Role of Iron Chelators in Mucormycosis.

Introduction

COVID-19 is a disease caused by novel SARS-CoV-2 virus that has played a havoc worldwide. The symptoms vary largely ranging from mild to life-threatening pneumonia. Despite immense efforts across the globe, there is no definitive treatment till date. Therefore, preventive measures and symptomatic therapy are the only better options at present. Secondary infections are common, especially in critically ill and hospitalized COVID-19 patients, fungal infections being 10 times more common.[1] Mucormycosis caused by Mucorales is one of the most life-threatening form of zygomycosis that occurs mainly in immunocompromised states, especially in diabetes mellitus, leukemia, and lymphoma.[2] In India, the prevalence of mucormycosis is 0.14 per 1000, that is almost 80 times greater when compared to developed countries.[3]

Fatality increases considerably up to 50% to 80% in case of intracranial or orbital involvement and immune suppression.[4] Therefore, early diagnosis and initiation of therapy are a must. Postponement of treatment can increase mortality and in spite of combining surgical and medical line of management at the initial stages, the prognosis of mucormycosis is somewhat poor.[5]

Mucormycosis is a fulminant, invasive fungal infection whose fatality ranges from 32% to 57%, commonly seen in the immunocompromised individuals and diabetics patients.[6789] India is the country with the second highest number of diabetics after China with over 116 million diabetics estimated in 2019.[10] Corticosteroids are used rampantly in the treatment of COVID-19 as they are held responsible for modulating inflammation-mediated lung injury and ultimately lessen the chances of progressing to respiratory failure.[11] In India, emergence of COVID-19 S-wave has compelled the rampant use of steroids in the management of COVID-19 thereby increasing the incidence of mucormycosis.

Regulation of Iron

Normally, regulation of free iron in a host occurs by extremely effective iron sequesters such as transferrin, ferritin, and lactoferrin.[12] The excessive glycosylation of transferrin and ferritin because of persistent hyperglycemia results in reduced iron affinity of these sequesters thereby releasing it in bloodstream and cells.[13] This mechanism might form the basis for corticosteroids-induced hyperglycemia in COVID-19 patients increasing the susceptibility to mucormycosis. Therefore, host iron acquisition is crucial for the growth enhancement of Mucorales.

Pathogenesis of Mucormycosis Role of Iron

Iron is quite essential for growth and development of any cell or organism. It is crucial for the virulence of all pathogenic microorganisms that have acquired complex approaches to obtain iron from their hosts.

In fungi, iron uptake occurs by certain transport systems that reduce ferric iron to ferrous form with the help of particular cell surface reductases often known as ferroxidases.

Iron in Ferrous Form later gets Internalized by Diverse Mechanisms

Iron-containing ferroxidases possess great affinity toward permeases (fungal transport proteins). The iron permease–ferroxidase complexes (Ftr1–Fet3) effortlessly traverse cell wall as well as membrane of the fungi, thereby providing iron intracellularly.

Fungi produce iron-specific chelators possessing low molecular mass commonly known as siderophores that are expelled out of fungi in the deferric form. Later, on binding to iron is taken up by the fungi

Fungal heme oxygenase that acquires iron from heme.[1415]

Role of iron Chelators in Mucormycosis

The siderophores have high affinity to iron. It is well documented from the past that hemodialysis patients during treatment with deferoxamine (DFO) have an increased susceptibility to zygomycosis. This seemed to be a paradox as DFO being an iron chelator should decrease the iron availability to fungi and decrease the susceptibility to mucormycosis.[1617] Although DFO is an iron chelator, it also acts as a xenosiderophore that has greater affinity for iron when compared to DFO. As a result, it is able to detach iron from it and provide it to the fungi.[18] Deferiprone and deferasirox (DFX) are effective iron chelators in clinical practice. However, these do not increase susceptibility to mucormycosis as compared with DFO. This might be attributable to their variation in chemical structure and chelating affinity. Furthermore, they do not behave like xenosiderophores as the iron uptake system of fungi might not be efficient enough to detach iron from them. The probable reasons for this may be attributed to either inadequate molecular mass or higher affinity for iron. Evidence in support of this is an in vivo study, where mice or guinea pigs infected with Rhizopus exhibited improvement in survival on treatment with deferiprone.[19]

Deferasirox received USFDA approval for treating iron overload in transfusion-dependent anemia in the year 2005. This led to its off-label use as an adjunctive therapy in advanced cases of mucormycosis, particularly in diabetic ketoacidosis (DKA) patients. A study by Ibrahim et al. showed that kidneys of mice treated with deferasirox had no noticeable hyphae and an inflammatory reaction consisting of neutrophils was present, while kidneys of placebo group had widespread filamentous fungi and there was a sparse or total absence of an inflammatory reaction.[20] According to Reed et al., a diabetic aged 40 years presented with aggressive zygomycosis who despite being started with a combination of high-dose liposomal amphotericin B and caspofungin and surgical debridement progressed with central nervous system involvement. Later, he was treated with 1000 mg daily with DFX that led to an improvement in new magnetic resonance imaging of the brain. This happened to be the first reported case of zygomycosis that was effectively managed by combining antifungals and an iron chelator.[21] Efficacy of deferasirox was confirmed in a study by Chamilos et al. in treating mucormycosis in the Drosophila fly model.[22] A study by Ibrahim et al. showed that DFX chelated iron from Rhizopus oryzae effectively and among 29 clinical isolates of Mucorales DFX exhibited in vitro cidal activity against 28 isolates. DFX also showed significant improvement in survival and reduction in fungal burden in tissue on administering to diabetic ketoacidotic or neutropenic mice with mucormycosis.[20]

A randomized, double-blind, placebo-controlled trial combined liposomal amphotericin B (LAmB) and DFX iron chelator (DEFEAT Mucor study) revealed that patients with mucormycosis treated with iron chelator failed to demonstrate benefit and had greater mortality rate at 90 days. Hence, the study did not substantiate the use of initial, adjunctive DFX for mucormycosis. Major limitations were that deferasirox group included patients with active malignancy, neutropenia, and received corticosteroids when compared to placebo group. Furthermore, the DFX group was less likely to have received additional antifungals, making the outcomes difficult to interpret. Thus, definitive conclusion cannot be drawn from the results of such studies.[23] Patients with DKA have greater chance of acquiring rhinocerebral ketoacidosis because of release of iron from binding proteins. Raised serum iron is vital for the virulence of mucormycosis.[24]

According to a study by Ibrahim et al., susceptibility testing confirmed in vitro inhibition of growth of R. oryzae and cidal activity after 48 h of incubation. Furthermore, in the DKA mouse model, deferiprone also offered protection against extremely lethal R. oryzae infection when compared to treatment with high-dose LAmB, pertaining to both survival and fungal burden of the brain.[25] Therefore, from the experimental data, it can be concluded that iron chelators can be used to treat mucormycosis provided; they are not used as xenosiderophores by Mucorales. Till date, there is not enough scientific evidence regarding the use of iron chelators in post-COVID-19 mucormycosis. Further exploration is necessary to assess the role of combined therapy with antifungals and iron chelators.

Conclusion

SARS-CoV-2infection has been challenging to mankind with the emergence of various variants. In addition to it, there is a lack of definitive therapy for COVID-19. Different classes of drugs are being used to treat symptomatically. Mucormycosis is one of the fulminant forms that occur mainly in immunocompromised states. Evidence from few studies suggests some role of few iron chelators. However, there is a lack of sufficient scientific evidence to substantiate the definitive role of iron chelators. Therefore, more evidence should be generated to evaluate the role of iron chelators that can further help in preventing complications.

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Conflicts of interest

There are no conflicts of interest.