The biologic plausibility argument rests on the fact that high iron concentrations have two negative effects in the context of infection. First, iron appears to impair the function of both neutrophils and T-cells. Patients on dialysis with iron overload have been shown to have reduced neutrophil function and phagocytosis. Similarly, impaired PMN function has been seen when neutrophils from healthy controls are incubated with ferric compounds. However, it should be pointed out that iron is vital for normal neutrophil function and individuals with iron deficiency also have impaired function. Clearly there is a sweet spot for neutrophil function but we are uncertain what it might be.
The evidence for a clinical effect for iron infusions on increasing infection frequency and severity is based on two separate strands (well summarized here). First, multiple observational studies have shown that high ferritin levels (particularly when >1000) are associated with an increased frequency of bacterial infections. There are clear limitations here. First, this finding is not consistent across all studies (4 of 14 studies did not find this association). Second, ferritin is an acute phase reactant itself and is not necessarily always elevated due to iron overload. Third, most of these studies were done in the pre-ESA era where much of this iron overload may have been due to transfusions. Finally, all of these studies were observational. As such, it is impossible to say if the risk of infection may not have been due to other factors which also lead to a higher iron requirement/ferritin levels.
The second strand of evidence is observational studies showing that higher doses or frequency of iron infusions are associated with a higher risk of future infection. Again, all of these studies are observational and so the same criticism as above applies. Similarly, there is a lack of consistent results across all studies although it should be said that the largest studies with the most patients did find an effect. However, in the most recent large study of ~120,000 medicare patients, while there was an increase in the risk of infection with higher doses of iron, the HR for infection for high vs. low dose was only 1.05. None of these studies examined the effect of ongoing iron administration on the severity of infection in dialysis patients. One could say that they are an argument against using iron in dialysis patients (which is not realistic) rather than arguments for stopping during an infection.
Today’s email is thus especially welcome. This is a study published in CJASN which examines the relationship between ongoing iron use and severity of infection in Medicare patients. In total, 22,820 individual who had received iv iron in the 14 days prior to admission with a bacterial infection were included. 10% of these patients also received the iron while they were inpatients or shortly afterwards and were included as the cases. The controls were individuals who did not receive iron (i.e the iron was stopped per guidelines). The receipt of iv iron was not associated with increased short or long term mortality, LOS or likelihood of readmission in the next 30 days.
What is the explanation for this finding? One important question is why those 10% of patients did not stop iv iron after admission despite the clear consensus suggesting that it should be done? Looking at the table of demographic and clinical characteristics, there was nothing sticking out that suggested a reason for this difference and there may have been unmeasured characteristics that explained the difference. The outcomes were hard (as they would have to be given the source of the data) but may miss some subtle differences in outcomes related to the infection itself. That said, mortality and readmission are probably the most important outcomes. Finally, again this study was observational and needs to be interpreted as such.
All that said, this is an excellent addition to the literature which raises many more questions that it answers. These are important questions – too much of what we do in nephrology is based on consensus rather than clinical trials. Perhaps this might stimulate someone to do the necessary trial to answer this question once and for all.