Human herpesvirus type 4 combined with Brucella abortus meningitis case report

Abstract

Objective

To observe and analyse the clinical characteristics, diagnosis and treatment of Human herpesvirus type 4 combined with Brucella abortus meningitis, in order to improve clinicians’ understanding of this disease.

Methods

The clinical data of a patient withHuman herpesvirus type 4 combined with Brucella abortus meningitis diagnosed on 8 January 2024 in Baotou People’s Hospital were analysed. Results The case was a middle-aged female patient with the main symptoms of dizziness and numbness and weakness of the limbs. The pathogenic microorganisms were detected as macrogenomic and copy number anomalies by double-homology: Human herpesvirus type 4 was detected as sequence number 13, and the serum Brucella abortus tiger-red plate agglutination test was positive.

Results

Brucella tube agglutination test: 1:400 ++. Symptoms improved significantly after treatment with doxycycline + rifampicin + cotrimoxazole tablets and prednisone acetate tablets.

Conclusion

Human herpesvirus type 4 (EBV) combined with Brucella abortus meningitis is a rare infectious encephalitis with a poor prognosis and high recurrence rate. A step therapy strategy of antibiotics combined with glucocorticoids is currently recommended to control acute phase symptoms and reduce the risk of recurrence.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-025-11444-x.

Introduction

It has been found that HHV-4 encephalitis combined with Brucella abortus meningitis occurs through the process of immunosuppression with increased chances of double infection, synergistic effect of blood-brain barrier disruption, amplification of inflammatory cascade response, and chronic infection with impaired tissue repair. In this article, we report a case of Human herpesvirus type 4 combined with Brucella abortus meningitis, and systematically describe its clinical features and points of differentiation, aiming to improve clinicians’ understanding of this disease, strengthen the differential diagnosis of encephalitis-related diseases, and reduce the incidence of misdiagnosis and underdiagnosis.

Case description

The patient is a 37-year-old woman who was admitted to Baotou Central Hospital on 2024-01-08 with “dizziness and numbness and weakness of the limbs for 2 months”. The patient was admitted to the local hospital, and no obvious abnormality was found in the nuclear magnetic resonance imaging (NMRI) of the head. She was treated with traditional Chinese medicine at a community Chinese medicine clinic, and her symptoms gradually worsened. 53 days before admission, she had numbness and weakness of the left upper limb, unsteady chopsticks, inflexibility in fastening buttons, accompanied by blurred vision, and numbness in her neck and chest. Thirty days before admission, she had hearing loss, dysarthria, voice trembling, unsteady walking, body shaking, no fever, no headache, no incontinence, no unconsciousness, and came to the clinic for a clear diagnosis and treatment. Since the onset of the disease, the patient’s mental state, diet and urination and defecation were normal. Past history: healthy.

Admission specialty examination: blood pressure 123/95mmHg, respiration: 19 times/min, body temperature: 36.4 ℃, pulse: 100 times/min. Development is normal, nutrition is moderate, generalized superficial lymph nodes are not enlarged, skin, mucous membranes do not see hemorrhages, trachea is centered, thyroid gland is not enlarged, HR 100 times/min, rhythmic, lungs do not have rales, the abdomen is flat and soft, no pressure pain, both lower limbs are not swollen. Specialty: clear, dysarthria, hearing loss, diplopia, bilateral pupils equal in size and round, about 3.0 mm in diameter, sensitive to light reflex, both eyes can move in all directions, no obvious central facial paralysis, upper limb muscle strength 4+, lower limb muscle strength 5, pinprick sensation is symmetrical bilaterally, tendon reflexes of limbs are not induced, mandibular reflex is not induced, palmaromandibular reflex is not induced, opening and closing of eyes is tilted; bilateral finger-nose test is not stable and accurate, bilateral heel-knee test is not stable, bilateral heel-knee test is not stable, bilateral heel-knees are not swollen. Unstable and accurate, bilateral heel-knee-shin test was unstable and accurate, wide step base when walking, normal vibratory and kinesthetic sensation, bilateral Babinski’s sign (+), positive cervical impedance, chin-thoracic distance of 3 transverse fingers, König’s sign (+).

Admission laboratory tests: potassium, sodium and chloride: sodium 135 mmol/l, chloride 93 mmol/l, blood tests, liver and kidney function, CRP, PCT, interleukin 6, T-cell test for tuberculosis infection, four infections (hepatitis B surface antigen, hepatitis C antibody, HIV antibody, syphilis serum specific antibody), thyroid function, rheumatoid immunity related indexes (aminocardia, antinuclear antibody, antinuclear antibody, anti-cardiolipin antibody, erythrocyte sedimentation rate). Antibody profile, antinuclear antibody, anticardiolipin antibody, erythrocyte sedimentation rate) were not abnormal. cerebrospinal fluid pressure after lumbar puncture on January 10, 2024 was 290 mmH2O, and cerebrospinal fluid (CSF) was routinely examined for cell counts: yellowish and transparent in appearance, Pandy’s test was positive (+++), erythrocyte count was 25 × 10^6/L, leukocyte count was 335 × 10^6/L [normal value (0.0), and the normal value (0.0) for the same test was 0.0]. L [normal value (0–8) ×10^6/L], leukocyte classification single nucleated cells 90%, leukocyte classification multiple nucleated cells 10%. Cerebrospinal fluid biochemistry: cerebrospinal fluid protein 3.33 g/L (normal value 0.08–0.43 g/L), cerebrospinal fluid glucose 3.4 mmol/L (normal value 2.2–4.4 mmol/L), cerebrospinal fluid chloride 102 mmol/L (normal value 120–130 mmol/L). Cerebrospinal fluid cytology: lymphocytes 85%, monocytes 2%, neutrophils 13%, no other abnormalities. Serum immunoglobulin G 12.00 g/L (normal value 7.51 ~ 15.6 g/L), cerebrospinal fluid immunoglobulin IgG 0.319 g/L (normal value 0.005 ~ 0.059 g/L), serum albumin 39.2 g/L (normal value 40 ~ 55 g/L), cerebrospinal fluid albumin 2.32 g/L (normal value 0.139 ~ 0.246 g/L), IgG composite index 44.92% (normal value 0 ~ 70%).), IgG synthesis index 44.92% (normal value 0 ~ 70%).Oligoclonal zones: positive CSF, negative blood. Novel cryptococcal ink stain microscopic examination: negative. Smear antacid stain microscopy: negative. Cerebrospinal fluid bacterial culture: negative. Serum and cerebrospinal fluid paraneoplastic neurosyndrome-associated antibodies negative. Cerebrospinal fluid virology positive for blood-cytomegalovirus IgM antibodies. Head nuclear magnetic resonance imaging (NMRI): bilateral frontal-parietal lobe brain tissue was slightly swollen; bilateral temporal, brainstem, skull base meninges and spinal membranes were abnormally strengthened, and meningitis and spondylitis were considered as possible, and cranio-cerebral MRA did not show any obvious abnormality (Fig. 1). Chest CT: bilateral thyroid nodules, bilateral lungs do not see obvious abnormal changes. Abdominal ultrasound: gallbladder wall roughness, gallbladder appendage bulging lesion, please combine with the clinical, recommended to review. Electromyography: F-wave of both upper limbs is decreased, F-wave of both lower limbs is not abnormal. Nerve conduction measurements in the extremities showed no significant abnormality.Electro-audiometry, hearing thresholds were 58dB HL for both right air conduction and bone conduction, and 66dB HL for left air conduction 76dB HL bone conduction. Preliminary diagnosis: viral meningitis?

Fig. 1.

MRI of patients with encephalitis

Acyclovir antiviral therapy was given with no improvement in symptoms. mNGS of cerebrospinal fluid was returned on January 15, 2024: Human herpesvirus type 4 was detected with sequence number 13, relative abundance 100%, high confidence; Brucella spp. was detected with sequence number 165, relative abundance 4.55%; Brucella melitensis was detected with sequence number 2, relative abundance 0.06%, low confidence. Sequence number 2, relative abundance 0.06%, low confidence. agglutination test returned January 17, 2024: serum Brucella tiger red plate agglutination test positive. Brucella test tube agglutination test result: 1:400 ++. ADDITIONAL DIAGNOSIS: Neurogenic brucellosis, viral meningitis. Treatment was given doxycycline (100 mg/times, 2 times/day,) + rifampicin (600 ~ 900 mg/times, 1 time/1 day) + ceftriaxone (intravenous drip, 2 g/times, 1 time for 12 h) Symptoms did not improve significantly. results after lumbar puncture was performed again on January 18th, 2024, showed that: the measured pressure was 300mmH20, the appearance of the cerebrospinal fluid was transparent and yellowish, and the cerebrospinal fluid routine: Leukocyte count 364.00 × 10^6/L, cerebrospinal fluid biochemistry: cerebrospinal fluid protein 3.04 g/L↑, cerebrospinal fluid chloride 105 mmol/L↓. Cerebrospinal fluid (CSF) routine cell count examination: Appearance, Pandy test↑, red blood cell count 38 × 10^6/L, white blood cell count 302 × 10^6/L, white blood cell sorting single nucleated cells 80%, white blood cell sorting multiple nucleated cells 20%. Cryptococcus neoformans ink staining microscopy: negative, smear antacid staining microscopy: negative.IgG synthesis index: Immunoglobulin G 12.00 g/L, cerebrospinal fluid immunoglobulin IgG 0.375 g/L ↑, cerebrospinal fluid albumin 2.7 g/L ↑, albumin 43.5 g/L, IgG synthesis index 50.35%. As there was no relief of symptoms, the patient strongly requested to be discharged from the hospital and after being informed of the risks, the patient was authorised to be discharged. She was discharged from the hospital to take oral doxycycline (100 mg/times, 2 times/day,) + rifampicin (600–900 mg/times, 1 time 1 day) at home, with no change in symptoms after 1 month. She visited Hohhot Second Hospital again and was given doxycycline (100 mg/times, 2 times/day) + rifampicin (600 ~ 900 mg/times, 1 time 1 day) + meropenem (intravenous drip, 1 g/times, 1 time 8 h) for half a month and her symptoms were still unimproved, and she was rechecked for a positive titer of serum antibodies against Brucella abortus.For further diagnosis and treatment, on April 30, the patient was admitted to Beijing Ditan Hospital to complete 3 lumbar puncture procedures, sent for examination, and adjusted the medication with the results of cerebrospinal fluid. The patient was given doxycycline (100 mg/times, 2 times/day) + rifampicin (600 ~ 900 mg/times, 1 time/day) + meropenem when she was first admitted to the hospital, and the medication was adjusted to dexamethasone 20 mg anti-inflammatory on May 16–18, dexamethasone 10 mg anti-inflammatory on May 19–26, dexamethasone 5 mg anti-inflammatory on May 27, and dexamethasone 5 mg anti-inflammatory on May 29, and dexamethasone (100 mg/dose, 2 times/day) + rifampicin (600-900 mg/dose, 1 time 1 day), prednisone acetate tablets (30 mg, 1 time daily), and cotrimoxazole tablets (2 tablets, Q12) after the significant improvement of symptoms. After six months of follow-up, the patient’s hearing has significantly improved, daily communication is not affected, and the weakness and numbness of both upper limbs and unsteady walking have significantly relieved, without affecting daily activities, and the overall prognosis is good (Specific cerebrospinal fluid examination and diagnostic flow charts are shown in Figs. 2 and 3).

Fig. 2.

Comparison of cerebrospinal fluid results

Fig. 3.

Diagnostic flow charts

Discussion

Disease characteristics of HHV-4 encephalitis

EBV, also known as Human herpesvirus-4, belongs to the γ subfamily of herpesviruses. Nearly 90–95% of adults worldwide are asymptomatic carriers of EBV. After initial exposure, the virus coexists in host cells throughout an individual’s life. However, most infected individuals rarely show any serious sequelae [1]. People with EBV are usually asymptomatic. Some may present with fatigue, fever, body aches, sore throat, pharyngitis and enlarged lymph nodes. Less than 1% of people with EBV develop neurologic complications, including encephalitis, meningitis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, transverse myelitis, or Bell’s palsy [2, 3]. Viral meningoencephalitis is the most common presentation. In rare cases, motor mutism and status epilepticus may occur [4]. Patients with EBV encephalitis may also have hepatomegaly or splenomegaly [5]. The pathogenesis of EBV encephalitis is unknown, but may be secondary to a direct mechanism of infection and an indirect immune response [6]. EBV encephalitis needs to be differentiated from encephalitis of other etiologies, meningitis, and similar diseases. For example, herpes simplex virus (HSV) encephalitis (temporal lobe involvement is common, cerebrospinal fluid PCR positive for HSV-DNA) [7], varicella-zoster virus (VZV) encephalitis (history of rash, cerebrospinal fluid positive for VZV-DNA or antibodies is common), cytomegalovirus (CMV) encephalitis, (most often seen in immunosuppressed patients, cerebrospinal fluid positive for CMV-DNA) [8]. Bacterial meningitis/encephalitis (e.g., tuberculous meningitis, suppurative meningitis: cerebrospinal fluid leukocyte elevation is more pronounced, sugar is decreased, protein is elevated, and bacterial cultures or PCR are positive), and autoimmune encephalitis (e.g., anti-NMDAR encephalitis: specific antibodies are detected in the serum or cerebrospinal fluid, and often accompanied by psychiatric behavioral abnormalities). Differentiation depends on cerebrospinal fluid pathogenetic testing, and in this case the diagnosis was confirmed mainly by mNGS testing. Currently, there is a lack of effective antiviral drugs for EBV encephalitis, and treatment is based on supportive symptomatic treatment, combined with antiviral and immunomodulatory therapy. Early rehabilitation interventions were carried out for cognitive and motor disorders. Most patients recover well after prompt treatment, but some are left with epilepsy, cognitive impairment or focal neurological deficits. Immunocompromised patients have a poorer prognosis.

Brucella abortus meningitis characteristics and diagnostic criteria

Human brucellosis is the most common zoonotic infection caused by any of the three main species of the genus Brucella [9]. Humans are usually the dead host and the main animal hosts are cattle, sheep, goats and pigs [10]. The incidence of neurobrucellosis was first described by Hughes in 1896 as accounting for approximately 3–5% of all cases of brucellosis [11]. Systemic symptoms that may occur include prolonged fever (demulcent), night sweats, malaise, arthralgia, anorexia, headache and back pain, and hepatosplenomegaly [12, 13]. Almost all organ systems are eventually involved and neurological infection occurs in up to 5%−10% of cases [14]. Brucella meningitis is a rare but serious complication of brucellosis [15], The clinical presentation of neurobrucellosis varies widely. Meningoencephalitis is characterised by headache, nausea and vomiting, cervical rigidity and impaired consciousness. Focal neurological damage manifests as hemiparesis and cranial nerve palsy. The general diagnostic approach to brucellosis includes history, physical examination, laboratory tests, imaging and pathogen testing [16]. Blood culture test is the gold standard for laboratory diagnosis of brucellosis. However, considering the long duration of brucellosis blood culture, the diagnosis of this case was mainly confirmed by mNGS. Cerebrospinal fluid analysis, positive brucellosis serology or culture, response to specific antibiotics, and significant improvement in cerebrospinal fluid parameters could explain it [17]. Nevertheless, there is growing evidence that molecular identification can help in the accurate diagnosis and treatment of brucellosis.

Here, pathogenetic testing for Brucella spp. and the Tiger Red Plate Agglutination Test (RBPT) or the Test Tube Agglutination Test (SAT) are active. Antimicrobial regimens and duration of treatment for brucellosis vary widely in the literature. However, prescribing three antibiotics for at least three months is recommended. It was decided to use a combination of rifampicin (aminoglycoside), doxycycline and meropenem in this patient to reduce the risk of progression. However, methotrexate-sulfamethoxazole is a combination antibiotic that can be used as an alternative treatment option for brucellosis [18].

Potential mechanisms of Human herpesvirus type 4 combined Brucella meningitis

The mechanisms of EBV and B. brucei coinfections in encephalitis have not been clearly studied, but based on the individual pathogenic mechanisms of the two pathogens, they may lead to CNS injury synergistically or superimposed by the following pathways: 2.3.1. immunosuppression and increased chance of dual infection. EBV infection suppresses T-cell function (e.g., CD8 + T-cell depletion), which weakens the host’s ability to immunologically clear brucellosis. Chronic inflammation caused by B. brucei infection may activate EBV lysis and replication through the NF-κB pathway.2.3.2. Synergistic effect of blood-brain barrier (BBB) disruption: EBV-infected B cells may cross the BBB through a “Trojan horse” mechanism while carrying B. brucei into the central nervous system. VirB protein and LPS of B. brucei can disrupt endothelial cell junctions, exacerbate BBB permeability, and promote the spread of EBV.2.3.3. Amplification of the inflammatory cascade: EBV activates IL-6 and TNF-α, and B. brucei activates IL-1β and IL-18, which synergistically lead to excessive inflammatory responses. Microglia/macrophages are over-activated, releasing large amounts of ROS and excitatory amino acids (e.g., glutamate), triggering neuronal apoptosis.EBNA1 protein of EBV and B. burgdorferi antigens may be molecularly mimicked, inducing cross-antibodies to attack neural tissues.2.3.4. Chronic Infection and Impaired Tissue Repair: Latent Membrane Protein of EBV (LMP1) sustains the activation of the NF-κB pathway, which inhibits apoptosis and maintains chronic inflammation. Granulomas compress the brain parenchyma and impede damage repair, while providing an immune-immunity microenvironment for EBV.

In terms of treatment, Human herpesvirus type 4 combined with Brucella melitensis meningitis responds better to therapy, and high-dose hormone combined with slow tapering therapy is mostly used as the preferred option in the clinic, and the treatment regimen of the patient in this case followed the recommended strategy of the Chinese Expert Consensus on Diagnosis and Treatment of Antimyelinating Oligodendrocyte Glycoprotein Immunoglobulin G Antibody-Related Diseases. However, the disease is characterized by easy recurrence, and some patients can be prevented by long-term maintenance of low-dose hormones combined with immunosuppressants, but it should be noted that hormone resistance may occur in some patients. Some studies have shown that natural human EBV infection is very common, more than 90% of young children aged 3–5 years have been infected with EBV, and more than 90% of adults have antibodies to EBV. EBV can be latent in B cells for a long time, and may be reactivated when immunosuppression occurs, leading to complications (e.g., encephalitis, lymphoproliferative disorders). There are few clinical studies of EBV and B. burgdorferi coinfection, and treatment options are based on case reports.The high prevalence of EBV may affect the treatment of B. burgdorferi encephalitis through immune interference and diagnostic complexity, but efficacy can be optimized through accurate pathogen detection and stratified management. More studies are needed to explore the mechanisms of interaction between the two pathogens in the future.

Limitation

The findings are derived from a single patient, which limits the generalizability of the conclusions. Larger cohort studies are needed to validate the observed clinical and therapeutic patterns in EBV and Brucella abortus coinfection.

Abbreviations

EBV

Epstein-Barr virus

mNGS

macrogenome second-generation sequencing

NMRI

Nuclear magnetic resonance imaging

CSF

Cerebrospinal fluid

VZV

Varicella-zoster virus

CMV

Cytomegalovirus

SAT

Test Tube Agglutination Test

Authors’ contributions

JJY: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Visualization, Writing–original draft, Writing–review and editing.FXZ: Conceptualization, Supervision, Validation, Writing–original draft, Writing–review and editing. XLG: Conceptualization, Methodology, Supervision, Validation, Writing–original draft, Writing–review and editing. JHL: Conceptualization, Methodology, Supervision, Validation, Writing–original draft, Writing–review and editing.

Funding

The author(s) declare that have financial support was received for the research, authorship, and/or publication of this article. Inner Mongolia Autonomous Region Academy of Sciences, “wearable repetitive transcranial magnetic stimulation combined with music therapy to improve symptoms of parkinson’s disease patients’ research and application of integrated management” (2024GLLH0494) and Inner Mongolia Autonomous Region Science and Technology Programme “The role of capsaicin receptor (TRPV1)-mediated oxidative stress in Parkinson’s disease and its mechanism” (2022YFSH0085) (JL).

Data availability

The raw data supporting the conclusion of this article will be made available by the first author. The survey protocols and all materials received ethical approval.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

I confirm that the patient has given informed written consent to the publication of their personal or clinical details and any identifiable images in this study.

Competing interests

The authors declare no competing interests.