephalitis (ARHE) recurring in an immunocompromised adult patient without neurosurgical interventions.

CASE PRESENTATION

Chief complaints

A 58-year-old Japanese man was transported to our hospital by ambulance with a complaint of a fever of 39°C, fatigue, and rigors.

History of present illness

Twelve hours prior, he had developed a fever of 39°C, fatigue, and rigors. He took an antipyretic, but the symptoms persisted.

History of past illness

The patient’s medical history included pneumonia when he was 51 years old. At the time, he underwent antibiotic treatment for 10 days.

Personal and family history

The patient had a 38-year history as a heavy smoker, averaging roughly 20 cigarettes daily, and was a social drinker. He did not undergo regular medical check-ups. He worked at a clerical job and was allergic to penicillin. He was married and had a family of four. The patient could engage in everyday activities without assistance, and had no known family history of hereditary or malignant diseases.

Physical examination

The patient was 180 cm tall and weighed 70 kg. At the emergency department (ED), he showed abnormal vital signs, with a blood pressure of 177/102 mmHg, heart rate of 116 regular beats/min, body temperature of 39.0°C, oxygen saturation of 95% under 1 L/min oxygen on nasal canula, respiratory rate of 30/min, and a Glasgow Coma Scale score of 14 points (E4V4M6). Nothing abnormal was detected upon physical examination, including skin or neurological findings, such as nuchal rigidity or jolt accentuation.

Laboratory examinations

Upon the patient’s arrival at the ED, a routine laboratory examination was undertaken, and it found raised levels of fibrin/fibrinogen degradation products, blood sugar, glycosylated hemoglobin A1c, and serum osmolality, as well as low levels of thyroid-stimulating hormone and free triiodothyronine (Table 1). A urine qualitative test revealed negative results for urinary tract infection. Two rapid urinary antigen detection kits, BinaxNOW™ Streptococcus pneumoniae (Abbott, USA) and BinaxNOW™ Legionella pneumophila (Abbott), both tested negative. He also tested negative on a rapid antigen test to check for influenza, Quick Chaser Flu A, B (S type) (Mizuho Medy, Japan), and on an ID NOW™ coronavirus disease 2019 assay (Abbott); a near-patient isothermal nucleic acid amplification test that, according to marketing, gives a qualitative result of positive, negative, or invalid within 15 min.

Table 1 Routine laboratory examination upon arrival at the emergency department.

Parameter	Measured value	Normal value
White blood cells (103/µL)	8.2	3.9-9.7
Neutrophils (%)	79	37-72
Lymphocytes (%)	17	25-48
Monocytes (%)	3	2-12
Eosinophils (%)	0	1-9
Basophils (%)	1	0-2
Hemoglobin (g/dL)	15.9	13.4-17.1
Platelets (103/µL)	190	153-346
Aspartate transaminase (IU/L)	19	5-37
Alanine aminotransferase (IU/L)	20	6-43
Lactic acid dehydrogenase (U/L)	192	124-222
Alkaline phosphatase (U/L)	83	38-113
γ-Glutamyl transpeptidase (IU/L)	31	0-75
Total bilirubin (mg/dL)	0.9	0.4-1.2
Total protein (g/dL)	7.7	6.5-8.5
Albumin (g/dL)	4.7	3.8-5.2
Creatine kinase (U/L)	59	57-240
Blood urea nitrogen (mg/dL)	13	9-21
Creatinine (mg/dL)	0.79	0.6-1
Amylase (IU/L)	112	43-124
Sodium (mEq/L)	136	135-145
Potassium (mEq/L)	4.3	3.5-5
Chloride (mEq/L)	99	96-107
Calcium (mg/dL)	8.8	8.5-10.2
Inorganic phosphorus (mg/dL)	3.1	2-4.5
C-reactive protein (mg/dL)	0.03	0-0.29
Plasma glucose (mg/dL)	238	65-109
Glycosylated hemoglobin A1c (NGSP) (%)	11	4.6-6.2
Activated partial thromboplastin time (seconds)	24.8	23-36
Prothrombin time (International normalized ratio)	1	0.85-1.15
Fibrinogen and fibrin degradation products (μg/mL)	8.9	0-10
D-dimer (μg/mL)	1	0-1
Ammonia (μg/dL)	31	28-70
Serum osmolality (mOsm)	295	275-290
Thyroid-stimulating hormone	0.16	0.56-4.3
Free triiodothyronine (pg/mL)	1.08	2.4-4.5
Free thyroxine (ng/dL)	1.52	1-1.7
Lactic acid (mmol/L)	1.3	0.44-1.78

NGSP: National Glycohemoglobin Standardization Program.

Imaging examinations

Head and thoracoabdominal computed tomography revealed negative results. An electrocardiogram revealed sinus tachycardia.

FINAL DIAGNOSIS

We established a diagnosis of infection with unknown origin.

TREATMENT

With the patient’s consent, we admitted him for treatment. The patient was treated with symptoms as they appeared. However, on hospital day 2, the fever continued, the Glasgow Coma Scale worsened to 8, and nuchal rigidity was confirmed. Continuous electroencephalography revealed spikes one or two times per second. A lumbar puncture performed to rule out cerebromeningitis showed colorless, transparent cerebrospinal fluid (CSF) and an initial pressure of 16 cmH₂O, cell count of 2/µL (mononuclear cell advantage), protein of 48.9 mg/dL, and glucose of 146 mg/dL (plasma glucose: 231 mg/dL). Based on this result, we ruled out bacterial meningitis (Table 2). Diffusion-weighted image (DWI) magnetic resonance imaging (MRI) on hospital day 3 showed a high-intensity area between the left temporal lobe and insular cortex, suggesting HSE (Figure 1A). We started 2250 mg/day intravenously administered ACV on the same day, with the intention of continuing it for ≥ 7 days. Despite intravenous administration of 1000 mg/day levetiracetam, spike waves were still observed on electroencephalogram readings. We determined that the patient had status epilepticus and started invasive mechanical ventilation on the same day. In addition, continuous infusion of fentanyl was administered for analgesia, and continuous infusion of propofol was administered for sedation. Nutritional management was provided via enteral feeding, and blood glucose was controlled with continuous insulin infusion. We also administered continuous heparin infusion to prevent deep vein thrombosis, as well as an intravenous proton pump inhibitor to prevent peptic ulcers. CSF taken on hospital day 2 tested positive for HSV DNA, confirming the diagnosis (Table 2). However, unresolved fever following administration of ACV, continued consciousness disorder, and positive CSF on hospital days 10 and 15 suggested ARHE, and we initiated combination treatment with vidarabine on hospital day 15. Later testing showed an ACV-resistant gene (T287M) in a genotypic assay of CSF taken on hospital day 15, and ARHE was confirmed on hospital day 22. A blood test on hospital day 25 revealed pancytopenia, possibly caused by vidarabine; consequently, the vidarabine treatment was terminated, and foscarnet was started. The patient’s fever decreased, and CSF on hospital days 22 and 29 showed negative results for HSV DNA, prompting us to end therapy on hospital day 29. Consciousness improved, and the patient moved to rehabilitation. However, on hospital day 62, the patient’s fever increased, and his consciousness worsened, suggesting recurrence. DWI-MRI revealed a high-intensity area around the right temporal lobe, and CSF tested positive for HSV DNA, confirming recurrent HSE (Figure 1B). ACV and foscarnet were initiated. The patient’s fever decreased, and his consciousness improved; and CSF on hospital days 78 and 93 tested negative for HSV DNA. We terminated foscarnet and ACV on hospital days 85 and 86, respectively. There was no further recurrence of HSE, and DWI-MRI on hospital day 117 revealed no new recurrence (Figure 1C).

Figure 1 Diffusion-weighted image, magnetic resonance imaging. A: On hospital day 3, a high-intensity area between the left temporal lobe and insular cortex was confirmed; B: On hospital day 48, a high-intensity area around the right temporal lobe was newly confirmed; C: On hospital day 117, no new recurrence was confirmed.

Table 2 Cerebrospinal fluid findings taken on 2^nd hospital day.

Parameter (Unit)	Measured value	Normal value
Appearance	Clear	Clear
pH	7.4	7.4-7.6
Initial pressure (cmH2O)	16	50-180
Cell count (/µL)	2	≤ 5
Mononuclear cell	2	≤ 5
Neutrophilic cell	0	0
Total protein (mg/dL)	48.9	≤ 45
Glucose (mg/dL)	146	45-80
Sodium (mEq/L)	145	143-154
Potassium (mEq/L)	2.8	2.7-3
Chloride (mEq/L)	120	120-130
VZV DNA quantitative	< 1.0 × 102	0
HSV DNA quantitative	< 1.0 × 102	0
VZV DNA qualitative	Negative	Negative
HSV DNA qualitative	Positive	Negative

VZV: Varicella zoster virus; DNA: Deoxyribonucleic acid; HSV: Herpes simplex virus.

OUTCOME AND FOLLOW-UP

Although the patient’s disease no longer recurred, prolonged bed rest and prolonged disuse of the muscles of this type can result in muscular atrophy. The patient was transferred to another hospital for continuous treatment, including ventilator weaning on hospital day 190. Afterwards, the recurrence of HSE did not occur. During the hospital stay, treatment was provided in accordance with the wishes of the patient and his family, and at the time of transfer, the family expressed their gratitude. The patient’s clinical course can be seen in Figure 2.

Figure 2 Clinical course of the patient. GCS: Glasgow Coma Scale; MRI: Magnetic resonance imaging; CSF: Cerebrospinal fluid; HSV: Herpes simplex virus; DNA: Deoxyribonucleic acid.

DISCUSSION

We report the first case of ARHE recurring in an immunocompromised adult patient without neurosurgical interventions. In this case, there are several points that are incompatible with previous reporting. First, the patient had no history of prolonged treatment with ACV or occurrence of ARHE. Second, HSE relapses occurred without any neurosurgical interventions. Consequently, there is value in reporting this event. When immunocompetent patients encounter HSV, the host’s immune system rapidly brings it under control, and the recurrent lesions that develop are both small and short-lived in nature[20]. Patients treated with antiviral agents generally tend not to develop resistance to the drugs[20]. Immunocompromised patients, in contrast, may not have the ability to bring HSV infections under control on their own[20]. Consequently, immunocompromised patients are susceptible to frequent, severe reactivations of HSV, and infections can ultimately result in fatal herpetic encephalitis or disseminated HSV infections[20].

In this case, the patient was found to be suffering from uncontrolled glycemia (glycosylated hemoglobin A1c 11%) at the ED, which may have led to his immunocompromised status. This may have led in turn to severe reactivation and finally to HSE, together with the emergence of HSV resistance to ACV. Therefore, we could propose hypotheses that an immunocompromised metabolic state independently drives emergence of ACV resistance. More specifically, ACV resistance is likely due to a combination of lost TK activity, altered TK substrate specificity, and altered DNA polymerase activity[5]. By far the most common causes of ACV resistance (95% of cases) are mutations in the viral UL23 gene encoding for the ACV-targeted TK protein, and TK mutations[5,21,22]. In this case, we detected the T287M mutation gene. As for the TK genotype of strains of HSV-1 resistant to ACV, resistance is known to be related to strain number No. 264-12, and substitutions and frameshifts from the natural genes N23, K36E, and A265T to the mutation gene T287M are related to resistance[23]. Therefore, this case is compatible with the previous article. In contrast, the mechanism or pathogenesis between immunocompromised status and the emergence of HSV resistance to ACV has yet to be fully elucidated.

In some cases, replicative recurrence has been associated with the innate immune response of neuronal cells being altered by genetic defects[12]. Additionally, there has been scant reporting of HSE recurrence: Only a handful of cases, which occurred after neurosurgical interventions[24]. HSV reactivation is seen in Japan only extremely rarely[13]. However, it is important for neurologists to learn to recognize this condition, as this disorder will become more prevalent as epilepsy surgery becomes more common[13]. In this case, HSE recurred without neurosurgical interventions, making it incompatible with previous reporting. Therefore, it could be said to constitute a new finding.

Treatment options for ACV-resistant HSV patients are comparatively constrained, due to the frequent development of severe herpes disease refractory to antiviral drug therapy in immunocompromised hosts[20]. As a direct consequence, physicians need to develop regimens to address not only receptive but also refractory HSV disease[20]. One alternative is foscarnet, which directly acts upon viral DNA polymerase[5,18]. When encountering a patient with a deteriorating clinical condition under ACV treatment, even if there is seemingly no increase in CSF HSV viral load, it can be beneficial to consider the possibility of ACV-resistant HSE, and consequently add foscarnet to the ACV treatment[5]. In one case report, an ACV-resistant HSE patient was ultimately treated successfully with a combination treatment of ACV and foscarnet[5]. In another case, a patient’s HSE was resolved after being treated with foscarnet for an unknown duration[25]. This is the only known case to date of ACV-resistant HSE occurring in an immunocompetent adult who had been, to that point, therapy-naïve[25]. In another case, an ACV-resistant HSE patient had their therapeutic regimen modified in its fifth week, to add vidarabine (15 mg/kg/day)[26]. In this case, antiviral drug treatment was discontinued after HSV DNA in the CSF eventually decreased to such a point that it became undetectable[26]. Another case report has covered a case of ACV-resistant HSE being successfully treated with adalimumab, an anti-tumor necrosis factor-α monoclonal antibody[27]. In this case being reported, we successfully treated ACV-resistant HSE with combined ACV and foscarnet. We found no articles regarding the standard treatment for cases involving recurrence. Based on this, an insufficient period of initial treatment with foscarnet may have led to recurrence. It is well established that viral replication, combined with overzealous inflammatory response, causes the cerebral damage that can result from HSE[11]. Ideally, adjunctive immunomodulatory drugs should first be administered during the increase in the inflammatory response, with a limited duration of administration to limit undesirable side effects[11]. Therefore, we should have administered the adjunctive immunomodulatory drugs to prevent the inflammatory response.

This case report has some limitations. First, it is limited to only one case report and case series of ARHE; as a result, it is possible that reporting bias has affected results, and that the actual situation surrounding, and nature of, the disease may be inconsistent with our results. Further evaluation of the impact of clinical presentation, laboratory, virology, imaging examinations, and treatment patterns, as well as outcomes, will necessitate carrying out further studies. Second is the impossibility of fully ruling out the potential involvement of any organisms not identified through culturing, as microbiological examinations lack 100% sensitivity or specificity.

CONCLUSION

Clinicians should always be aware of ARHE when treating HSE, especially in immunocompromised patients. In addition, ARHE recurred in the patient following remission; therefore, it is necessary to discuss the length of treatment periods. Managing infectious and postinfectious complications will require the development of new antiviral therapies and vaccines, as well as therapies targeting the host’s immune response and/or metabolic dysfunction.