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Is iron therapy for anemia harmful in the setting of infection?

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The harmful effects of iron therapy in the setting of infection are more theoretical than observed, with no irrefutable data to support them. On the other hand, there are also no convincing data to support the benefit of this therapy. If iron is to be used, frequent monitoring of serum iron markers is prudent to avoid iron overload during treatment.

ANEMIA OF INFLAMMATION IS COMPLEX

Anemia that develops in the hospital, especially in the setting of infection or inflammation, is similar hematologically to anemia of chronic disease, except for its acute onset.1

The pathogenesis of anemia in such settings is complex, but the most important causes of this common syndrome include shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the bone marrow to endogenous erythropoietin, and impaired iron metabolism mediated through the action of inflammatory cytokines.2,3 Other important causes include nutritional deficiencies (iron, vitamin B12, and folic acid)4 and blood loss.5,6

Moreover, anemia of inflammation may be difficult to differentiate from iron-deficiency anemia because the serum iron markers are unreliable in inflammation.1

The reported prevalence of anemia during hospitalization has ranged from 55% on hospital wards7 to 95% in intensive care units.8

Transfusion of packed red blood cells is the fastest treatment for anemia in hospitalized patients and it is the one traditionally used, but many concerns have been raised about its efficacy and adverse effects.9 Erythropoietin, with or without iron therapy, has emerged as an alternative in treating anemia of inflammation.10,11

IRON THERAPY

Iron is widely used to treat anemia, especially in hospitalized patients and those with chronic kidney disease.2 The intravenous route is more commonly used than the oral route, since it has faster action, is better tolerated, and has better bioavailability.1,2

Controversy over benefit

Whether iron supplementation increases the red blood cell mass and reduces the need for blood transfusion is controversial.10,12 Pieracci et al13 documented these benefits in critically ill surgical patients, whereas van Iperen et al11 did not find such benefits in critically ill patients receiving intravenous iron and erythropoietin.

Harmful effects

Some authors1,14 object to giving iron to hospitalized patients (especially critically ill patients) who have infections on the grounds that it is risky, although definitive evidence is lacking.15

Most of the harmful effects of iron have been linked to elevated serum ferritin levels and to non–transferrin-bound iron, more than to iron per se.16 Ferritin is an acute-phase reactant; thus, ferritin levels may be elevated in inflammation and infection regardless of the body iron status.1

Anaphylactic reaction. This rare complication of iron dextran therapy is not much of a concern at present with the newer formulations of iron such as iron gluconate and iron sucrose.16

Oxidative stress. Iron-derived free radicals can cause a rise in inflammatory cytokine levels, especially if the ferritin level is elevated (> 500 μg/L). This cytokine rise is worrisome, as it may have acute detrimental effects on cellular homeostasis, leading to tissue injury,15 while chronically it might be related to enhanced atherosclerosis and cardiac disease.16

Iron overload. In vitro and animal studies have documented an association between elevated ferritin levels (500–650 μg/L) and decreases in T-cell function, polymorphonuclear neutrophil migration, phagocytosis, and bacterial eradication.15 Studies in hemodialysis patients have identified iron overload as an independent risk factor for bacterial infection, but the confounding role of the dialysis process cannot be disregarded.17,18

Bacterial growth. Many bacteria depend on iron for their growth; examples are Escherichia coli; Klebsiella, Pseudomonas, Salmonella, Yersinia, Listeria, and Staphylococcus species; and Haemophilus influenzae. In vitro studies have linked increased bacterial growth with increased transferrin saturation in plasma.15,19

Iron therapy and infection risk

The theory linking iron with risk of infection arose from the observation that patients with hemochromatosis are more susceptible to certain bacterial infections, especially Vibrio vulnificus.20 A few human studies, most of them in chronic hemodialysis patients, have examined the relation between iron therapy and infection risk, with conflicting results.21–26 Multiple studies13,19,21,22,25–27 found no relation between iron therapy and risk of infection or death.

Canziani et al23 found that the risk of infection was higher with higher intravenous doses of iron than with lower doses.

Collins et al24 found a higher risk of sepsis and hospitalization in patients who received iron for a prolonged duration (5–6 months) than in those who did not.

Feldman et al,27 in their report of a study of iron therapy in hemodialysis patients, suggested that previously observed associations between iron administration and higher death rates may have been confounded by other factors.

Iron therapy in concurrent infection

There are no data in humans on the effects of iron therapy on outcomes during concurrent infection or sepsis.15,28 However, mice with sepsis had worse outcomes when treated with intravenous iron.28

A CONUNDRUM IN CLINICAL PRACTICE

After reviewing the available literature, we concur with most of the authors1,15,16,18,19,29 that despite the worrisome theoretical adverse effects of iron therapy in patients with infections, there are no convincing data to support those fears. On the other hand, there are also no convincing data to favor its benefit.

More definitive studies are needed to answer this question, which has been a conundrum in clinical practice. Patients who might benefit from iron therapy should not be deprived of it on the basis of the available data. Frequent monitoring of serum iron markers during therapy to avoid iron overload seems prudent.

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