Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis

Schӧn, Thomas; Eliáš, Daniel; Moges, Feleke; Melese, Endalkachew Belayneh; Tessema, Tesfaye Sisay; Stendahl, Olle; Britton, Sven; Sundqvist, Tommy

doi:10.1183/09031936.03.00090702

Cited by 77 publications

(61 citation statements)

References 27 publications

(33 reference statements)

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“…This represents an RESEARCH important incremental step in knowledge and contributes to policy relevant evidence. Symptoms improve with tuberculosis treatment, and all but one study 24 have failed to show a significant additional improvement with adjunctive nutrition. 21 26 Early sputum clearance contributes to a decreased period of infectiousness and can have a major influence on tuberculosis control.…”

Section: Conflicting Evidence Of Effectiveness In Previous Trialsmentioning

confidence: 99%

Food incentives to improve completion of tuberculosis treatment: randomised controlled trial in Dili, Timor-Leste

Martins

Morris

Kelly

2009

BMJ

110

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Objective To determine the effectiveness of the provision of whole food to enhance completion of treatment for tuberculosis.Design Parallel group randomised controlled trial.Setting Three primary care clinics in Dili, Timor-Leste.Participants 270 adults aged ≥18 with previously untreated newly diagnosed pulmonary tuberculosis.Main outcome measures Completion of treatment (including cure). Secondary outcomes included adherence to treatment, weight gain, and clearance of sputum smears. Outcomes were assessed remotely, blinded to allocation status.Interventions Participants started standard tuberculosis treatment and were randomly assigned to intervention (nutritious, culturally appropriate daily meal (weeks 1-8) and food package (weeks 9-32) (n=137) or control (nutritional advice, n=133) groups. Randomisation sequence was computer generated with allocation concealment by sequentially numbered, opaque, sealed envelopes.Results Most patients with tuberculosis were poor, malnourished men living close to the clinics; 265/270 (98%) contributed to the analysis. The intervention had no significant beneficial or harmful impact on the outcome of treatment (76% v 78% completion, P=0.7) or adherence (93% for both groups, P=0.7) but did lead to improved weight gain at the end of treatment (10.1% v 7.5% improvement, P=0.04). Itch was more common in the intervention group (21% v 9%, P<0.01). In a subgroup analysis of patients with positive results on sputum smears, there were clinically important improvements in one month sputum clearance (85% v 67%, P=0.13) and completion of treatment (78% v 68%, P=0.3).Conclusion Provision of food did not improve outcomes with tuberculosis treatment in these patients in Timor-Leste. Further studies in different settings and measuring different outcomes are required.Trial registration Clinical Trials NCT0019256.

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Section: Conflicting Evidence Of Effectiveness In Previous Trialsmentioning

confidence: 99%

Food incentives to improve completion of tuberculosis treatment: randomised controlled trial in Dili, Timor-Leste

Martins

Morris

Kelly

2009

BMJ

110

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“…L-arginine supplementation, aimed at enhancing NOdependent immunity against TB, was attempted in M. tuberculosis-infected patients in two independent studies. Schö n et al (44) treated TB patients with oral L-arginine and observed subtle benefits, including increased sputum conversion and reduced cough and chest pain in HIV 2 patients. Yet a more recent study found no clinical benefit in supplementing L-arginine to M. tuberculosis-infected patients (45).…”

Section: Discussionmentioning

confidence: 99%

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Rapovy¹,

Zhao²,

Bricker³

et al. 2015

The Journal of Immunology

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Microbicidal NO production is reliant on inducible NO synthase–mediated l-arginine metabolism in macrophages (MΦs). However, l-arginine supply can be restricted by arginase activity, resulting in inefficient NO output and inhibition of antimicrobial MΦ function. MΦs circumvent this by converting l-citrulline to l-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine MΦs supplied l-arginine, l-citrulline, or both amino acids. Using liquid chromatography–tandem mass spectrometry, we determined that l-arginine synthesized from l-citrulline was less effective as a substrate for arginase-mediated l-ornithine production compared with l-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette–Guérin infection and costimulation with IFN-γ, we observed that MΦ arginase activity did not inhibit production of NO derived from l-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in l-arginine. Furthermore, we found that arginase-expressing MΦs preferred l-citrulline over l-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of l-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.

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“…Macrophages in the lungs of humans (6,7) and macaques (8) with TB express functional iNOS. Correlative evidence suggests that the action of iNOS may contribute to human control of TB (1,3,9,10).…”

mentioning

confidence: 99%

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

Cunningham‐Bussel¹,

Zhang

Nathan³

2013

Proc. Natl. Acad. Sci. U.S.A.

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In high enough concentrations, such as produced by inducible nitric oxide synthase (iNOS), reactive nitrogen species (RNS) can kill Mycobacterium tuberculosis (Mtb). Lesional macrophages in macaques and humans with tuberculosis express iNOS, and mice need iNOS to avoid succumbing rapidly to tuberculosis. However, Mtb's own ability to produce RNS is rarely considered, perhaps because nitrate reduction to nitrite is only prominent in axenic Mtb cultures at oxygen tensions ≤1%. Here we found that cultures of Mtbinfected human macrophages cultured at physiologic oxygen tensions produced copious nitrite. Surprisingly, the nitrite arose from the Mtb, not the macrophages. Mtb responded to nitrite by ceasing growth; elevating levels of ATP through reduced consumption; and altering the expression of 120 genes associated with adaptation to acid, hypoxia, nitric oxide, oxidative stress, and iron deprivation. The transcriptomic effect of endogenous nitrite was distinct from that of nitric oxide. Thus, whether or not Mtb is hypoxic, the host expresses iNOS, or hypoxia impairs the action of iNOS, Mtb in vivo is likely to encounter RNS by producing nitrite. Endogenous nitrite may slow Mtb's growth and prepare it to resist host stresses while the pathogen waits for immunopathology to promote its transmission.

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Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis

Cited by 77 publications

References 27 publications

Food incentives to improve completion of tuberculosis treatment: randomised controlled trial in Dili, Timor-Leste

Food incentives to improve completion of tuberculosis treatment: randomised controlled trial in Dili, Timor-Leste

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

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