Renee Newby, MD (2018)

Renee Headshot

Nominated From: University of Washington

Research Site: Peru

Research Area: Infectious Disease

Primary Mentor: Joseph Zunt

Research Project

 

Early diagnosis of tuberculosis meningitis to promote improved outcomes

 

Though tuberculosis (TB) is a treatable and curable disease, it remains one of the 10 leading causes of death worldwide now surpassing the mortality rate of HIV/AIDS. In 2015, among HIV-infected people, at least 1/3 were infected with TB, 1.2 million new cases of TB developed and 35% of deaths were attributable to TB.1 Globally, in 2014 there were an estimated 9.6 million new cases of TB. In Peru, the incidence of new TB cases in 2014 was 88.8/100,000 and in Lima-Callao, the incidence was 155.5/100,000. In 2013 and 2014, 60% of new TB cases in Peru were concentrated in Lima.2 Though the incidence is decreasing, the impact of TB on Lima, Peru remains significant.

When TB reaches the central nervous system (CNS), mortality is much higher. The most important risk factor for developing CNS tuberculosis is HIV infection, increasing the risk of developing active disease 20-30 times that of people without HIV. Cases that reach the CNS including tuberculous meningitis (TBM) and tuberculomas make up 1% of all TB cases3. Though TBM is often treatable if caught early, detection requires clinical recognition, imaging and affordable molecular diagnostic tools. TBM appears similar clinically yet has higher mortality than other forms of meningitis.2 In a preliminary study, mortality rates among patients with confirmed TBM and those with non-confirmed, but probable TBM were 50% and <30% respectively. Implementing appropriate treatment early is essential for decreasing morbidity and mortality. Criteria have been developed to clinically predict TBM vs. non-TB meningitis using models such as Thwaites’, in which, length of history, white-blood-cell count, total cerebrospinal fluid white-cell count, and cerebrospinal fluid neutrophil proportion are the main predictive measures. This model has increased early diagnosis, with sensitivities and specificities of 86% and 79% respectively.4

Specific Aims

Aim 1. Quantify morbidity and mortality associated with TBM using a longitudinal cohort of patients with and without TBM. Overall mortality, TBM-associated mortality, and neurological assessments to determine morbidity will be performed at 1 and 3-months post-diagnosis.
1a) Determine if outcomes of meningitis differ for patients with confirmed TBM and non-TB meningitis patients. We hypothesize that confirmed TB meningitis cases will have greater in-hospital mortality as well out-patient morbidity and mortality.
1b) Determine if outcomes of TB meningitis differ for patients with HIV coinfection compared to those who are HIV-uninfected. We hypothesize that the immunodeficiency seen in HIV patients will be associated with increased morbidity and mortality among patients with newly diagnosed TBM.

Aim 2. 2a) Identify factors associated with diagnosis of TBM as well as morbidity and mortality among those with TB and non-TB meningitis. We hypothesize that differences in clinical findings, HIV status and TB exposures increase the likelihood of TBM diagnosis. We also hypothesize that factors including lower socioeconomic status, past medical history, and HIV status contribute to morbidity and mortality of TBM.
2b) Develop a rule for clinical prediction of TBM diagnosis as well as patient outcome, primarily mortality, among patients with TBM and non-TB meningitis with and without HIV coinfection. We hypothesize that differences in clinical presentation among patients with TBM vs. non-TB meningitis can be used to predict the diagnosis of TBM and severity of morbidity and mortality.

Research Significance

Despite advanced diagnostic equipment, rapid detection of tuberculous (TB) meningitis remains difficult in all parts of the world and earlier diagnosis and treatment result in improved outcome. This study would compare the outcomes of starting presumptive treatment of TB meningitis in Peru – where TB meningitis is much more common than in the United States; results of this study could influence guidelines for presumptive treatment of TB meningitis for Peru and the United States.

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