The deadliest form of tuberculosis is tuberculosis meningitis (TBM), which causes inflammation in the brain. Even with the best treatment available, about half of patients with TBM become disabled or die, often because they have a stroke. Strokes are caused by blood clots or other blockages in blood vessels in the brain. Aspirin is known to prevent blood clots and helps reduce inflammation. Some scientists wonder if it might help patients with TBM by preventing blockages in blood vessels.

Now, Nguyen et al. show that adding aspirin to existing TBM treatments may reduce strokes in some patients. In the experiments, 120 patients with TBM were randomly assigned to receive a low dose of aspirin (81 mg/day), a high dose of aspirin (1000mg/day), or an identical tablet that contained no medication. All the patients also took the anti-tuberculosis drugs and steroids usually used to treat the condition. Both doses of aspirin appeared to be safe. Patients who received aspirin were less likely to have a stroke or die in the first two months of treatment than patients who received the fake pill. But the difference was so small it could have been caused by chance.

In the 92 patients with clear evidence of tuberculosis bacteria in their brains, the benefit of aspirin was larger and unlikely to be due to chance. The benefit was greatest for those who received the higher dose of aspirin, only 10.7% of these patients died or had a stroke, compared with 14.8% of those who received a low dose of aspirin, or 34% of those who received the fake pill. Next, Nguyen et al. looked at brain fluid taken from the TBM patients before and after they received the aspirin or fake medication. The experiments showed that patients treated with high dose aspirin had much lower levels of a clot-promoting substance called thromboxane A2 and more anti-inflammatory molecules.

Larger studies are needed in children and adults to confirm that aspirin helps prevent strokes or death in patients with TBM. Studies are also needed on patients who have both TBM and HIV infections. But if more studies show aspirin is safe and effective, adding this medication to TBM treatment may be an inexpensive way to prevent death or disability.

New host-directed therapies are urgently required for all forms of tuberculosis, but especially for tuberculous meningitis (TBM), the most lethal form of the disease, which kills or disables around half of sufferers (Thwaites, 2013). Therapeutic strategies to improve outcomes can be broadly divided into those directed against the bacteria and their enhanced killing, and those directed at the host and the control of the inflammatory response. To date, attempts to optimise bacteria-directed anti-tuberculosis regimens have not been shown to clearly benefit patients with TBM (Ruslami et al., 2013; Heemskerk et al., 2016). In contrast, host-directed therapy with adjunctive anti-inflammatory corticosteroids has been shown to reduce mortality from TBM, although without reduced disability amongst survivors (Prasad et al., 2016). There is, therefore, an urgent need to explore alternative therapeutic strategies that may prevent the long-term neurological sequelae of TBM and complement the short-term survival benefits of dexamethasone.

Cerebral infarction is the commonest cause of irreversible neurological injury from TBM (Lammie et al., 2009). TBM-related infarcts are typically located in the territories of the proximal middle cerebral artery and the medial lenticulostriate and thalamoperforating vessels, where the basal meningeal inflammatory exudate is most intense (Lammie et al., 2009; Hektoen, 1896; Misra et al., 2011). Their pathogenesis remains controversial, in particular the role of vessel thrombosis. Some autopsy studies have either failed to find arterial thrombosis associated with infarcts, or found it to be uncommon (Doniach, 1949); whereas others have reported that thrombosis is common, especially when associated with tuberculous vasculitis (Poltera, 1977). The limited available evidence suggests that TBM-related infarcts are caused by a combination of vasospasm, intimal proliferation, and thrombosis (Lammie et al., 2009).

Aspirin acts by irreversibly inhibiting the cyclooxygenase pathway of arachidonic acid metabolism and the production of prostanoids (Vane, 1971). Low dose aspirin (75–150 mg) prevents ischaemic cerebrovascular disease (Richman and Owens, 2017) and higher dose aspirin (up to four grams daily) is used for the treatment of some inflammatory conditions (e.g. rheumatic fever) (Cilliers et al., 2015). Its anti-inflammatory effects are thought to occur at doses >600 mg daily, through the inhibition of pro-inflammatory prostaglandins (e.g. PGE₂, PGF_2α and PGD₂) and the unstable prostanoid, thromboxane A₂ (TXA₂) (Botting, 2010). Low dose aspirin causes less inhibition of pro-inflammatory prostaglandins, but causes clinically significant inhibition of TXA₂ and platelet aggregation. Until recently, the inhibitory effect on platelets and thrombus formation was thought to explain aspirin’s well-documented reduction in the risk of death from stroke and myocardial infarction (Raju et al., 2011). However, these effects may be augmented by aspirin’s ability to trigger the production of 15-epi-lipoxins, 17R-resolvins and protectins, molecules that alongside the recently discovered maresins actively promote the resolution of inflammation (Spite and Serhan, 2010). The ‘pro-resolution’ properties of aspirin are not shared with any other non-steroidal anti-inflammatory drugs (NSAID), or corticosteroids. It represents a potentially unique mode of action by which aspirin, alongside the prevention of thrombosis, might prevent infarctions and speed resolution of intra-cerebral inflammation and improve outcomes from TBM. Furthermore, there are intriguing data from murine models of tuberculosis which suggest aspirin and other non-steroidal anti-inflammatory drugs may enhance Mycobacterium tuberculosis killing (Byrne et al., 2007; Vilaplana et al., 2013).

Two previous trials of adjunctive aspirin for TBM have been reported. The first randomised 118 Indian adults with TBM to standard anti-tuberculosis chemotherapy, with or without aspirin (150 mg daily) (Misra et al., 2010). By 3 months, brain magnetic resonance imaging (MRI) proven infarction occurred in 13 (43%) in the placebo arm and 8 (24%) in the aspirin group (p=0.18). Aspirin was associated with a reduction in mortality (43% versus 22%, p=0.02) without a significant increase in adverse events. The results are hard to interpret, however, because of the variable use of prednisolone between the treatment arms. Participants who received prednisolone and aspirin appeared to benefit the most. The second trial randomised 146 South African children with TBM to standard anti-tuberculosis chemotherapy plus placebo (n = 50), low-dose aspirin (75 mg/day) (n = 47), or high-dose aspirin (100 mg/kg/day) (n = 49) (Schoeman et al., 2011). Aspirin had no significant impact on survival, motor or cognitive outcomes.

We hypothesised that aspirin prevents TBM-related brain infarction by its anti-thrombotic, anti-inflammatory, and pro-resolution effects. We chose to investigate two aspirin doses: a low dose (81 mg/day) with anti-thrombotic but minimal anti-inflammatory activity; and a higher dose (1000 mg/day) with both anti-thrombotic and anti-inflammatory activity. Our primary objective was to demonstrate the safety, tolerability, and potential efficacy of 81 mg and 1000 mg aspirin when added to dexamethasone for the first 60 days of TBM treatment. Our secondary objective was to investigate the potential mechanisms of actions of the two aspirin doses by examining the profiles of lipid mediators, including the pro-inflammatory eicosanoids and aspirin triggered pro-resolving mediators, in the cerebrospinal fluid (CSF) of participants.

Between October 2014 and May 2016, 192 patients were assessed for eligibility and 120 were randomised (Figure 1 and supplementary file 2): 41 received placebo, 39 received aspirin 81 mg/day, and 40 received aspirin 1000 mg/day. Two participants in the placebo group were lost to follow-up after 57 and 217 days, respectively. Gastro-intestinal bleeding event data were missing for seven participants (three placebo, 4 aspirin 81 mg) because they either died or were lost to follow-up before day 60. MRI-proven new intracranial bleeding event or infarct data were missing for 15 subjects (six placebo, 7 Aspirin 81 mg, 2 Aspirin 1000 mg) because they either died (four placebo, 6 aspirin 81 mg, 1 aspirin 1000 mg), were lost to follow-up before day 60 (1 placebo), or they were too unwell to have scans within 60 ± 10 days (two placebo, 1 aspirin 81 mg, 2 aspirin 1000 mg).

Figure 1

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The per-protocol population excluded 22 participants (Figure 1): two had a confirmed alternative diagnosis (Listeria monocytogenes meningitis and Mycobacterium avium intracellulare meningitis), one had confirmed MDR TBM, and 19 received <30 days of study drug for reasons other than death (five placebo; 8 aspirin 81 mg; 9 aspirin 1000 mg).

Planned sub-group analyses

Planned sub-group analyses for the primary efficacy outcome are reported in Table 4. No clear subgroup signal was seen for any subgrouping variable except for the diagnostic category which showed a significant interaction with the aspirin treatment effect (P_{heterogeneity} = 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 1000 (10.7%) in aspirin 1000 mg; p=0.06). These beneficial effects were most marked in the aspirin 1000 mg group (aspirin 81 mg vs placebo: odds ratio (OR) 0.33, 95% CI 0.09–1.20, p=0.093; aspirin 1000 mg vs. placebo: OR 0.23, 95% CI 0.06–0.93, p=0.039) (Figure 2). These effects equate to the number-needed-to-treat (NNT) to prevent an infarct or death by day 60 of 5 for aspirin 81 mg and 4 for aspirin 1000 mg.

Figure 2 with 2 supplements see all

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Table 4

	Placebo (events/n (risk%))	Aspirin 81 mg (events/n (risk%))	Aspirin 1000 mg (events/n (risk%))	P-value comparison	P-heterogeneity
Diagnostic criteria  - Definite  - Probable/Possible	11/32 (34.4%) 0/6 (0%)	4/27 (14.8%) 3/8 (37.5%)	3/28 (10.7%) 3/10 (30.0)	0.06 0.30	0.01
MRC Grade  - I  - II  - III	4/16 (25.0%) 4/17 (23.5%) 3/5 (60.0%)	1/15 (6.7%) 4/17 (23.5%) 3/4 (75.0%)	1/14 (7.1%) 4/19 (21.1%) 1/5 (20.0%)	0.33 1.00 0.42	0.44
Previous tuberculosis treatment  - Yes  - No	1/2 (50.0%) 10/36 (27.8%)	1/1 (100%) 7/35 (20.0%)	0/1 (0%) 6/37 (16.2%)	1.00 0.51	0.28
Drug susceptibility*  - MDR-TB  - Rifampicin mono-resistance  - Isoniazid resistance (with or without streptomycin resistance)  - No or other resistance	0/0 (0%) 0/1 (0%) 3/6 (50.0%) 5/10 (50.0%)	1/1 (100%) 0/0 (0%) 1/1 (100%) 1/7 (14%)	0/0 (0%) 0/0 (0%) 1/2 (50.0%) 1/12 (8%)	1.00 0.09	0.17
LTA4H genotype†  - CC  - CT  - TT	3/18 (16.7%) 7/16 (43.8%) 1/4 (25.0%)	4/13 (30.8%) 3/16 (18.8%) 1/6 (16.7%)	0/16 (0%) 5/19 (26.3%) 0/1 (0%)	0.05 0.30 1	0.13

1. *4 participants not genotyped. P-value for the heterogeneity was obtained from likelihood ratio tests for an interaction term between treatment and the grouping variable in a logistic regression model.

   ^†Outcomes unavailable in two participants in the placebo group with DST available (one lost to follow-up at day 57 and one did not have MRI information at day 60).

CSF lipid mediator profiles

We investigated the impact of aspirin on the concentrations of lipid mediators of inflammation, extracted, identified and quantified from CSF using lipid mediator profiling and LC-MS/MS (Figure 3 - child). Partial least squared discriminant analysis 2-dimensional score plot of CSF taken from all surviving participants 30 days from randomization showed clustering of lipid mediators according to treatment group suggesting dose-dependent effects (Figure 3A). Furthermore, in those participants who received >30 days of study drug we compared baseline with day 30 CSF and found dose-dependent inhibition of TXB₂ (the stable metabolite of TXA₂) and up-regulation of pro-resolving protectins, with significant differences observed in the aspirin 1000 mg group compared to placebo (Figure 3B; supplementary file 6).

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There is much current interest in novel host-directed therapies against tuberculosis (Wallis et al., 2016). We conducted a phase two randomised controlled trial with the aim of showing the safety and potential efficacy of either low (81 mg/day) or higher (1000 mg/day) dose aspirin when added to anti-tuberculosis drugs and dexamethasone for the treatment of HIV-uninfected adults with TBM. We found that aspirin was not associated with a significant increase in grade 3 or four adverse events. In both the ITT and the per-protocol population, the observed risk of death or new brain infarction by day 60 was lower in the aspirin arms compared to placebo, although this was not statistically significant. Planned sub-group analyses, however, suggested that aspirin 1000 mg may benefit those with microbiologically confirmed TBM. This finding was supported by an analysis of CSF lipid mediators of inflammation, which demonstrated aspirin 1000 mg was associated with significant inhibition of pro-thrombotic TXA₂ and upregulation of pro-resolution protectins.

The important characteristics of the trial participants, which influences the generalisability of the findings, were that they were HIV-uninfected, had relatively mild disease (87.5% MRC grade I or II), a high proportion (35.1%) had brain infarcts evident at baseline, and most (76.7%) had a microbiologically confirmed diagnosis of TBM. The high proportion of microbiologically confirmed disease is especially relevant, as many centres report much lower proportions (typically 20–50%). The characteristics of populations of suspected but unconfirmed case of TBM may vary substantially between centres and influence treatment effects. In addition, all participants were treated with adjunctive dexamethasone, which is known to reduce deaths from TBM in this population (Thwaites et al., 2004).

Combining dexamethasone with aspirin did not significantly increase gastro-intestinal bleeding of any severity, or any other category of grade 3 or four adverse event. There was a non-significant increase in non-severe (grade 1 or 2) gastro-intestinal bleeding events (mostly small volumes of digested blood aspirated from nasogastric tubes) in the aspirin-treated participants and in all these cases the study drug was stopped immediately. A larger trial is needed to determine whether aspirin truly increases these events and to assess their clinical significance. However, as the risk of severe gastric bleeding appears to be very low, the future management of minor bleeding events in aspirin-treated patients could be less conservative, especially as the per-protocol analysis suggested participants who received >30 days of aspirin may benefit more than those who stopped aspirin earlier.

Our findings are similar to the previous trial of aspirin (150 mg/day) for adults with TBM conducted in India (Misra et al., 2010), which reported aspirin in combination with prednisolone was associated with a reduction in brain infarcts (22% versus 55% in controls; p=0.08) and death (13% verus 14% in controls; p=0.05). Treatment with aspirin without prednisolone was not associated with improved outcomes. In both the Indian trial and the trial conducted in South African children (Schoeman et al., 2011), which included a high dose (100 mg/kg/day) arm, the use of aspirin was not associated with increased adverse events. In particular, aspirin did not appear to increase the risk of gastro-intestinal bleeding in either study. If these data are taken together with the results of the current study, they strongly suggest aspirin at doses ranging from 81 mg to 1000 mg per day can be safely added to anti-tuberculosis and corticosteroid therapy. Determining which dose is likely to be most effective is difficult, but our findings suggest that higher doses (1000 mg/day or equivalent in children) are likely to more effective.

The strength of our trial is that it addressed both the potential clinical role of aspirin and its mechanism of action by serial brain imaging and analysis of a panel of 71 lipid mediators, their precursors, pathway markers and further metabolites in the CSF. There are, however, some important limitations. First, assessment of the primary efficacy endpoint required participants to be well enough to have an MRI at baseline and day 60. Three screened patients were judged too unwell to have baseline imaging and enter the trial, and five participants were too unwell for imaging at day 60. Therefore, our findings may not be generalisable to those with very severe disease at baseline.

The trial was not powered to show an impact on longer term survival or neurodisability and therefore does not provide definitive, practice-changing evidence that adjunctive aspirin improves outcomes in all adults with TBM. However, the findings support the hypothesis that aspirin has effects on tuberculosis-associated neuro-inflammation that are independent of dexamethasone and may lead to additional improvements in clinical outcomes. The clinical findings need to be interpreted cautiously, but the planned sub-group analysis suggested a clinical benefit of aspirin in those with microbiologically confirmed disease, especially at 1000 mg. This potential clinical effect is supported by the CSF analysis, which showed dose-dependent inhibition of TXA₂ by aspirin, modest inhibition of prostaglandins, and the upregulation of potentially protective protectins. The serial brain images also support the assertion that aspirin’s benefit may be driven by the upregulation of these pro-resolving molecules: 60% of infarcts seen at baseline had resolved by day 60 in the aspirin 1000 mg group compared with 14.2% in the aspirin 81 mg group and 42.9% in the placebo group.

In summary, this phase two randomised placebo-controlled trial suggests that daily aspirin 81 mg or 1000 mg can be given safely with dexamethasone and anti-tuberculosis drugs for the treatment of HIV-uninfected adults with TBM. The trial also provides new data that indicate aspirin induces dose-dependent inhibition of TXA₂ and upregulation of protectins within the central nervous system that may reduce the incidence and promote the resolution of TBM-associated brain infarcts and inflammation and thereby improve outcome. These findings provide strong support for the conduct of a large phase 3 trial of adjunctive aspirin for TBM, but may also have relevance for the treatment of other forms of tuberculosis, adding to the growing evidence that aspirin and other non-steroidal anti-inflammatory drugs may be useful novel adjunctive agents in tuberculosis treatment (Kroesen et al., 2017).

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Author details

1. Nguyen TH Mai

   1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
   2. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

   Contribution

   Conceptualization, Data curation, Investigation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

2. Nicholas Dobbs

   Western General Hospital, Edinburgh, United Kingdom

   Contribution

   Data curation, Formal analysis, Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

3. Nguyen Hoan Phu

   1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
   2. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

   Contribution

   Conceptualization, Data curation, Supervision, Investigation, Methodology, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

4. Romain A Colas

   Lipid Mediator Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

   Contribution

   Resources, Formal analysis, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

5. Le TP Thao

   Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

   Contribution

   Data curation, Formal analysis, Validation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

6. Nguyen TT Thuong

   Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

   Contribution

   Conceptualization, Formal analysis, Investigation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

7. Ho DT Nghia

   1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
   2. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

   Contribution

   Data curation, Supervision, Investigation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

8. Nguyen HH Hanh

   1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
   2. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

   Contribution

   Data curation, Investigation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

9. Nguyen T Hang

   Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

   Contribution

   Data curation, Investigation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

10. A Dorothee Heemskerk

    1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
    2. Department of Medical Microbiology and Infection Control, VU medical centre, VU University Amsterdam, Amsterdam, Netherlands

    Contribution

    Data curation, Investigation, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

11. Jeremy N Day

    1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
    2. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

    Contribution

    Conceptualization, Investigation, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

12. Lucy Ly

    Lipid Mediator Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

    Contribution

    Resources, Data curation, Formal analysis, Investigation, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

13. Do DA Thu

    Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

    Contribution

    Resources, Data curation, Investigation, Visualization, Writing—review and editing

    Competing interests

    No competing interests declared

14. Laura Merson

    Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

    Contribution

    Data curation, Supervision, Investigation, Methodology, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4168-1960

15. Evelyne Kestelyn

    1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
    2. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

    Contribution

    Data curation, Supervision, Investigation, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

16. Marcel Wolbers

    Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam

    Contribution

    Formal analysis, Supervision, Validation, Investigation, Methodology, Writing—original draft, Writing—review and editing

    Competing interests

    No competing interests declared

17. Ronald Geskus

    1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
    2. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

    Contribution

    Data curation, Formal analysis, Supervision, Validation, Investigation, Methodology, Writing—original draft, Writing—review and editing

    Competing interests

    No competing interests declared

18. David Summers

    Western General Hospital, Edinburgh, United Kingdom

    Contribution

    Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing—review and editing

    Competing interests

    No competing interests declared

19. Nguyen VV Chau

    1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
    2. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

    Contribution

    Conceptualization, Supervision, Investigation, Methodology, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

20. Jesmond Dalli

    Lipid Mediator Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

    Competing interests

    No competing interests declared

21. Guy E Thwaites

    1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam
    2. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

    Contribution

    Conceptualization, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

    For correspondence

    gthwaites@oucru.org

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-2858-2087

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