Should iron supplementation be continued in patients
with infection?
Response from Sarah F. Hale, PharmD |
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.[1] Therefore,
the decision to supplement iron in patients with infections requires careful
consideration of risk vs benefit.[2]
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.[3] 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.[4]
On the other hand, iron overload can have immune-debilitating effects by
inhibiting neutrophil phagocytosis and proliferation.[2,4-6]
Iron homeostasis is maintained through careful
regulation of duodenal absorption and recycling of iron stores.[7] 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.[7]
Infection and inflammation alter iron homeostasis
through immune-mediated mechanisms that further restrict the supply of readily
available iron.[2]
Cytokines stimulate the acute-phase protein hepcidin to suppress absorption of dietary
iron, which may be accompanied by an increase in reticuloendothelial iron
storage.[1,2]
These iron-withholding strategies serve as an effective natural
defense against pathogens, and iron
supplementation during infection may overcome these protective strategies.[8]
To acquire iron, invading microbes have evolved
mechanisms to overcome host defense strategies.[6] Escherichia coli, Klebsiella
pneumoniae, and Salmonella species secrete iron
chelators, known as siderophores, to compete with transferrin for available
iron.[5] 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.[9]
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[10]
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[11]
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.[12]
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.
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