What is the role of iron supplementation in active tuberculosis infections? Does it worsen or improve cure rates?

Comment by InpharmD Researcher

Published studies have not found iron supplementation to be either beneficial or harmful in patients with active tuberculosis, though this may be influenced by the use of various forms, dosages, and durations of iron. One study has found iron supplementation to be well-absorbed only after tuberculosis treatment and not during. Regardless, iron deficiency and anemia have been found as strong predictors of mortality and increased risk of tuberculosis recurrence. Target levels for serum iron concentrations in this patient population were not identified within literature.

Background

A recent review described the association between iron status and clinical outcomes and iron supplementation in patients with tuberculosis. The relationship between tuberculosis and anemia is complicated, and the presence of anemia in tuberculosis patients is linked to poor outcomes. However, both iron deficiency as well as excess iron may increase susceptibility to and progression of tuberculosis. Several iron metabolism pathways have been indicted for anemia of infection, including hepcidin-mediated iron sequestration, the inflammatory inhibition of erythropoiesis and a shorter life cycle of erythrocytes. Iron biomarkers associated with the progression of tuberculosis include plasma or serum ferritin levels, sputum positivity, and hepcidin. Limited preclinical data have observed inconsistent results in animal studies, and few clinical trials are currently available to provide insight into iron supplementation in tuberculosis patients. One small study examined iron supplementation in two iron-deficient tuberculosis patients, finding increased disease activity resulting from iron supplementation; similarly, another study provided similar outcomes, finding dietary iron intake plus elevated macrophage iron stores were positively correlated with active disease and 1.3 fold increased hazard ratio of mortality. Another case-study also observed activation of tuberculosis with intravenous iron administration. Conversely, another study has shown supplementation with 75 mg of ferrous fumarate twice daily resulted in elevated circulating hemoglobin, total mean cell volume, erythrocyte count and packed cell count at one month in patients with pulmonary tuberculosis. A final study provided insight regarding iron metabolism in tuberculosis patients undergoing treatment, finding that iron supplementation in tuberculosis patients should be initiated only upon completion of tuberculosis treatment, if still needed for patients remaining anemia, as this is the point where absorption is most efficient. A summary of most relevant clinical studies is provided in Tables 1 and 2. [1], [2], [3], [4], [5], [6]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the role of iron supplementation in active tuberculosis infections? Does it worsen them vs improve cure rates? What are the target blood iron levels for a patient with active tuberculosis?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Summary of studies evaluating iron supplementation in active tuberculosis infections
Reference/Design	Population	Intervention	Results
Cercamondi et al., 2021 Prospective, single-center cohort study	N= 18 Inclusion: Aged 16-45 years; sputum smear-positive for TB and no rifampin resistance via GeneXpert Mycobacterium tuberculosis/RIF; body weight > 40 kg; not severely anemia (Hb > 70 g/L); HIV-negative; malaria-free; negative pregnancy test and not breastfeeding Exclusion: Not described	Patients in Tanzania with TB were studied at baseline and then every 2 weeks throughout treatment. PO and IV iron tracers were administered at baseline, after intensive phase (at weeks 8 or 12) and after completion of treatment (at week 24). Patients were not allowed to take mineral or vitamin supplements up to two weeks prior and during the study. Treatment was according to Tanzanian national TB guidelines, in which there was an 8-week intensive phase (daily PO isoniazid, rifampicin, ethambutol, and pyrazinamide), followed by 16 weeks of daily isoniazid and rifampicin. Patients who were TB sputum-negative by week 8 received the second isotope administration, while those who were sputum-positive received the second isotope administration at week 12. The third isotope was delivered at week 24.	Prior to treatment, hepcidin and ERFE were greatly elevated, with negligible iron absorption. Hepcidin and IL-6 decreased ~70% by week 2 (p< 0.01). ERFE did not significantly decrease until week 8 (p< 0.01). Iron absorption increased ~20-fold after treatment, with an Hb increase of ~25% (p< 0.001 for both). By week 14, serum iron was significantly increased (p< 0.005). Authors' Conclusion: Iron is well-absorbed only after tuberculosis treatment and supplementation should be reserved for patients remaining anemic after treatment.
Isanaka et al., 2012 Prospective, randomized, placebo-controlled trial	N= 887 No anemia or iron deficiency (n= 135) Iron deficiency without anemia (n= 111) Anemia without iron deficiency (n= 182) Iron deficiency anemia (n= 256) Inclusion: ≥2 positive sputum smears for AFB in direct microscopy Exclusion: Baseline Hb ≤ 70 g/L; history of >1 mo of TB treatment in the previous year	Patients in Tanzania were randomized and stratified by HIV status to receive daily micronutrients or placebo concurrent with 8 months of anti-TB treatment per the Tanzania National Tuberculosis and Leprosy Program guidelines. Resistance to anti-TB drugs in this population was low (5%). Sputum was collected at baseline, 1, 2, 5, 8, and 12 months after initiation as well as every 6 months after until end of follow-up. Micronutrient supplementation was comprised of 1,500 μg of retinol, 20 mg of thiamin, 20 mg of riboflavin, 25 mg of vitamin B-6, 100 mg of niacin, 50 μg of vitamin B-12, 500 mg of vitamin C (niacinamide ascorbate and ascorbic acid), 200 mg of vitamin E (racemic-α-tocopheryl acetate), 0.8 mg of folic acid, and 100 μg of selenium.	No association was found between anemia or iron deficiency without anemia at baseline and risk of treatment failure 1 month after initiation. However, anemia without iron deficiency associated with increased risk of TB recurrence (adjusted RR 4.10; 95% CI 1.88-8.91; p< 0.001). Adjusted RR of death: Iron deficiency within anemia: 2.89; 95% CI 1.53-5.47; p= 0.001 Anemia without iron deficiency: 2.72; 95% CI 1.50-4.93; p= 0.001 Iron deficiency anemia: 2.13; 95% CI 1.10-4.11; p= 0.02 Authors' Conclusion: Both iron deficiency and anemia strongly predicted mortality and HIV disease progression and that anemia without iron deficiency was associated with increased risk of TB recurrence.
Das et al., 2003 Prospective, single-center, placebo-controlled study	N= 129 Placebo (n= 43) Fe-supplemented (n= 43) Fe+other hematinics-supplemented (n= 43) Inclusion: Adult male patients; aged 15-60 years; pulmonary TB; Hb 80-110 g/L Exclusion: Female patients; ages < 15 years and > 60 years; critically ill patients or patients with disseminated TB; massive hemoptysis or severe anemia	Patients in India with TB were matched using age and socioeconomic status against healthy subjects as controls. Patients were hospitalized for the initial 2 months of treatment to be under supervision, and then afterwards were discharged with instructions to continue maintenance therapy. Initial therapy consisted of PO ethambutol 800 mg, isoniazid 300 mg, rifampicin 450 mg, and pyrazinamide 1,500 mg daily, 30 min before breakfast. Maintenance therapy consisted of rifampicin 450 mg and isoniazid 300 mg once daily. Micronutrient supplementation was administered twice daily prior to breakfast and dinner. Supplementation consisted of one of the following: placebo containing 75 mg sucrose; ferrous fumarate containing 75 mg elemental Fe; ferrous fumarate containing 75 mg elemental Fe with other hematinics (zinc sulfate 25 mg, L-histidine hydrochloride 2 mg, lysine hydrochloride 12.5 mg, glycine hydrochloride 5 mg, thiamine 2.5 mg, riboflavin 1.5 mg, pyridoxine 0.75 mg, cyanocobalamin 1.25 mg, ascorbic acid 20 mg, folic acid 0.25 mg) After discharge from the hospital, supplements were stopped and patients advised to continue usual diet.	Blood hemoglobin concentration, MCV, and PCV were significantly higher at 1 month in both Fe groups vs. placebo group Difference was not significant at 2 and 6 months Serum Fe and Fe saturation of transferrin were significantly higher in both Fe groups vs. placebo up to 2 months Difference was not significant at 6 months Radiological and clinical improvement similar in all groups. Authors' Conclusion: These observations suggest that Fe supplementation in mild to moderate anemia associated with pulmonary tuberculosis accelerated the normal resumption of hematopoiesis in the initial phases by increasing Fe saturation of transferrin. However, consistent improvement of hematological status was dependent only on the improvement of the disease process.
Gangaidzo et al., 2001 Prospective, single-center, case control study	N= 196 Patients with TB (n= 98) Control patients (n= 98) Inclusion and exclusion criteria were not described.	Patients in Africa with pulmonary TB were matched against control subjects by age, sex, and area of residence. Patients were hospitalized for 2 months and treated with isoniazid 300 mg/day, rifampicin 10 mg/kg/d, ethambutol 25 mg/kg/d, and streptomycin 15 mg/kg/d. Then, isoniazid and rifampicin were continued for four additional months outpatient. Patients were followed up to 9 months after treatment initiation. Amount of traditional home-prepared beer consumed over a patient's lifetime was used to indicate dietary iron exposure; increased dietary iron was defined as an estimated lifetime consumption of >1000 L of traditional beer.	Traditional beer exposure was associated with increased iron stores. Increased dietary iron associated with increased odds of developing active TB by 3.5-fold (95% CI 1.4-8.9; p= 0.009). Increased dietary iron associated with increase in estimated hazard ratio of death by 1.3-fold (95% CI 0.4-6.4; p= 0.2). Authors' Conclusion: These findings are consistent with the hypothesis that elevated dietary iron may increase the risk of active pulmonary tuberculosis.
Abbreviations: AFB, acid-fast bacilli; CI, confidence interval; ERFE, erythroferrone; Fe, iron; Hb, hemoglobin; IV, intravenous; MCV, mean corpuscular volume; PCV, packed cell volume; PO, oral; RR, risk ratio; TB, tuberculosis

References:

[1] Cercamondi CI, Stoffel NU, Moretti D, et al. Iron homeostasis during anemia of inflammation: a prospective study of patients with tuberculosis. Blood. 2021;138(15):1293-1303. doi:10.1182/blood.2020010562
[2] Isanaka S, Mugusi F, Urassa W, et al. Iron deficiency and anemia predict mortality in patients with tuberculosis. J Nutr. 2012;142(2):350-357. doi:10.3945/jn.111.144287
[3] Das BS, Devi U, Mohan Rao C, Srivastava VK, Rath PK, Das BS. Effect of iron supplementation on mild to moderate anaemia in pulmonary tuberculosis. Br J Nutr. 2003;90(3):541-550. doi:10.1079/bjn2003936
[4] Gangaidzo IT, Moyo VM, Mvundura E, et al. Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis. 2001;184(7):936-939. doi:10.1086/323203

Clinical studies investigating iron supplementation in TB patients.
Reference	Participants	Iron intervention	Outcome
Devi et al.	n = 117 male PTB patients 15–60 years old and Hb of 80–110 g/L n = 50 healthy male controls matched for age and socio-economic status.	1 capsule twice/ day of (1) placebo containing 75 mg of sucrose; (2) ferrous fumarate containing 75 mg of elemental Fe; (3) ferrous fumarate containing 75 mg of elemental Fe with other hematinics for 2 months while hospitalized.	↑ Hb, MCV and PCV at 1 month in both Fe-supplemented groups. This difference disappeared at 2 and 6 months. Serum Fe and Fe saturation of transferrin was ↑ in both Fe-supplemented groups for up to 2 months. Radiological and clinical improvements similar in all three groups.
Cercamondi et al.	n = 18 mostly anemic men and women aged 16–45 years old with a positive sputum smear confirmed by gene expert.	Test meal with 6mg of ⁵⁷Fe iron as ferrous sulphate administered at baseline then 8- and 24-weeks post-treatment. At baseline intravenous infusion with ⁵⁴Fe or ⁵⁸Fe as Fe³⁺Ci, after a meal.	Significant ↓ in inflammation markers: AGP, CRP and IL-6, and 70% ↓ in hepcidin at 2 weeks. Hemoglobin ↑ and anemia prevalence ↓ from 89% to 22%. TSAT ↑ and ferritin ↓ significantly but sTfR did not change from baseline until treatment completion. Negative correlation between hepcidin and serum iron, indicating Fe sequestration during infection, weakened upon treatment. At baseline, inflammation resulted in Fe sequestration and inhibited absorption and erythropoiesis. With treatment, hepcidin was suppressed and erythropoiesis upregulated for recovery of Hb. Fractional Fe absorption increased 10- and 20-fold as infection resolved.
Fe: iron, Fe³⁺Ci: iron citrate, Hb: hemoglobin, IL: interleukin, MCV: mean cell volume, PCV: packed cell volume, PTB: pulmonary TB, sTfR: soluble transferrin receptor, TB: tuberculosis, TSAT: transferrin saturation, ↑: higher, ↓: lower.

References:

Adapted from:
Nienaber A, Uyoga MA, Dolman-Macleod RC, Malan L. Iron Status and Supplementation during Tuberculosis. Microorganisms. 2023;11(3):785. Published 2023 Mar 18. doi:10.3390/microorganisms11030785