Cerebral Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation Diagnosed by Megagenomic Analysis
Cerebral toxoplasmosis is a rare but potentially fatal opportunistic infection that can occur following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This case report describes a 19-year-old Chinese male who developed cerebral toxoplasmosis six months after undergoing haploidentical allo-HSCT for acute T-lymphoblastic leukemia. The patient presented with symptoms including dysarthria, vomiting, high fever, and headache. Despite extensive diagnostic efforts, the underlying cause of his condition remained elusive until the application of high-throughput pathogenic megagenomic sequencing, which ultimately identified Toxoplasma gondii as the causative agent.
The patient’s initial clinical evaluation included a series of diagnostic tests aimed at identifying infectious pathogens. Cerebrospinal fluid (CSF) culture, serum toxoplasma antibody, serum galactomannan antigen assay, (1,3)-b-D-glucan antigen assay, and tuberculosis (TB) interferon gamma release assay all yielded negative results. Cerebral magnetic resonance imaging (MRI) revealed multifocal mass and nodular mixed-density lesions with significant peripheral edema in the T2 sequence. An eccentric target sign was observed in the enhanced T1 sequence, a finding that can be indicative of various conditions including tumor growth, invasive fungal infection, and tuberculosis.
Flow cytometry of the CSF showed an increased number of monocytes but no evidence of leukemic blasts. Despite empirical treatment with antibiotics such as imipenem and antifungal agents like caspofungin, the patient’s condition deteriorated rapidly. Within two weeks of admission, he developed generalized epilepsy and fell into a coma. Given the severity of his condition, an emergent decompressive craniectomy and cerebral biopsy were performed. Post-surgical pathology studies revealed no signs of tumor but identified a marked number of foamy macrophages in the brain tissue. Traditional staining methods, including hexamine silver staining and anti-fast staining, failed to detect any microorganisms.
The definitive diagnosis was achieved through high-throughput pathogenic megagenomic sequencing of the biopsied brain tissue. This advanced technique identified a significant abundance of Toxoplasma gondii genomes, with 7046 reads specifically attributed to the parasite. This finding confirmed the diagnosis of cerebral toxoplasmosis. Despite the initiation of targeted therapy with pyrimethamine and sulfadiazine, the patient succumbed to the disease, highlighting the aggressive nature of this infection in immunocompromised individuals.
Toxoplasmosis following allo-HSCT is typically a reactivation of a prior latent infection, with 90% of cases occurring within the first six months post-transplant. The risk of reactivation is heightened in patients with delayed immune reconstitution, such as those undergoing haploidentical allo-HSCT, and in those receiving continued immunosuppression for graft-versus-host disease. Serological testing for Toxoplasma gondii IgG in both donors and recipients is recommended, particularly for patients from endemic areas. However, it is important to note that standard serological assays may fail to detect T. gondii antibodies in immunocompromised patients, leading to potential diagnostic challenges.
In terms of imaging, cerebral toxoplasmosis typically presents on MRI as multiple lesions that are hypointense on T1-weighted pre-contrast images and hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. These lesions often exhibit focal nodular or ring enhancement following the administration of gadolinium contrast. The presence of a target sign on MRI, as observed in this case, can be suggestive of various conditions, necessitating a comprehensive diagnostic approach.
The role of diagnostic metagenomics in clinical settings is increasingly recognized, particularly in cases where conventional methods fail to identify the causative pathogen. High-throughput metagenomic analysis, as employed in this case, offers a powerful tool for identifying unknown pathogens in complex clinical scenarios. This case underscores the potential of metagenomic sequencing to provide definitive diagnoses in challenging cases, thereby guiding appropriate therapeutic interventions.
In conclusion, cerebral toxoplasmosis is a severe opportunistic infection that can occur following allo-HSCT, particularly in the context of delayed immune reconstitution and ongoing immunosuppression. The diagnostic process can be complicated by the limitations of traditional serological and staining methods, especially in immunocompromised patients. Advanced techniques such as high-throughput megagenomic sequencing play a crucial role in identifying the causative pathogens in such cases, facilitating timely and accurate diagnosis. Despite advances in diagnostic capabilities, the prognosis for cerebral toxoplasmosis remains poor, emphasizing the need for heightened awareness and preventive measures in at-risk populations.
doi.org/10.1097/CM9.0000000000000087
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