Biomarkers and host-parasite interactions in neurocysticercosis and other helminths

National Institute Of Allergy And Infectious Diseases

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Abstract

The larval form of the Taenia solium tapeworm can travel to the brain and most often causes seizures as parenchymal disease. Subarachnoid neurocysticercosis is usually caused by an aberrant proliferative form of Taenia solium causing mass effect and arachnoiditis, is relapsing and highly recalcitrant to treament. We previously developed a highly sensitive and specific qPCR assay for detection of Taenia solium, the causative organism, based on targeting a highly repetitive region. We have demonstrated the utility in the assay, when used on CSF, in predicting cure in those with subarachnoid and ventricular neurocysticercosis. The patients we studied in validating the sensitivity and specificity of the assay had long term NIH follow up and comprise the longest follow up of patients proven to be disease free in the literature. We have performed the validation to use this assay under a Clinical Laboratory Improvements Amendment Certificate for the clinical reporting out of these results to clinicians from around the country. Given the relapsing nature of this disease without a proven end point in treatment previously, this provides some guidance to clinicians as to when to stop treatment. (OConnell EM, Harrison S, Dahlstrom E, Nash TE, Nutman TB. A novel, highly sensitive qPCR assay for the diagnosis of subarachnoid and ventricular neurocysticercosis and for assessing response to treatment. Clin Inf Dis. 2020. Apr 15. PMID: 31232448.) Much remains unknown about the inflammation in subarachnoid neurocysticercosis, yet it is the main driver of morbidity and mortality in this population. Patients from the NIH Clinical Center with subarachnoid neurocysticercosis had CSF obtained early in treatment and at the time of cure and comprehensive cytokine and chemokine profiling was performed. IL-10, IL-12, IFNy, CXCL-10, IL-13, INFa2, MIP1a, MIP1b, and VEGF are found in significantly higher levels in those early in symptomatic disease compared with healthy control CSF. Ratios of IL-12p70 to IL-10 was also associated with a shorter time to cure. Additionally, following cure, high levels of IL-10, CXCL-10, and IL-12p70 remained in the CSF. (Harrison S, Thumm L, Nash TE, Nutman TB, OConnell EM. The local inflammatory profile and predictors of treatment success in subarachnoid neurocysticercosis Clin Inf Dis. 2020. In Press.) Our long term success at the NIH Clinical Center in treating subarachnoid neurocysticercosis (SUBNCC) was described. Thirty of 34 SUBNCC patients were treated with extended cysticidal and anti-inflammatory regimens and followed up a median of 4.2 years posttreatment (range: 15 for 4 years, 20 2 years, 26 > 1 year, and 3 < 1 year). The median ages at the time of first symptom, diagnosis, and enrollment were 29.7, 35.6, and 37.9 years, respectively; 58.8% were male and 82.4% were Hispanic. The median time from immigration to symptoms (minimum incubation) was 10 years and the estimated true incubation period considerably greater. Fifty percent also had other forms of NCC. Common complications were hydrocephalus (56%), shunt placement (41%), infarcts (18%), and symptomatic spinal disease (15%). Thirty patients (88.2%) required prolonged treatment with albendazole (88.2%, median 0.55 year) and/or praziquantel (61.8%; median 0.96 year), corticosteroids (88.2%, median 1.09 years), methotrexate (50%, median 1.37 years), and etanercept (34.2%, median 0.81 year), which led to sustained inactive disease in 29/30 (96.7%) patients. Three were treated successfully for recurrences and one has continuing infection. Normalization of cerebral spinal fluid parameters and cestode antigen levels guided treatment decisions. All 15 patients with undetectable cestode antigen values have sustained inactive disease. There were no deaths and moderate morbidity posttreatment. Corticosteroid-related side effects were common, avascular necrosis of joints being the most serious (8/33, 24.2%). Prolonged cysticidal treatment and effective control of inflammation led to good clinical outcomes and sustained inactive disease which is likely curative. (Nash TE, OConnell EM, Hammoud DA, Wetzler L, Ware JM, Mahanty S. Natural History of Treated Subarachnoid Neurocysticercosis. AJTMH. 2020. Jan. PMID: 31642423.) Amplification and sequencing of the COX1 gene using conserved cestode primer sequences allowed description of two emerging cestode infections in the US: 1. A patient in Pennsylvania, USA, with common variable immunodeficiency sought care for fever, cough, and abdominal pain. Imaging revealed lesions involving multiple organs. Liver resection demonstrated necrotizing granulomas, recognizable tegument, and calcareous corpuscles indicative of an invasive cestode infection. Sequencing revealed 98% identity to a Versteria species of cestode found in mink. (Lehman B, Leal SM Jr, Procop GW, O'Connell E, Shaik J, Nash TE, Nutman TB, Jones S, Braunthal S, Shah SN, Cruise MW, Mukhopadhyay S, Banzon J. Disseminated Metacestode Versteria Species Infection in Woman, Pennsylvania, USA Emerg Inf Dis. 2019. Jul. PMID: 31211937) 2. Echinococcus multilocularis is one of the most severe and lethal parasitic diseases of humans most often reported in Europe and Asia. Only one previous case has been documented in the contiguous United States from Minnesota in 1977. European haplotypes have been identified in carnivores and domestic dogs as well as recently in patients in Western and Central Canada. Using COX1 gene sequencing we were able to definitively identify Echinococcus multilocularis as the causative agent of our patient's liver and lung lesions that clustered most closely with the European haplotype. We have identified the first case of a European haplotype Echinococcus multilocularis in the United States. Given the recent identification of this haplotype in Canada this appears to be an emerging infectious disease in North America. Finally, (unpublished), we completed a prospective, randomized controlled trial comparing the use of imatinib to placebo in the treatment of Loiasis, a filarial infection found in Central/West Africa. Interim analysis reveals no effect of the drug in microfilarial levels. We are now undertaking analysis of plasma drug levels to better understand these results.