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Although gene sequencing has elucidated several mutations associated with mild cytopenias in older individuals, iron deficiency remains the most common cause of anemia. Oral iron has remained the frontline standard despite evidence that it is poorly tolerated, often ineffective, and frequently harmful. Studies of different formulations of intravenous iron have shown it effective, with marginal to no toxicity. Serious adverse events have not been described and the failure to address its administration in iron-deficient elderly patients is an unmet clinical need. This article outlines situations in which oral iron should be proscribed and offers an approach to administration of available formulations.

Iron deficiency is the commonest cause of anemia during pregnancy; however, its prevalence is highly determined by nutritional and socioeconomic status. Oral iron is the frontline therapy, but is often poorly tolerated. Awareness of the available intravenous formulations is essential for management. Before delivery, risk factors such as multiparity and heavy uterine bleeding increase the prevalence of iron deficiency and should be motivation for early diagnosis and treatment. Neonates born with iron deficiency have a statistically significant increment in both cognitive and behavioral abnormalities that persist after repletion, highlighting the need for heightened awareness of the diagnosis. A smartphone application providing information on nutrition and treatment is provided. New formulations of intravenous iron with carbohydrate cores, which bind elemental iron more tightly, minimize the release of labile free iron to allow complete replacement doses of intravenous iron in 15 to 60 minutes, facilitating and simplifying care.

Iron-deficiency anemia is the most common hematologic problem in the world. Although oral iron is often viewed as front-line therapy, extensive published evidence has accumulated that IV iron is superior, in both efficacy and safety, to oral iron in many clinical situations and should be introduced much sooner in the treatment paradigm of iron-deficient patients. In this chapter, we will review the formulations of IV iron that allow total complete replacement doses in 1 or 2 sessions including practical tips for administration. We realize safety concerns abound and therefore will analyze evidence based overstated concerns regarding serious adverse events highlighting unnecessary interventions for minor, self-limiting infusion reactions, which infrequently occur with intravenous iron administration. Recent data for the use of IV iron in a variety of clinic situations will be reviewed including women with heavy uterine bleeding, pregnancy, bariatric surgery, inflammatory bowel disease, and restless legs syndrome. Briefly discussed is the new frontier of IV iron’s use in the prevention of acute (high altitude) mountain sickness. It is clear that in many clinical situations IV iron is a new and improved standard of care offering advantages over oral iron in efficacy, toxicity, and convenience to patients and health care providers.

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

In the last several years, intravenous therapy with iron products has been more widely used. Although it has been a standard procedure in dialysis-associated anemia since the early 1990s, its use is expanding to a host of conditions associated with iron deficiency, especially young women with heavy uterine bleeding and pregnancy. Free iron is associated with unacceptable high toxicity inducing severe, hemodynamically significant symptoms. Subsequently, formulations that contain the iron as an iron carbohydrate nanoparticle have been designed. With newer formulations, including low-molecular-weight iron dextran, iron sucrose, ferric gluconate, ferumoxytol, iron isomaltoside, and ferric carboxymaltose, serious adverse events are rare.

Conditions known as iron-deficiency syndromes are very common in various patient populations, and they can adversely affect the outcomes of the patients, in addition to increasing their risk of getting transfused. Iron-deficiency syndromes include absolute iron deficiency (absence of storage iron), functional iron deficiency (when demand for iron exceeds the supply in face of intense stimulation erythropoiesis) and iron sequestration (in which existing storage iron becomes unavailable); these conditions often co-exist in hospitalised patients, making the diagnosis and management more difficult. Nonetheless, iron is emerging as a safe and effective therapy in patients suffering from these conditions. Notably, several intravenous iron formulations are available and they can be used safely and effectively to restore the body iron levels (possibly even in a single treatment episode). Data from ongoing clinical trials are expected to further establish the role of these products in treatment of patients with anaemia.

Recent guidance from the Centers for Medicare and Medicaid Services restricting erythropoiesis-stimulating agents (ESAs) in chemotherapy and cancer-related anemias has resulted in an increase in transfusions. Nine studies, without published contradictory evidence, have shown optimization of the response to ESAs by intravenous (IV) iron when the iron was added to the treatment of chemotherapy-induced anemia. The synergy observed, although greater in iron deficiency, was independent of pretreatment iron parameters. Three studies demonstrated decreased transfusions when IV iron is administered without ESAs. Discordant recommendations regarding IV iron currently exist among the American Society of Hematology/American Society of Clinical Oncology guidelines, the National Comprehensive Cancer Network, and the European Society of Medical Oncology. This discordance is at least partly the result of misconceptions about the clinical nature and incidence of adverse effects with IV iron. Other reasons for this discordance are presented in this review. Based on thousands of studied patients, we conclude that IV iron is safe and probably safer than most physicians realize. Education is needed relating to the interpretation of minor, subclinical infusion reactions that resolve without therapy. IV iron without ESAs may be an effective treatment for chemotherapy-induced anemia and warrants further study. We present evidence supporting the conclusion that baseline serum hepcidin levels may predict responses to IV iron, and we examine the published evidence supporting the conclusion that IV iron should be a standard addition to the management of chemotherapy and cancer-related anemia.

This section reviews the history, pharmacology, administration, efficacy, and toxicity of intravenous iron. Intravenous iron offers advantages over oral iron for the treatment of iron deficiency anemia across a wide range of disease states associated with absolute and functional iron deficiency. However, there remain concerns about the acute safety profiles of the available preparations and the potential for long-term toxicity with their repeated administration. Seven intravenous iron formulations are available. Confusion concerning the relative toxicities of the different formulations abounds. The similarities and differences are discussed. Iron repletion has been associated with adverse outcomes in infections. The relationship, if any, between intravenous iron administration and infections is reviewed. The potential advantages of total dose infusion (TDI), complete repletion in a single setting, are highlighted. A new paradigm for iron replacement therapy in iron deficiency anemia is presented.

Erythropoiesis-stimulating agents (ESAs) are no longer indicated for patients with anemia of cancer not on chemotherapy and for patients receiving chemotherapy for hemoglobin levels greater than 10 g/dL. Transfusions once again appear to be the standard of care; one study showed that the transfusion rate increased just 6 months after the implementation of the new National Coverage Decision on ESAs, and further increases are expected. However, transfusions can increase the morbidity and mortality in patients with cancer, depending on the red blood cell storage conditions. The role of intravenous iron remains largely undefined despite seven randomized clinical trials demonstrating that intravenous iron added to ESAs improves outcomes compared with ESAs alone. No clear recommendation is available regarding when iron supplementation should be provided.

Chemokines, including monokine induced by interferon-γ (Mig/CXCL9), are produced both in allografts and during the direct T-cell infiltration that mediates graft rejection. Neither the specific production nor contribution of allograft donor versus recipient Mig in allograft rejection is currently known. C57BL/6 mice with a targeted deletion in the Mig gene were used as both skin allograft donors and recipients in a class II major histocompatibility complex-mismatched graft model to test the requirement for donor- versus recipient-derived Mig for acute rejection. B6.Mig−/−allografts had a 10-day prolonged survival in B6.H-2bm12recipients when compared with wild-type C57BL/6 allograft donors, and B6.H-2bm12skin allografts had a 5-day prolonged survival in B6.Mig−/−versus wild-type recipients. Transplantation of B6.Mig−/−skin grafts onto B6.H-2bm12.Mig−/−recipients resulted in further prolonged allograft survival with more than 30% of the grafts surviving longer than 60 days. Prolonged allograft survival was also associated with delayed cellular infiltration into grafts but not with altered T-cell proliferative responses to donor stimulators. Immunohistochemical staining of allograft sections indicated that Mig is produced by both donor- and recipient-derived sources, but Mig from each of these sources appeared in different areas of the allograft tissue. These results therefore demonstrate the synergy of donor- and recipient-derived Mig in promoting T-cell infiltration into allografts.

It is estimated anemia affects over 30% of the world's population, with iron deficiency (ID) the overwhelmingly most common cause. Whether absolute due to blood loss and/or iron sequestration to underlying morbidity, the need for repletion especially in females, is a formidable medical issue. The diagnosis of iron deficient erythropoiesis has been traditionally based on the biochemical parameters ferritin and percent transferrin saturation (TSAT), mean cell volume and hemoglobin (Hb) concentration. In recent years, reticulocyte Hb content has emerged as a parameter helpful in identifying iron deficient erythropoiesis and informing a need, or lack thereof, for replacement.

ABSTRACTBackground:The incidence of anaemia is high in many chronic conditions, yet it often receives little attention.Scope/methods:A panel of international experts with experience in haematology, nephrology, oncology, rheumatology and pharmacy was convened to prepare strategic guidelines. A focused literature search was conducted after key issues had been identified. A series of recommendations was agreed, backed, wherever possible, by published evidence which is included in the annotations.Recommendations:Anaemia is a critical issue for patients with chronic diseases. Healthcare professionals need to recognise that anaemia is a frequent companion of cancer and chronic conditions such as rheumatoid arthritis and heart failure. It reduces patients' quality of life and can increase morbidity and mortality. Anaemia should be considered as a disordered process in which the rate of red cell production fails to match the rate of destruction which leads eventually to a reduction in haemoglobin concentration; this process is common to all chronic anaemias. The aim of anaemia management should be to restore patient functionality and quality of life by restoring effective red cell production. Blood transfusion can elevate haemoglobin concentration in the short term but does nothing to address the underlying disorder; red cell transfusion is, therefore, not an appropriate treatment for chronic anaemia. Patients with anaemia of chronic disease may benefit from iron therapy and/or erythropoiesis stimulating agents (ESAs). Intravenous iron should be considered since this can be given safely to patients with chronic diseases while intramuscular iron causes unacceptable adverse effects and oral iron has limited efficacy in chronic anaemia.Conclusion:The management of anaemia calls for the development of a specialist service together with education of all healthcare professionals and transfer of skills from areas of good practice. Improvement in the management of anaemia requires a fundamental change of attitude from healthcare professionals.

The 2-5A/RNase L system is a regulated RNA decay pathway that mediates some of the antiviral and tumor suppressor activities of the interferons. Previously, we demonstrated that RNase L-null mice have increased susceptibility to viral infections and are partially deficient in induced and spontaneous apoptosis. To determine if RNase L functions in cellular, as well as innate, immunity, skin allograft rejection and contact hypersensitivity (CHS) experiments were performed in RNase L+/+ and RNase L-/- mice. Although no consistent alterations in CHS were found, we did observe a delay of 5 days in the acute rejection of class II major histocompatibility complex (MHC) disparate skin allografts in mice lacking RNase L. Accordingly, histologic examinations of the allografts harvested from RNase L-/- mice revealed a dramatic reduction in inflammatory infiltrates, suggesting a delay in T-cell priming or a deficiency in immune cell trafficking. Results consistent with a proinflammatory role for RNase L extend the known functions of the 2-5A/RNase L system beyond innate immunity into some, but not all, types of cellular immunity.

Increased expression of chemokine mRNA is observed in allogeneic but not syngeneic skin grafts 3–4 days after transplantation. The recipient cells mediating this early inflammatory response in allografts remain unidentified.

Larvae of the aspen blotch miner, Phyllonorycter salicifoliella Chambers (Lepidoptera: Gracillariidae), feed within leaves of three host-tree species in north-central Minnesota, USA. Far more individuals occur on Populus tremuloides than on P. balsamifera or P. grandidentata. We tested whether this pattern of host use reflected variable performance among alternative hosts by examining survivorship, sources of mortality, pupal mass, feeding efficiency, and development time of miners on each tree species. We also determined foliar water, nitrogen, condensed tannin, and phenolic glycoside content of host trees to test if host-tree chemical attributes were responsible for differences in performance. There was no significant difference in egg-to-adult survival among miners on different hosts, although dominant sources of mortality did vary. Miners on P. grandidentata suffered less parasitism and more predation than those on the other hosts, even though most parasitoid species attacked miners on all hosts. The other performance parameters varied among host species, but not in a consistent pattern. Pupal mass was greatest on P. tremuloides and P. balsamifera, the hosts with comparatively high foliar nitrogen and low phenolic glycoside concentrations. However, feeding efficiency was greatest and development time shortest for miners on P. grandidentata. Thus, pupal mass was the only index of performance maximized on P. tremuloides, the most commonly used host. Infrequent occurrence of Phyllonorycter salicifoliella on P. grandidentata results in part from phenological differences between this and the other host species. Low oviposition rates on P. balsamifera are correlated with low abundance of this host at the study site and a phenolic glycoside profile different from that of the other host species.

To assess the accuracy of a simplified approach for the diagnosis of iron deficiency anemia (IDA) based on the complete blood cell count (CBC) and reticulocyte analysis.

Introduction: A litany of recent evidence supports the morbidity of intra-natal iron-deficiency anemia and its prodrome, iron deficiency. Oral iron administered during second and third trimesters does not get to the developing fetus if the mother is iron deficient. This is especially concerning as the rapidly developing fetal brain is in particular need of iron sufficiency. Intra-natal iron deficiency is associated with autism, schizophrenia and abnormal brain structure. The obstetrical literature reports an unacceptably high incidence of gastrointestinal adverse events with oral iron. The time iron honored standard in the United States for intravenous iron replenishment in gravidas is iron sucrose. While safe and effective, four to seven visits are required to accomplish what newer formulations can achieve with one.Methods: Ferumoxytol is a superparamagnetic iron oxide linked to polyglucose sorbitol carboxymethylether-binding elemental iron tightly allowing administration of complete replacement doses in 15–30 min. Herein, we report the results of 131 consecutive, non-selected, iron-deficient second- and third-trimester pregnant women who received either 510 mg of intravenous (IV) ferumoxytol twice or 1020 mg once.Results: Hemoglobin and iron parameter increments were highly statistically significant. No adverse events were reported. We report how a single infusion is safe and effective as the same dose over two visits, saving an unnecessary visit and IV placement, while reducing cost.Conclusion: Ferumoxytol represents an efficacious and safe method of administration of IV iron which improves convenience for patients and practitioners, and is cost saving due to fewer visits.Plain language summary One or two infusions of intravenous iron for iron deficiency or iron-deficiency anemia of pregnancy simplifies care This study was conducted to highlight the inconvenience of multiple doses of IV iron and how administering the same dose in one or two infusions simplifies care. We report how a single infusion is as safe and effective as the same dose over two visits, saving an unnecessary visit and IV placement, while reducing cost. This study supports a growing body of evidence, to date, unreported, with ferumoxytol in pregnancy, reporting improved convenience and decreased costs with higher doses of IV iron in one or two visits.

In the past 4 months, the Centers for Medicare & Medicaid Services (CMS) has imposed restrictions on the use of eryth- ropoiesis-stimulating agents (ESAs) in oncology. ESAs can no longer be used to treat patients with hemoglobin (Hb) levels of more than 10 grams/dL or patients with cancer-related anemia who are not on chemotherapy. New recommendations to deny coverage of patients receiving curative (adjuvant) chemotherapy and patients with metastatic breast and head and neck cancer have been made by the Oncology Drug Advisory Committee (ODAC) to the Food and Drug Administration (FDA). ESAs are contraindicated in patients with untreated absolute iron deficiency. No International Statistical Classification of Diseases and Related Health Problems, 9th revision, code exists for iron-restricted erythropoi- esis (functional iron deficiency). This omission is particularly important, as aptly pointed out by Shord and Cuellar1in this issue of JAPhA, because five of five recent publications in the oncology literature (see article by Shord and Cuel- lar) have shown a markedly improved Hb response, decreased time to target Hb, decreased ESA exposure for equivalent benefit, and huge cost savings when intravenous (I.V.) iron was added to ESA therapy. These benefits, in all five papers, were independent of the baseline iron parameters, serum iron, total iron binding capacity, and serum ferritin. Adverse events with I.V. iron were negligible in all of the studies.

Auerbach: AMAG Pharmaceuticals: Research Funding; Pharmacosmos A/S: Research Funding. Lykke:Pharmacosmos A/S: Employment.

Auerbach: AMAG Pharmaceuticals: Research Funding; Pharmacosmos A/S: Research Funding.

Background

Background: Intravenous (IV) iron is often used to treat iron deficiency anemia (IDA) in patients unresponsive to, or intolerant of, oral iron. IV iron has been associated with rare, but potentially serious acute hypersensitivity reactions (HSRs). The few randomized trials which assessed comparative risks of adverse events (AEs) with IV iron formulations are limited by small numbers and lack statistical power to identify differences in low frequency AEs such as HSRs. We have attempted to correct this deficit in the literature, by conducting a randomized double-blind clinical trial comparing two IV iron preparations.

Auerbach: AMAG Pharma: Consultancy, Research Funding; Pharmacosmos: Consultancy, Research Funding; American Regent/Luitpold: Consultancy.

Off Label Use: Total dose infusion of low molecular weight iron dextran is off label.

No relevant conflicts of interest to declare.

60 consecutive patients with IDA (hemoglobin [Hgb] <11 g/dL, transferrin saturation [TSAT] ≤19%, ferritin <100 ng/mL) and a history of intolerance of, or inadequate response to oral iron, received 1020 mg (34 mL) of FER diluted in 100 mL normal saline via infusion pump over 15 minutes. Vital signs were measured for 1 hour post-dose and adverse events (AEs) were collected via phone call 1, 2, and 7 days post-dose, and at clinic visits at 4 and 8 weeks post-dose. Efficacy assessments (Hgb, TSAT, ferritin, red blood cell distribution width [RDW]) occurred at 4 and 8 weeks post-dose. The primary endpoint was safety and tolerability (rate of AEs), while secondary efficacy endpoints included mean change in Hgb level, TSAT and RDW from Baseline to Week 4 and 8.The mean age was 53.4 (24 – 89) years. The most common underlying cause for IDA was menorrhagia, followed by gastric bypass. No serious AEs occurred, and all but 2 received the planned dose. One subject complained of cough and flushing after initiation of the infusion and requested discontinuation with symptoms abating within 2 minutes without treatment. A second subject developed cough and pruritus, was treated with diphenhydramine and steroids and the symptoms resolved in minutes. Tryptase, a mast cell degranulation marker, was normal in both subjects. Twenty-six of 60 patients reported AEs. Thirteen of the AEs were mild and transient reactions associated with the infusion, none of which received therapy with the exception of the one previously described. All symptoms resolved completely within minutes. Thirteen reported mild self limited arthralgias, myalgias and/or headache within 24–48 hours after treatment.At baseline, the mean Hgb was 9.4 g/dL, TSAT 7.7%, ferritin 57 ng/mL and RDW 16.5%. At 4 weeks, the mean Hgb increase was 2.1 g/dL, and by 8 weeks, the mean increase in Hgb was 2.6 g/dL. The peak increase in TSAT occurred at Week 4, increasing from 15.2 to 23.1%, compared to an increase of 13.2 to 20.9% at Week 8. Similarly, ferritin was maximal at week 4 (214 ng/mL) and had decreased by week 8 to 118 ng/mL. In approximately 90% of subjects, the RDW was increased at both four and 8 weeks post-ferumoxytol administration, consistent with reticulocytosis and ongoing hematopoietic response.Ferumoxytol, administered as a 1.02g TDI over 15 min was well tolerated with no SAEs in IDA patients with a history of intolerance of, or inadequate response to oral iron. Ferumoxytol also demonstrated excellent efficacy in this population with a diverse group of etiologies for IDA. By 4 weeks, Hgb had increased 2.1 g/dL with a continued further increase to 2.6 g/dL by Week 8. RDWs were elevated at 4 and 8 weeks in 90% of subjects, consistent with an ongoing hematologic response. This study of 60 iron deficient anemia patients demonstrates the safety and ease of administering a complete 1.02g replacement dose of IV iron in 15 minutes with ferumoxytol. If these results are corroborated in other studies, the infusion of 1.02 g of ferumoxytol as a 15 minutes infusion represents an improved method of treating iron deficient anemia.Off Label Use: 1020 mg of ferumoxytol is off label as the maximum approved dose is 510 mg. Further the drug was administered to patients with a host of conditions associated with iron deficiency and currently is only on label for iron deficiency associated with chronic kidney disease. The purpose is to provide a full replacement dose of iron in 15 minutes, representing a significant improvement in the management of iron deficient anemia. Strauss:AMAG Pharmaceuticals, Inc.: Employment.