Tuberculosis (TB) is characterised by chronic non-resolving inflammation. The effects of the host immune and inflammatory response to reduce iron acquisition by the bacteria, together with other contributing factors, predispose TB patients to anaemia of infection and iron deficiency anaemia (IDA). The presence of anaemia in TB patients has been linked to poor clinical outcomes. However, due to the reliance of the bacteria on iron, the management of anaemia in TB is complicated, and anaemia of infection is likely to resolve with correct TB drug treatment. On the other hand, IDA may require iron supplementation. This review aims to describe iron metabolism in TB and how this contributes to the development of iron deficiency and anaemia. Additionally, we summarise the evidence on the association between iron status and clinical outcomes as well as the available preclinical and clinical trials on iron supplementation in TB.

Background: The potential role of adjunctive anti-inflammatory therapy to enhance tuberculosis (TB) treatment has recently received increasing interest. There is, therefore, a need to broadly examine current host-directed therapies (HDTs) that could accelerate treatment response and improve TB outcomes.Methods: This systematic review and meta-analysis included randomised controlled trials of vitamin D and other HDT agents in patients receiving antibiotic treatment for pulmonary TB. Sputum smear conversion rate at 4–8 weeks was the primary outcome. Secondary outcomes included blood indices associated with infectivity and inflammation, chest radiology and incidence of adverse events.Results: Fifty-five studies were screened for eligibility after the initial search, which yielded more than 1000 records. Of the 2540 participants in the 15 trials included in the meta-analysis, 1898 (74.7%) were male, and the age at entry ranged from 18 to 70 years. There was a 38% significantly (RR1.38, 95%CI = 1.03–1.84) increased sputum smear negativity in patients administered with vitamin D in addition to standard TB treatment than those receiving only the TB treatment. Patients treated with other HDT anti-inflammatory agents in addition to TB treatment also had a 29% significantly increased sputum smear conversion rate (RR1.29, 95%CI = 1.09–1.563). Lymphocyte to monocyte ratio was significantly higher in the vitamin D treatment groups compared to the controls (3.52 vs 2.70, 95%CIfor difference 0.16–1.11,p = 0.009) and (adjusted mean difference 0.4, 95% CI 0.2 -- 0.6;p = 0.001); whilst tumour necrosis factor-alpha (TNF-α) showed a trend towards a reduction in prednisolone (p < 0.001) and pentoxifylline (p = 0.27) treatment groups. Vitamin D and N-acetylcysteine also accelerated radiographic resolution in treatment compared to placebo at 8 weeks. No differences were observed in the occurrence of adverse events among all HDT treatments.Conclusions: Vitamin D and other anti-inflammatory HDT medications used as adjunct TB treatment may be well tolerated and effective. They significantly improved sputum smear conversion rate and chest radiological appearance, and also exhibited an inflammation resolution effect.

Progressive inflammation and anemia are common in tuberculosis (TB) and linked to poor clinical outcomes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have inflammation-resolving properties, whereas iron supplementation in TB may have limited efficacy and enhance bacterial growth. We investigated effects of iron and EPA/DHA supplementation, alone and in combination, on inflammation, anemia, iron status markers and clinical outcomes in Mycobacterium tuberculosis-infected C3HeB/FeJ mice. One week post-infection, mice received the AIN-93 diet without (control) or with supplemental iron (Fe), EPA/DHA, or Fe+EPA/DHA for 3 weeks. Mice supplemented with Fe or EPA/DHA had lower soluble transferrin receptor, ferritin and hepcidin than controls, but these effects were attenuated in Fe+EPA/DHA mice. EPA/DHA increased inflammation-resolving lipid mediators and lowered lung IL-1α, IFN-γ, plasma IL-1β, and TNF-α. Fe lowered lung IL-1α, IL-1β, plasma IL-1β, TNF-α, and IL-6. However, the cytokine-lowering effects in the lungs were attenuated with Fe+EPA/DHA. Mice supplemented with EPA/DHA had lower lung bacterial loads than controls, but this effect was attenuated in Fe+EPA/DHA mice. Thus, individually, post-infection EPA/DHA and iron supplementation lowered systemic and lung inflammation and mitigated anemia of infection in TB, but not when combined. EPA/DHA also enhanced bactericidal effects and could support inflammation resolution and management of anemia.

Not only is glutamine deficiency an independent predictor of mortality in intensive care unit (ICU) patients, but glutamine supplementation is also recommended for its proven outcome benefits. However, recent data suggest that early glutamine supplementation in certain patient groups increase mortality. The aim of this study was to investigate plasma glutamine levels of adult ICU patients in the South African setting and to determine relationships between glutamine levels, gender, diagnostic categories and selected inflammatory markers. The data from this study will be used as baseline measurement to support a large scale study that will be undertaken in the South African ICU population. This cross-sectional, analytical study included 60 mixed adult ICU patients within 24 h post ICU admission. Plasma glutamine levels were determined on admission. The relationship between glutamine levels, Interleukin-6 (IL-6) and C-reactive protein (CRP); as well as gender- and diagnosis-related differences in glutamine levels were also investigated. A non-parametric ROC curve was computed to determine the CRP concentration cut-off point above which glutamine becomes deficient. The median plasma glutamine level (497 μmol/L) was in the normal range; however, 38.3 % (n = 23) of patients had deficient (930 μmol/L). No significant difference could be detected between glutamine levels and gender or diagnosis categories as a group. When only the medical and surgical categories were compared, the median plasma glutamine level of the medical patients were significantly lower than that of the surgical patients (p = 0.042). Glutamine showed inverse associations with CRP levels (r = −0.44, p < 0.05) and IL-6 concentrations (r = −0.23, p = 0.08). A CRP cut-off value of 95.5 mg/L was determined above which glutamine levels became deficient. About a third of patients (38 %) were glutamine deficient on admission to ICU, whereas some presented with supra-normal levels. While glutamine levels correlated inversely with inflammatory markers, and a CRP value of above 95.5 mg/L indicated potential glutamine deficiency, the clinical application of this finding needs further investigation.

Non-resolving inflammation is characteristic of tuberculosis (TB). Given their inflammation-resolving properties,n-3 long-chain PUFA (n-3 LCPUFA) may support TB treatment. This research aimed to investigate the effects ofn-3 LCPUFA on clinical and inflammatory outcomes ofMycobacterium tuberculosis-infected C3HeB/FeJ mice with either normal or lown-3 PUFA status before infection. Using a two-by-two design, uninfected mice were conditioned on either ann-3 PUFA-sufficient (n-3FAS) or -deficient (n-3FAD) diet for 6 weeks. One week post-infection, mice were randomised to eithern-3 LCPUFA supplemented (n-3FAS/n-3+ andn-3FAD/n-3+) or continued onn-3FAS orn-3FAD diets for 3 weeks. Mice were euthanised and fatty acid status, lung bacterial load and pathology, cytokine, lipid mediator and immune cell phenotype analysed.n-3 LCPUFA supplementation inn-3FAS mice lowered lung bacterial loads (P= 0·003), T cells (P= 0·019), CD4⁺T cells (P= 0·014) and interferon (IFN)-γ(P< 0·001) and promoted a pro-resolving lung lipid mediator profile. Compared withn-3FAS mice, then-3FAD group had lower bacterial loads (P= 0·037), significantly higher immune cell recruitment and a more pro-inflammatory lipid mediator profile, however, significantly lower lung IFN-γ, IL-1α, IL-1βand IL-17, and supplementation in then-3FAD group provided no beneficial effect on lung bacterial load or inflammation. Our study provides the first evidence thatn-3 LCPUFA supplementation has antibacterial and inflammation-resolving benefits in TB when provided 1 week after infection in the context of a sufficientn-3 PUFA status, whilst a lown-3 PUFA status may promote better bacterial control and lower lung inflammation not benefiting fromn-3 LCPUFA supplementation.