Optimizing Treatment to Improve TBM Outcomes in Children: Substudy on Clinical Profile and CSF Biorepository of the Pediatric Suspected Meningitis Cases

This sub-study is being led by PIs Dr. Kelly Dooley and Dr. Chhaya Valvi.

Meningoencephalitis is associated with significant morbidity and mortality. Several viruses, bacteria, and fungal pathogens including Neisseria meningitidis, Streptococcus pneumoniae, Mycobacterium tuberculosis, Herpes Simplex Virus, and Cryptococcus neoformans cause acute and subacute meningoencephalitis. Furthermore, each of these pathogens present unique diagnostic challenges. Timely etiological diagnosis is crucial in preventing deaths and debilitating neurological sequelae. Diagnosing meningoencephalitis poses significant challenges in identifying the underlying pathogen, as the clinical syndrome is not specific, and there are significant limitations in conventional microbiological methods which are not timely, and often have poor sensitivity and specificity. Early pathogen detection is critical, as it may facilitate treatment and prognosis as well as prophylaxis. Definitive diagnosis of meningoencephalitis etiology is critical for public health surveillance and interventions. Previous studies in South and Southeast Asia have identified a diverse array of meningoencephalitis pathogens in children including typical bacterial and viral causes, vector-borne bacterial and viral causes such as scrub typhus and Japanese encephalitis, as well as emerging infectious diseases unique to India such as Chandipur virus. There is significant interest in enhancing diagnostic assays and biomarkers in the CSF of patients with meningoencephalitis, though there have been few studies evaluating these assays in the pediatric population in India. Recent advances in diagnostic platforms including multiplex portable polymerase chain reaction devices and isothermal molecular amplification techniques may allow for more sensitive diagnosis of meningoencephalitis pathogens in resource limited settings. Advanced techniques including TaqMan array cards, multiplex immunoassays, and next-generation sequencing have the potential to simultaneously identify numerous pathogens in CSF and identify novel pathogens, offering the potential to revolutionize public health surveillance for meningoencephalitis, though the utility in resource-limited, tropical settings has not been well studied. Case reports have highlighted the ability to identify neurotropic pathogens in patients in whom diagnosis cannot be made by conventional techniques. Therefore, understanding the spectrum of clinical presentation and corroborative laboratory research to enable rapid etiological diagnosis is essential.

Aims:

We aim to establish a clinically well characterized cohort of infants and children presenting with suspected meningoencephalitis and an associated biorepository of cerebrospinal fluid (CSF).

Aim 1: To study the baseline demographic, clinical and diagnostic characteristics of infants and children presenting with suspected meningoencephalitis.

Aim 2: To establish a biorepository of CSF specimens obtained from the cohort of infants and children presenting with suspected meningoencephalitis, which could be used for future research in performing surveillance for CSF pathogens and evaluating novel diagnostics and biomarkers.