Validation of Angiostrongylus cantonensis combined with herpes simplex virus type 1 in cerebrospinal fluid by next-generation sequencing
Angiostrongylus cantonensis is a parasitic nematode that is one of the major causes of eosinophilic meningitis and meningoencephalitis. Infection typically occurs through the consumption of raw or undercooked paratenic or intermediate hosts, such as mollusks. This case report describes a rare instance of combined infection of A. cantonensis and herpes simplex virus type 1 (HSV-1) in a patient, diagnosed using next-generation sequencing (NGS) of cerebrospinal fluid (CSF).
The patient was a 59-year-old male from Guangdong Province, China, who presented with paroxysmal dizziness, fatigue, and a low-grade fever of 38.1°C for 18 days. Subsequently, he developed severe headache, nausea, vomiting, and a high fever of 39.0°C, prompting him to seek medical attention. Initial brain magnetic resonance imaging (MRI) revealed slight leukoencephalopathy. He was initially diagnosed and treated for presumed cerebral infarction, but his symptoms worsened, leading to his transfer to a central hospital.
At the central hospital, serum testing revealed positive HSV-1 IgM, and antiviral therapy was initiated. Despite this, the patient’s condition deteriorated, and he became unconscious. One month after the onset of symptoms, he was transferred to Nanfang Hospital, Southern Medical University.
Upon admission, the patient was febrile (38.0°C) with a Glasgow Coma Scale (GCS) score of 7 (E1V1M5). Clinical examination revealed neck stiffness and bilaterally positive Kernig signs. Laboratory findings showed prominent eosinophilia, with an eosinophil ratio of 21.9% in peripheral blood. Electroencephalogram (EEG) demonstrated 3–4 Hz 30 to 50 mV delta waves. Lumbar puncture yielded clear CSF with moderate pleocytosis (cell count of 310/mL) and an abnormally elevated eosinophil count of 40%. Tests for autoimmune encephalitis-related antibodies in both serum and CSF were negative, as were polymerase chain reaction (PCR) tests for various viruses, including HSV-1, HSV-2, Varicella-zoster virus, Epstein-Barr virus, and Cytomegalovirus.
Given the elevated eosinophil levels in both blood and CSF, parasite antibodies were tested. NGS of the CSF was performed using the Illumina NextSeq 550 platform (Vision Medicals Co., Ltd, USA). A repeated brain MRI showed obvious leukoencephalopathy on T2-weighted and fluid-attenuated inversion recovery (T2W-FLAIR) images. Empirical treatment with Acyclovir and Ceftriaxone was initiated based on the positive serum HSV-1 IgM and elevated C-reactive protein/procalcitonin (CRP/PCT) levels.
Three days later, NGS results reported positive reads for A. cantonensis and HSV-1 in the CSF, with 17,202 and 16 reads, respectively. Additionally, serum IgG for A. cantonensis was positive. Treatment was adjusted to include Albendazole and methylprednisolone. The patient’s temperature and eosinophil levels gradually normalized, and his consciousness improved, with a GCS score of 10 (E4V1M5).
A repeated NGS of CSF after two weeks of anthelmintic therapy showed 6,416 reads of A. cantonensis and no reads of HSV-1. After a three-week intermission, a third round of anthelmintic therapy was initiated. A third NGS of CSF showed no reads of either A. cantonensis or HSV-1. The patient’s consciousness continued to improve, with a GCS score of 14 (E4V4M6), and he was discharged for rehabilitation. Follow-up brain MRI after two rounds of anthelmintic therapy showed distinct recovery of leukoencephalopathy. Six months later, the patient’s modified Rankin Scale score was 0.
A. cantonensis is a significant cause of eosinophilic meningitis and meningoencephalitis. Brain imaging findings in such cases are diverse but nonspecific, often showing multiple nodular enhancing lesions and linear enhancement in the pia. Some studies have reported leptomeningeal enhancement and increased signal intensity in the subcortical white matter of the cerebrum and cerebellum on T2W-FLAIR images. The abnormal signal intensity in the deep white matter may indicate gliosis or worm migratory tracks. The movement of migrating worms can result in the separation of axons from nutrient cells, though the exact mechanisms remain incompletely understood.
NGS, a method that simultaneously sequences millions of DNA fragments, has recently been applied to diagnose brain infections. It provides comprehensive, timely, and actionable information, particularly in cases of multiple or rare infections. In this case, NGS results correlated with traditional tests and treatment response, confirming the diagnosis of combined A. cantonensis and HSV-1 infection.
The mechanism of combined infection may involve the disruption of the blood-brain barrier by A. cantonensis. The parasite initiates a series of responses in the central nervous system, potentially leading to blood-brain barrier breakdown. Matrix metallopeptidase 9, a protease that degrades extracellular matrix proteins, may play a role in this process. Animal studies suggest that eosinophils release matrix metallopeptidase 9 into the subarachnoid space, activating a proteolytic cascade that disrupts the blood-brain barrier.
In clinical practice, pathogenic detection often relies on smear, culture, and pathology, which can be time-consuming and lack sensitivity. NGS, capable of detecting a wide range of central nervous system pathogens within 48 hours, is particularly useful for early diagnosis, especially in cases of multi-infection.
This case highlights the utility of NGS in diagnosing complex infections and underscores the importance of considering parasitic infections in patients with eosinophilic meningitis or meningoencephalitis, particularly in regions where A. cantonensis is endemic.
doi.org/10.1097/CM9.0000000000000588
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