Intravenous iron for the treatment of iron deficiency in adults with cystic fibrosis: a prospective observational cohort study

TL;DR

Intravenous iron treatment improved hemoglobin and exercise capacity in adults with cystic fibrosis and iron deficiency, without causing infection-related issues.

Contribution

This study demonstrates the safety and efficacy of intravenous iron in treating iron deficiency among cystic fibrosis patients.

Findings

Intravenous iron improved blood hemoglobin concentration in cystic fibrosis patients.

Exercise capacity increased without adverse effects on infection markers.

Abstract

Iron deficiency is common in chronic cardiorespiratory disease. In patients with heart failure and iron deficiency, intravenous iron improves exercise capacity and quality of life [1]. Similar benefits have been reported in patients with pulmonary hypertension [2] and COPD [3]. The mechanism remains unclear, but in addition to its importance in erythropoiesis, iron availability influences the hypoxia-inducible factor (HIF) transcriptional pathway and modulates physiological responses to hypoxia, particularly within the pulmonary circulation [4].

In this pilot study in 20 adults with cystic fibrosis and iron deficiency, treatment with intravenous iron improved blood haemoglobin concentration and exercise capacity, without any adverse effect on clinical or laboratory markers of infection
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Full text

To the Editor:

Iron deficiency is common in chronic cardiorespiratory disease. In patients with heart failure and iron deficiency, intravenous iron improves exercise capacity and quality of life [1]. Similar benefits have been reported in patients with pulmonary hypertension [2] and COPD [3]. The mechanism remains unclear, but in addition to its importance in erythropoiesis, iron availability influences the hypoxia-inducible factor (HIF) transcriptional pathway and modulates physiological responses to hypoxia, particularly within the pulmonary circulation [4].

In people with cystic fibrosis (CF), mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene leads to defective chloride transport [5]. In the lungs, this causes bronchiectasis and chronic bacterial infection. In the gut, it leads to malabsorption and nutritional deficiency. Iron deficiency is present in up to 60% of people with CF, including those on CFTR modulators [6]. However, it often goes untreated, due to concerns about gastrointestinal upset with oral iron, or the risk of infection with intravenous iron. In particular, the airways of people with CF are often colonised with iron-dependent bacteria such as Pseudomonas aeruginosa, and it has been suggested that increasing iron availability could encourage bacterial growth and worsen respiratory infection [7].

We conducted a single-centre open-label pilot prospective observational cohort study in adults with CF and iron deficiency, defined as ferritin ≤15 mg·L^−1^ or transferrin saturation ≤16% within the previous 4 months. Exclusion criteria included pregnancy or breastfeeding, organ transplantation, liver failure, current or recent iron supplementation, and active non-tuberculous mycobacterial pulmonary disease. The study was approved by the South Central Hampshire-A Research Ethics Committee, and was registered at clinicaltrials.gov (NCT03632525). Participants provided written informed consent.

20 patients (mean±sd age 30.1±10.2 years; 50% female) were recruited between March 2019 and March 2020 during routine clinical care in the Oxford Adult Cystic Fibrosis Centre. The recruitment target was predefined, but as a pilot study, no formal power calculation was performed. At baseline, 50% had chronic Pseudomonas aeruginosa infection and 95% were pancreatic insufficient. All were iron deficient, but only 40% were anaemic, and the majority would not have received intravenous iron as part of routine care at our centre at the time of the study, due to uncertainty about the risk–benefit balance. In relation to genotype, 55% of participants were homozygous for F508del and 35% were heterozygous for F508del. No participants were taking CFTR modulator therapy at baseline, but tezacaftor/ivacaftor was commenced in six participants between weeks 8 and 16.

Participants attended four study visits (0, 4, 8 and 16 weeks). At each visit they performed spirometry, provided venous blood and sputum samples, performed a modified shuttle walk test [8], and completed quality of life questionnaires. After these assessments at the week 4 visit, all participants received an intravenous infusion of 20 mg·kg^−1^ ferric carboxymaltose (FCM; Ferinject, Vifor Pharma UK), up to a maximum of 1000 mg if the haemoglobin concentration was <14 g·L^−1^, or 500 mg if ≥14 g·L^−1^. The FCM was given in 250 mL 0.9% saline over 15–30 min.

The primary outcome was a within-patient comparison of the incidence of new infective events in the 4 weeks before and after iron. The definition of a new infective event is provided in table 1. A key secondary outcome was a comparison of the incidence of infective events in the 12 weeks before and after iron (by conducting a retrospective review of the clinical notes). Other clinical and laboratory outcomes are summarised in table 1.

There was no difference in the incidence of new infective events in the 4 weeks before and after iron, and no difference for the 12 weeks before and after iron. Antibiotic use was similar across these periods and there was no apparent impact of iron on sputum microbiological diversity. These findings are in keeping with the safety of intravenous iron in other populations vulnerable to infection, including patients on immunosuppressive therapy [9] or in the critical care setting [10]. Our results also accord with those of a previous study of oral iron supplementation in adults with CF and iron deficiency, in which 6 weeks of oral ferrous sulphate did not alter sputum microbiological diversity [11].

Iron led to a substantial and sustained increase in iron availability, with a corresponding increase in haemoglobin. The cause of iron deficiency in people with CF is unclear, but candidate mechanisms include blood loss into airways, menstrual loss, malabsorption, and so-called “functional” iron deficiency, in which infection and/or inflammation inhibits iron uptake in the gut and causes sequestration within reticuloendothelial macrophages. In our study, hepcidin levels were suppressed at baseline, with elevated serum soluble transferrin receptor levels. This pattern is characteristic of absolute, rather than functional, iron deficiency, and the elevated erythropoietin and low haemoglobin concentration at baseline suggest iron-restricted erythropoiesis. In other settings, hepcidin and erythropoietin are used to identify patients likely to respond to iron supplementation, which might also prove helpful in those with CF [12].

An important finding in the current study is the apparent increase in exercise capacity. Exercise has numerous benefits in people with CF, including improved airway clearance and bone protection. If sustained, improved exercise capacity seems likely to improve long term clinical outcomes. In the current trial, it may result from the increased haemoglobin concentration after iron, but similar increases are independent of haemoglobin in patients with other cardiorespiratory conditions [1–3]. Possible mechanisms include a direct impact on cardiac function or a prolonged reduction in the pulmonary vascular sensitivity to hypoxia, which is known to occur following intravenous iron [13]. There was no clear fall in the systolic pulmonary artery pressure after iron in the current study, but measurements were possible in only around half the participants, and were made only at rest.

There was no effect of iron on any domain of the CFQ-R (Cystic Fibrosis Questionnaire-Revised) or SF-36 (Short Form-36) quality of life measures, but the study lacked statistical power for these outcomes. Of note, only one participant (5%) reported fatigue during the 4 weeks after iron, compared with four participants (20%) in the 4 weeks before iron. In contrast, five participants (25%) experienced transient flu-like symptoms, including myalgia, in the days following iron. One possible cause is hypophosphataemia, which is common after FCM, and can cause malaise and/or myalgia [14].

This study has a number of limitations. First, as a pilot study in 20 patients with a non-randomised design, it is not possible to attribute changes in outcomes definitively to iron administration. However, in the absence of any other prospective data on the safety of intravenous iron in people with CF, our results do assuage concerns about the risk of worsening infection-related outcomes raised by previous case series [7]. Second, although our primary outcome is a broad, multifaceted measure of infective status, it has not been previously validated. Third, our study was relatively short, and we cannot exclude adverse or beneficial effects beyond the 12-week follow up period. In this context, iron deficiency has recently been shown to be associated with impaired adaptive immunity and vaccine efficiency [15]. If this were to be the case for people with CF, there may be long-lasting positive effects of treating iron deficiency on the incidence of respiratory infection.

Finally, this study was conducted before the widespread use of CFTR modulator therapy in people with CF. The introduction of such therapy in six patients between weeks 8 and 16 could not have influenced the primary outcome, but could have influenced some secondary outcomes. In relation to the shuttle walk distance, the increase after iron remained significant when these six participants were excluded from the analysis.

In summary, in this pilot study, administration of intravenous iron in adults with CF and iron deficiency had no adverse impact on infective status, but was associated with a sustained improvement in iron status, correction of anaemia and improved exercise capacity. This preliminary result paves the way for a larger randomised controlled trial of intravenous iron supplementation in people with CF, focused on the potential for longer-term benefits. If confirmed in larger studies, our results would also have implications for the use of intravenous iron in other groups at high risk of infection, including those with non-CF bronchiectasis or patients in the critical care setting.

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