Intracranial infection caused by Streptococcus intermedius and torque teno virus: A case report

Abstract

Infectious diseases of the central nervous system are commonly characterized by delayed diagnosis due to the diversity of pathogens, subtle clinical symptoms, and nonspecific early imaging findings. These diseases are associated with high morbidity and mortality rates. This report presents a rare case of intracranial mixed infection caused by co-infection with Streptococcus intermedius and torque teno virus. This report involves a retrospective analysis of the clinical features, laboratory investigations, and treatment outcomes of intracranial infection, along with diagnostic and therapeutic strategies for such rare mixed infections. The results demonstrated that cerebrospinal fluid metagenomic sequencing plays a crucial role in the microbiological diagnosis of intracranial mixed infection. This report describes the case of a man in his late 30s in whom Streptococcus intermedius and torque teno virus were simultaneously detected in the cerebrospinal fluid. The infection exhibited rapid progression and high aggressiveness, significantly increasing the risk of mortality. This study emphasizes the invasive clinical course of this infection. Despite active and intensive treatment, the patient ultimately succumbed to the illness. It remains unclear whether torque teno virus infection plays a direct role in the pathogenesis or contributes to the severity of the intracranial mixed infection. This case highlights the importance of multidisciplinary collaboration in the diagnosis and treatment of complex intracranial infections, providing clinicians with a novel approach for the differential diagnosis of mixed infections and increasing the clinical awareness and understanding of such rare mixed infections involving the central nervous system.

Background

Streptococcus intermedius is a gram-positive coccus widely distributed in various parts of the human body. ¹ Clinically, infections caused by S. intermedius in the soft tissues, sinuses, pleura, and other areas are relatively common. ² S. intermedius is primarily considered a constituent of the normal oral microbiota, although it can also be isolated from extraoral sites. ¹ It is commonly found in the oral cavity, and it has increasingly been recognized as a clinically important pathogen, frequently associated with soft tissue infections, paranasal sinusitis, and pleural space infections. ² In addition, cases of pericarditis and hepatic abscesses caused by S. intermedius have been documented. ³ However, cases of S. intermedius infection leading to central nervous system (CNS) infections are rare. ⁴ S. intermedius demonstrates strong neurotropism and can cause intracranial infections such as parenchymal brain abscesses, subdural empyema, and epidural empyema, which are associated with high morbidity and mortality. Currently, S. intermedius is increasingly recognized as a significant pathogen causing intracranial infections, characterized by rapid disease progression and complex clinical management. ⁴ Torque teno virus (TTV) is a single-stranded DNA virus, first discovered and identified in 1997 ⁵ and officially named by the International Committee on Taxonomy of Viruses in 2009. ⁶ Its genome size is approximately 3800 bp, ⁷ and it is generally considered a human commensal virus in humans.^5–7 Due to the rarity of co-infection with S. intermedius and TTV, this intracranial mixed infection is exceedingly rare. Herein, we report a unique case of intracranial infection caused by two pathogens—S. intermedius and TTV—which were simultaneously detected in the cerebrospinal fluid (CSF).

Case information report

Case presentation

The patient was a man in his late 30s who was admitted to Gansu Provincial Hospital (Lanzhou, Gansu Province) on 27 June 2024 with persistent headache that had lasted 10 days, accompanied with fever and altered consciousness for 1 day.

Ten days prior to admission, the patient experienced right-sided dental pain, followed by intermittent headaches, which were not initially considered significant. The headache progressively worsened. One day before admission, the patient developed intermittent fever and altered consciousness, with a maximum body temperature of 38.5°C. Head computed tomography (CT) showed a softening lesion in the right frontal lobe, with localized bone defects in the right frontal sinus (Figure 1). The patient was admitted with a diagnosis of intracranial space-occupying lesion.

Figure 1.

Head computed tomography (on June 26 2024) showing a softening lesion in the right frontal lobe, as indicated by the red arrow.

Upon presentation at our hospital, physical examination revealed a body temperature of 37.5°C, heart rate of 89 beats/min, respiration rate of 21 breaths/min, blood pressure of 134/82 mmHg, Glasgow Coma Scale (GCS) score of 14, pupils equal and reactive to light with a diameter of approximately 3.5 mm, normal superficial and deep sensation, limb muscle strength of 4/5, normal muscle tone, physiological reflexes present, and no pathological reflexes. Meningeal irritation signs were weakly positive.

Medical history

The patient underwent craniotomy 10 years ago for the treatment of head trauma and was hospitalized 1 year ago for viral encephalitis, which improved with treatment. No other significant medical history was reported.

Diagnosis and treatment after admission

Upon admission, CSF analysis showed a positive Pandy’s test, with 5000 red blood cells/mm³, and a total white blood cell count of 115,849/mm³, comprising 84% polymorphonuclear cells and 16% mononuclear cells. Biochemical analysis of the CSF revealed an adenosine deaminase level of 37.26 U/L, chloride level of 133.89 mmol/L, glucose level of 11.13 mmol/L, and total protein level of 5.97 g/L. Cytology indicated 85% neutrophils and 15% transformed lymphocytes. Blood tests showed a white blood cell count of 16.7 × 10⁹/L, 83.39% neutrophils, and a lymphocyte count of 0.76 × 10⁹/L. Infection markers were elevated, with a C-reactive protein level of 57.52 mg/L, serum amyloid A level of 83.39 mg/L, PL-6 level of 240.36 pg/mL, and procalcitonin level of 2.499 ng/mL. The blood glucose level was 15.44 mmol/L, and urine tests were positive for glucose, protein, and ketone bodies, with microalbuminuria >0.15 g/L. A preliminary diagnosis of intracranial infection was established. After obtaining signed informed consent for treatment from the patient’s family, empirical antimicrobial therapy was initiated with vancomycin (1 g intravenous drip (ivgtt) q12h) and meropenem (2 g ivgtt q8h). Despite treatment, the patient’s fever persisted. On 30 June 2024, he developed coma on the fifth day after admission, with the GCS score dropping to 8. Burr hole drainage was performed, and yellow-white, rice soup-like purulent CSF was drained, which was sent for culture and analysis. After the surgery, due to the lack of improvement in consciousness, persistent high fever, and respiratory distress, the patient was transferred to the intensive care unit (ICU). In the ICU, the drainage fluid was subjected to metagenomic next-generation sequencing (mNGS) and culture. The patient’s glycated hemoglobin level was 8.5%, with an average blood glucose concentration of 11 mmol/L. On 1 July 2024, the sixth day after admission, the patient developed respiratory failure; he underwent endotracheal intubation followed by mechanical ventilation. Subsequently, on 2 July 2024, mNGS confirmed the presence of Streptococcus, identified as S. intermedius and TTV type 22 (Figure 2). The CSF culture also revealed the growth of Streptococcus, confirming S. intermedius, and the antibiotic sensitivity test indicated sensitivity to vancomycin.

Figure 2.

High-confidence pathogen genome coverage map. A represents the total genome base pairs of Streptococcus intermedius, and B represents the total genome base pairs of torque teno virus type 22.

Meropenem was discontinued, and vancomycin (1 g ivgtt q12 h) was continued for antimicrobial treatment. At 13:00 on 2 July 2024, the seventh day after hospitalization, the patient developed septic shock and died despite resuscitation efforts. On 3 July 2024, following the patient’s death, postmortem blood culture results confirmed the presence of Streptococcus, specifically S. intermedius. The antibiotic susceptibility test findings were consistent with the sensitivity results previously obtained from the drainage fluid culture.

Discussion

The global incidence of CNS infectious diseases is approximately 1–2 per 100,000 people annually. ⁸ CNS infections are severe disorders caused by the invasion of pathogenic microorganisms into the brain parenchyma, meninges, or spinal cord, often resulting in neurological dysfunction and high mortality. Common pathogens include bacteria, viruses, fungi, and parasites. Clinical manifestations are diverse, and diagnosis relies on neuroimaging, CSF analysis, and microbiological testing. According to epidemiological studies conducted in Europe, the annual incidence of bacterial infections of the CNS in adults is estimated to range from 0.7 to 3.2 cases per 100,000 population. ⁸ These infections progress rapidly and can lead to severe neurological damage or even death, with a global fatality rate of approximately 8.8%. The mortality rate of mixed infections is significantly higher than that of single pathogen infections, ranging from 30% to 50%. ⁹ For the treatment of CNS infectious diseases, precise microbiological diagnosis and early combination antimicrobial therapy play a crucial role in improving patient outcomes.

This case showed the following distinctive features:

Rare mixed infection: co-infection with Streptococcus

We simultaneously detected the presence of S. intermedius and TTV, which caused an extremely rare intracranial infection, with no previous reports of TTV in the literature. This makes diagnosis and treatment challenging. The CSF of this patient was subjected to mNGS. To minimize the risk of contamination, strict quality control measures were implemented throughout the entire mNGS workflow, including the use of both negative and positive controls, physical separation of pre- and post-amplification areas, and background subtraction during bioinformatics analysis. No reads corresponding to the target pathogens were detected in the negative control samples, supporting the authenticity of the findings. mNGS of the CSF revealed the presence of S. intermedius with a total genome size of 1,932,951 bp, of which 1,626,272 bp were covered, corresponding to a coverage rate of 84.13%. For TTV, the genome size was 3847 bp, with 1016 bp covered, yielding a coverage rate of 26.41%. These results support the likelihood of co-infection with both the pathogens. However, due to the family’s refusal to authorize an autopsy, we were unable to obtain pathological confirmation of viral presence in the brain tissue, which remains a limitation of this case report. Although TTV is commonly detected in various bodily fluids of healthy individuals, ¹⁰ the viral load is closely linked to immunosuppression ¹¹ and may be useful in the prediction of organ transplant rejection and infection risks.^12,13 Studies have revealed that TTV infection can cause biochemical and histological changes in the liver tissue and bile duct epithelial cells, ¹⁴ indirectly suggesting its potential pathogenicity. ¹⁵ In 2021, Liu et al. reported the case of a patient with X-linked agammaglobulinemia who tested positive for TTV in the CSF; after excluding other pathogens, it was concluded that TTV caused encephalitis, indicating that this virus exerts pathogenic effects in patients with severe immunodeficiency and induces severe clinical symptoms. ¹⁶ mNGS can detect the nucleic acid sequences of multiple pathogens and plays an important role in the diagnosis of infectious diseases. Initially, this case lacked effective microbiological evidence, making precise treatment challenging. However, mNGS subsequently detected S. intermedius and TTV.

2. Complex underlying conditions: The patient’s medical history was complicated; he underwent craniotomy 10 years ago and had viral encephalitis 1 year ago, both of which may have caused intracranial tissue damage and immune system alterations, increasing the risk of re-infection. Diabetic patients have impaired innate and adaptive immune functions, significantly increasing susceptibility to infections. The infection can breach local defense barriers, leading to septicemia through hematogenous dissemination.

3.    Rapid disease progression: The patient’s condition rapidly deteriorated since symptom onset. The patient’s history of dental pain, combined with mNGS results and microbial culture of the drainage fluid, suggested that the infection likely originated from a dental source, spreading directly to the intracranial area. Infection persisted throughout the clinical course, and blood culture results indicated S. intermedius infection, which led to septic shock. Despite aggressive antimicrobial and supportive therapy, the disease was difficult to control, and the patient ultimately died due to septic shock. This suggests that combined infection with S. intermedius and TTV may cause enhanced pathogenicity; owing to the patient’s weakened immune function, the inflammatory response elicited by the infection was more severe, resulting in multiple organ failure and poor treatment outcomes.

S. intermedius is highly virulent, and TTV may have pathogenic potential. Cases of CNS infections caused by the simultaneous invasion of these two pathogens are rare. When diagnosing and treating intracranial mixed infections, mNGS plays a critical role in reducing the mortality rate of CNS infectious diseases. With continuous advancements in diagnostic and treatment technologies, improved clinical data, and increased reporting of rare clinical cases, we believe that the level of diagnosis and treatment for CNS infectious diseases will continue to improve, leading to a significant decrease in mortality rates among patients with these conditions.

Cases of CNS infection with simultaneous detection of S. intermedius and TTV are relatively rare. Upon detection of these two pathogens, the optimal treatment strategy should be to prioritize effective antimicrobial therapy while also addressing the potential impact of viral co-infection. S. intermedius, known for its high virulence in intracranial infections, should be treated with antibiotics to which the isolate is susceptible. First-line options include penicillin-class agents and third-generation cephalosporins; in cases of β-lactam resistance, vancomycin may be considered. In contrast, TTV is a nonenveloped, single-stranded DNA virus for which no specific antiviral therapy is currently available. Although TTV is often considered a commensal virus, it may become reactivated under immunosuppressive conditions and is associated with worsened clinical outcomes in co-infected individuals. Therefore, rather than direct antiviral treatment, the management of TTV co-infection should focus on comprehensive evaluation and modulation of the host immune status. Immunological support and adjustment of immunosuppressive therapies, if applicable, may help mitigate the impact of TTV and improve the overall prognosis. In summary, the most effective treatment strategy should be based on adequate antimicrobial therapy, combined with individualized immunological support and necessary surgical intervention to ensure optimal clinical outcomes for patients.

This case suggests that co-infection with S. intermedius and TTV leads to severe CNS infections. In clinical practice, greater vigilance is warranted for such mixed infections, particularly in patients with intracranial infections of unknown etiology. Although this case provides valuable clinical insights, the underlying mechanisms and causal relationships require further investigation.