Nominated From: University of Minnesota
Research Site: Uganda
Research Area: Infectious Disease
Primary Mentor: David Boulware
Macrophage migration in neural tissue of patients co-infected with Cryptococcus and Tuberculosis
In 1993, the World Health Organization declared Tuberculosis (TB) a global emergency . Dr. P.H. Green first described TB meningitis in 1836. Dr. Green was able to make a clinical pathologic correlation to define the illness. He saw granulations and tubercular infiltrate of the pia accompanied by hydrocephalous . At that time, the condition was invariably fatal, and the prognosis remained the same for about 100 years at which time streptomycin was discovered.
While rare in technically advanced countries, TB meningitis is a serious cause of morbidity and mortality in developing, tropical countries. Sub-Saharan Africa had the highest burden of new TB cases in 2011 with an estimated incidence of over 260 cases per 100,000 population . Projected rates of mortality in the year 2030 are expected to be high . In African countries, poor nutrition, poverty, household crowding, drug resistant TB strains, AIDS, and malfunctioning TB control programs are important risk factors .
The hallmark of TB infection is inflammation and a complex cascade of immunopathology. The inflammatory reaction can lead to disease and tissue damage that is not limited to the first presentation. Some patients experience ‘paradoxical reaction’ (PR) which is seen after the start of therapy and is defined as worsening of existing lesions or increase in the amount of lesions. In general, patients present with fever, lymphadenitis, and pulmonary manifestations. Additionally, patients can deteriorate post-therapy. Epidemiologic studies have estimated the frequency of PR between 2-23% .
Another type of paradoxical reaction occurs mainly in patients with TB who are co-infected with HIV. Immune reconstitution inflammatory syndrome (IRIS) is often seen in patients undergoing TB therapy after beginning highly active retroviral therapy (HAART), also known as paradoxical TB-IRIS. Unmasking TB-IRIS is another variation of IRIS often seen after starting HAART in patients not currently undergoing treatment for TB. It is important to note that TB-IRIS can occur in HIV seronegative patients given that the phenomenon is seen patients who are immune compromised or have multibacillary disease .
Few studies have reviewed the role of cytokines in TB meningitis in relation to clinical and cytological changes . A study performed in South Africa that monitored pro-inflammatory plasma markers and monocyte subsets in TB-HIV co-infected patients found elevated levels of inflammatory cytokine production by monocytes in TB-IRIS patients compared to controls. The study implicated monocytes and their cytokines as potential targets for TB-IRIS prevention .
There is a dearth of diagnostics tools and treatments for TB-IRIS. Risk factors include disseminated TB at the time of diagnosis and if HIV-positive, a low CD4 count. It is thought that a pathologic immune reaction to mycobacterial antigens during immune response can lead to IRIS, although the exact mechanism is unknown. Understanding the immunopathogenesis could lead to more targeted therapies to prevent TB-IRIS .
Our main goal is to understand the timing of macrophage migration in neural tissue in patients who die with known TB-IRIS. Few studies have examined the neural tissue in TB-IRIS patients postmortem. Although this study is somewhat exploratory in nature, we expect to correlate quantity of macrophages in neural tissue and potentially cytokine production with treatment status. It is likely that there will be a difference in the amount of macrophages present in patients based TB treatment status. Additionally, the length of status can affect the migration of macrophages and provide insight into the time of onset of TB-IRIS. Therefore, we propose this study in hopes of impacting management patients with TB-IRIS patients.
To characterize the inflammatory infiltrate present in neural tissue in decedents clinically diagnosed with tuberculous immune reconstitution inflammatory syndrome (TB-IRIS) under active treatment versus decedents who are treatment naïve.
- To compare the neural tissue of decedents clinically diagnosed with TB-IRIS with the control group for:
- Macrophage infiltrate.
- Quantify amount of tuberculosis organisms using special AFB stains.
- Quantify levels of fungal organisms using special GMS stains.
- To determine cause of death.
- David Boulware, University of Minnesota
- David Meya, Makerere University
- Robert Lukande, Makerere University