Can Iron Worsen Infection?

Question

Should iron supplementation be continued in patients with infection?

Response from Sarah F. Hale, PharmD
Pharmacy Practice Resident, Pharmacy Department, Albany Medical Center, Albany, New York

Iron serves as an essential nutrient for metabolic pathways in both humans and microorganisms. Pathogenic microorganisms, including bacteria, fungi, and protozoa, require iron for growth and proliferation. As a defense strategy, hosts have developed numerous mechanisms to reduce the availability of iron to invading pathogens. Therefore, the decision to supplement iron in patients with infections requires careful consideration of risk vs benefit.

Iron-deficiency anemia is associated with a relatively poor prognosis in multiple disease states, including chronic kidney disease and cancer. Replacement therapy often is warranted to maintain adequate systemic oxygenation and promote erythropoiesis. In addition to its role in oxygen transport and metabolic pathways, iron plays a pivotal role in human immune function by promoting lymphocyte activation and proliferation. On the other hand, iron overload can have immune-debilitating effects by inhibiting neutrophil phagocytosis and proliferation.

Iron homeostasis is maintained through careful regulation of duodenal absorption and recycling of iron stores. Under normal physiologic conditions, iron is not readily accessible in the host for use by invading pathogens. Nearly 75% of host iron is found in erythrocyte hemoglobin, with the remainder either stored intracellularly as ferritin or bound tightly to extracellular proteins such as transferrin.

Infection and inflammation alter iron homeostasis through immune-mediated mechanisms that further restrict the supply of readily available iron. Cytokines stimulate the acute-phase protein hepcidin to suppress absorption of dietary iron, which may be accompanied by an increase in reticuloendothelial iron storage. These iron-withholding strategies serve as an effective natural defense against pathogens, and iron supplementation during infection may overcome these protective strategies.

To acquire iron, invading microbes have evolved mechanisms to overcome host defense strategies. Escherichia coli, Klebsiella pneumoniae, and Salmonella species secrete iron chelators, known as siderophores, to compete with transferrin for available iron. Staphylococcus aureus uses nonsiderophore mechanisms to acquire iron from hemoglobin. By secreting hemolytic toxin, S aureus lyses erythrocytes to release hemoglobin, which binds to a surface receptor on the bacteria. Iron is transported as heme into the bacterial cell for use as a nutrient.

In vitro evidence suggests that increased iron availability promotes bacterial growth and virulence. Risk for infection with intravenous (IV) iron has also been supported in limited animal studies. For example, Zager and colleagues demonstrated in a murine model of E coli sepsis that administration of IV iron sucrose was associated with a mortality rate of nearly 60%.

No clinical trials have evaluated the clinical impact of iron supplementation in patients with active infections. However, the relationship between iron and infection has been investigated in patient populations at high risk for infection, such as chronic kidney disease and organ transplantation. Teehan and colleagues evaluated iron storage levels in hemodialysis patients receiving IV iron and found that patients with replete iron indices were at increased risk for bacteremia compared with patients having deficient iron stores. Serum iron markers were also associated with risk for infectious complications and death in patients after liver transplantation.

Limited clinical data suggest potential harm from iron supplementation, making its use in patients with or at high risk for serious infection a concern. The ability of iron to enhance microbial growth and affect host immune function, data from animal studies, and observational studies in humans support the potential for harm. Whether using oral or IV administration, the risks of iron supplementation may outweigh the benefit of treating anemia in many infected patients.

Avoiding iron supplementation in patients at high risk for infection, such as neutropenic or posttransplant patients, and during active or resistant infection is reasonable given the plausible biologic mechanisms that iron may promote microbial growth and disrupt the body’s neutrophil immune response. However, further clinical research is needed to fully elucidate the complex interactions between iron, immunity, and infection.