1. Microbiology and Infectious Disease

Tuberculous Meningitis: Can aspirin help?

Using a combination of aspirin, anti-tuberculosis drugs and steroids may help to reduce the number of strokes and deaths in patients with tuberculous meningitis.
https://doi.org/10.7554/eLife.35906
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  1. Ashwini Kalantri
  2. Shriprakash Kalantri
(2018)
Tuberculous Meningitis: Can aspirin help?
eLife 7:e35906.
https://doi.org/10.7554/eLife.35906
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  1. Ashwini Kalantri  Is a corresponding author
  2. Shriprakash Kalantri  Is a corresponding author
  1. Mahatma Gandhi Institute of Medical Sciences, India

Tuberculosis is a highly infectious disease that, over the millennia, has killed more people than wars or famines (World Health Organization, 2017). Roughly one third of the world's population – almost two billion people – are thought to carry the pathogen that causes the disease. It particularly affects low-income countries, and almost two million people died from the disease in such countries in 2017 (Dheda et al., 2016).

The most lethal and disabling form of tuberculosis is tuberculous meningitis, which causes inflammation in the brain (Wilkinson et al., 2017). This type of tuberculosis happens when the bacteria move to the protective covering of the brain, the meninges, and form small lesions that can rupture and so prompt the symptoms of the disease. Most untreated patients die within two months of the onset of illness (Thwaites et al., 2013).

Tuberculous meningitis (TBM) is commonly treated with a combination of steroids (to reduce the inflammation) and anti-tuberculosis drugs (to fight the bacteria). Although this combination of treatments can improve survival, the mortality rates and severe cases of disability continue to be unacceptably high (Heemskerk et al., 2016; Thwaites et al., 2004). People with TBM often suffer from complications due to fluids that accumulate in the brain cavities, and from inflamed blood vessels that can lead to blood clots, the main cause of strokes. Could drugs that prevent clots and reduce inflammation help patients with TBM?

Now, in eLife, Guy Thwaites and colleagues – including Nguyen Mai as first author – report that a common anti-inflammatory drug may hold the key to answering this question (Mai et al., 2018). The researchers – who are based in Vietnam, the UK and the Netherlands – designed a clinical trial to test the efficacy and safety of aspirin in patients with TBM.

Aspirin is a drug commonly used to avert or treat heart attacks and strokes. It prevents blood clots from forming and also reduces inflammation. Patients taking aspirin suffer fewer heart attacks, strokes and deaths than those who do not, albeit at the cost of a small number of bleeding events (Antithrombotic Trialists' (ATT) Collaboration et al., 2009).

In the experiments, 120 Vietnamese adults were randomly assigned to receive a low dose of aspirin (81 mg/day), a high dose of aspirin (1000 mg/day), or an identical tablet that did not contain any medication (called the placebo). All groups were also given anti-tuberculosis drugs and steroids for the first 60 days. Mai et al. then assessed the efficacy of aspirin by analyzing brain scans and measuring markers of thrombosis and inflammation in the fluid surrounding the brain and the spinal cord.

The results showed that aspirin reduced stroke-associated disability and death, at least for a short time. Compared to the placebo, a low dose of aspirin lowered the risk by 7%, and a high dose by 13%. However, given the small number of patients in the study, these results should be interpreted with caution. Encouragingly though, the risk of bleeding in the brain or stomach did not increase significantly in patients receiving aspirin, regardless of the dose. Thus, this trial suggests that aspirin is safe when used alongside the drugs normally used to treat TBM.

In March 1882, Robert Koch discovered the bacterium that causes tuberculosis – a turning point in our understanding of the disease (Blevins and Bronze, 2010). A century later, accurate diagnosis and potent drugs have helped to reduce the number of deaths caused by this illness. But researchers and physicians have failed to replicate this success story in TBM.

Could aspirin, used in combination with standard treatments, cut the Gordian knot to solve or even prevent the complications associated with TBM? Could it improve long-term survival and offer disability-free life to patients? Mai et al. show that aspirin might be able to achieve these goals to some extent. The trial was, however, not designed to answer all these questions. A larger phase 3 trial, which compares this new approach with the best currently available treatment, will be needed to confirm that aspirin is indeed safe and able to reduce the number of strokes and deaths in patients with TBM.

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Author details

  1. Ashwini Kalantri

    Ashwini Kalantri is in the Department of Community Medicine, Mahatma Gandhi Institute of Medical Sciences, Sevagram, India
    For correspondence
    ashwini@mgims.ac.in
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5013-4371

  2. Shriprakash Kalantri

    Shriprakash Kalantri is in the Department of Medicine, Mahatma Gandhi Institute of Medical Sciences, Sevagram, India
    For correspondence
    sp.kalantri@gmail.com
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1633-1029

Publication history

  1. Version of Record published: March 21, 2018 (version 1)

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© 2018, Kalantri et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ashwini Kalantri
  2. Shriprakash Kalantri
(2018)
Tuberculous Meningitis: Can aspirin help?
eLife 7:e35906.
https://doi.org/10.7554/eLife.35906

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    A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults

    Nguyen TH Mai, Nicholas Dobbs ... Guy E Thwaites
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    1. Microbiology and Infectious Disease

    A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults

    Nguyen TH Mai, Nicholas Dobbs ... Guy E Thwaites
    Research Article Updated

    Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ≥1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.

  2. Listen to Guy Thwaites explain how aspirin could help treat a form of tuberculosis.

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    Aspirin helps to reduce inflammation and the number of strokes associated with tuberculous meningitis.

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    Altered transcriptomic immune responses of maintenance hemodialysis patients to the COVID-19 mRNA vaccine

    Yi-Shin Chang, Kai Huang ... David L Perkins
    Research Article

    Background:

    End-stage renal disease (ESRD) patients experience immune compromise characterized by complex alterations of both innate and adaptive immunity, and results in higher susceptibility to infection and lower response to vaccination. This immune compromise, coupled with greater risk of exposure to infectious disease at hemodialysis (HD) centers, underscores the need for examination of the immune response to the COVID-19 mRNA-based vaccines.

    Methods:

    The immune response to the COVID-19 BNT162b2 mRNA vaccine was assessed in 20 HD patients and cohort-matched controls. RNA sequencing of peripheral blood mononuclear cells was performed longitudinally before and after each vaccination dose for a total of six time points per subject. Anti-spike antibody levels were quantified prior to the first vaccination dose (V1D0) and 7 d after the second dose (V2D7) using anti-spike IgG titers and antibody neutralization assays. Anti-spike IgG titers were additionally quantified 6 mo after initial vaccination. Clinical history and lab values in HD patients were obtained to identify predictors of vaccination response.

    Results:

    Transcriptomic analyses demonstrated differing time courses of immune responses, with prolonged myeloid cell activity in HD at 1 wk after the first vaccination dose. HD also demonstrated decreased metabolic activity and decreased antigen presentation compared to controls after the second vaccination dose. Anti-spike IgG titers and neutralizing function were substantially elevated in both controls and HD at V2D7, with a small but significant reduction in titers in HD groups (p<0.05). Anti-spike IgG remained elevated above baseline at 6 mo in both subject groups. Anti-spike IgG titers at V2D7 were highly predictive of 6-month titer levels. Transcriptomic biomarkers after the second vaccination dose and clinical biomarkers including ferritin levels were found to be predictive of antibody development.

    Conclusions:

    Overall, we demonstrate differing time courses of immune responses to the BTN162b2 mRNA COVID-19 vaccination in maintenance HD subjects comparable to healthy controls and identify transcriptomic and clinical predictors of anti-spike IgG titers in HD. Analyzing vaccination as an in vivo perturbation, our results warrant further characterization of the immune dysregulation of ESRD.

    Funding:

    F30HD102093, F30HL151182, T32HL144909, R01HL138628. This research has been funded by the University of Illinois at Chicago Center for Clinical and Translational Science (CCTS) award UL1TR002003.