Novel Perspectives on Mucormycosis: Pathophysiology, Presentation, and Management

(Review article) BY: Devesh Shirsath

SUMMARY : Mucormycosis is a potentially fatal fungus that affects immunocompromised patients. While these infections are becoming more common, survival rates remain low. A better understanding of the disease’s pathogenesis could lead to new treatments in the future. For example, it is now clear that iron metabolism is important in controlling mucormycosis infections and that deferoxamine plays a role in this process.

INTRODUCTION : Infections caused by fungi of the class Zygomycetes, which includes the orders Mucorales and Entomophthorales, are known as zygomycoses. Entomophthorales are uncommon causes of entomophthoromycosis, a form of subcutaneous and mucocutaneous infection that primarily affects immunocompetent hosts in developing countries.

Mucorales fungi are divided into six families, each of which may cause both superficial and deep infections.Species belonging to the family Mucoraceae are isolated more frequently from patients with mucormycosis than any other family.

Among the Mucoraceae, Rhizopus oryzae (Rhizopus arrhizus) is by far the most common cause of infectionOther less frequently isolated species of the Mucoraceae family that cause a similar spectrum of infections include Rhizopus microsporus var. rhizopodiformis, Absidia corymbifera, Apophysomyces elegans, Mucor species, and Rhizomucor pusillus Increasing cases of mucormycosis have been also reported due to infection with Cunninghamella spp. (in the Cunninghamellaceae family) To date, rare case reports have demonstrated the ability of species belonging to the remaining four families to cause mucormycosis

PATHOGENESIS : Mucorales are killed by normal hosts’ mononuclear and polymorphonuclear phagocytes, which produce oxidative metabolites and the cationic peptides defensins.

These phagocytes are the main host defence mechanism against mucormycosis, according to clinical evidence. Patients that are neutropenic, for example, are more likely to develop mucormycosis.

Patients with phagocyte dysfunction are also at a higher risk of developing mucormycosis.Additionally, corticosteroid treatment affects the ability of mouse bronchoalveolar macrophages to prevent germination of the spores in vitro or after in vivo infection induced by intranasal inoculation.

FIG. 1.

Pathogenetic mechanisms of and host defense mechanisms against mucormycosis. To cause disease, the agents of mucormycosis must scavenge from the host sufficient iron for growth, must evade host phagocytic defense mechanisms, and must access vasculature to disseminate. In a normal host, primary defense mechanisms against mucormycosis include sequestration of iron in serum by specialized iron-binding proteins.phagocytes including circulating neutrophils (2a) and tissue macrophages (2b), and endothelial cells

Role of Iron in Pathogenesis :

A recently identified important clinical feature is the increased susceptibility to mucormycosis of patients with elevated available serum iron. It has been known for two decades that patients treated with the iron chelator deferoxamine have a markedly increased incidence of invasive mucormycosis

However, it is now clear that iron chelation is not the mechanism by which deferoxamine enables mucormycosis infections. While deferoxamine is an iron chelator from the perspective of the human host, Rhizopus spp. actually utilize deferoxamine as a siderophore to supply previously unavailable iron to the fungus

Rhizopus spp. can absorb 8- and 40-fold more iron from deferoxamine than Aspergillus fumigatus and Candida albicans, respectively, and this increased iron absorption is linearly associated with Rhizopus spp. growth in serum.

Fungal-Endothelial Interactions :

The nearly universal existence of extensive angioinvasion with resulting vessel thrombosis and tissue necrosis is a hallmark of mucormycosis infections. The tendency of the organism to hematogenously disseminate from the original site of infection to other target organs is linked to angioinvasion.

As a result, endothelial cell disruption and penetration into blood vessels is possibly a crucial step in the organism’s pathogenetic strategy. In vitro, R. oryzae spores, but not germlings (i.e. pregerminated spores), can bind to subendothelial matrix proteins such as laminin and type IV collagen.

Similarly, we have recently found that R. oryzae spores adhere to subendothelial matrix proteins significantly better than do R. oryzae hyphae, however spores and hyphae adhere equivalently to human umbilical vein endothelial cells

CLINICAL PRESENTATION :

General Principles : Mucormycosis is characterised by vascular invasion, which results in thrombosis and tissue infarction/necrosis, as previously mentioned. Mucormycosis is almost always associated with a lack of host protection and/or an increase in available serum iron, though rare cases have been identified in otherwise healthy individuals.

Epidemiology and Disease Manifestations :

Mucormuycosis is less common than other opportunistic fungal infections including Candida and Aspergillus species.

According to one population-based report, the incidence of mucormycosis is 1.7 cases per million people per year, or around 500 cases per year in the United States.In autopsy series, the prevalence of mucormycosis has ranged from 1 to 5 cases per 10,000 autopsies, making the infection 10- to 50-fold less common than invasive Candida or Aspergillus infections.Finally, in patients at higher risk, such as those undergoing allogeneic bone marrow transplantation, the prevalence of mucormycosis has been described to be as high as 2 to 3%

Types of Mucormuycosis :

1. Miscellaneous forms
2. Disseminated mucormycosis
3. Gastrointestinal mucormycosis
4. Cutaneous mucormycosis
5. Pulmonary mucormycosis.
6. Rhinocerebral mucormycosis.

TREATMENT :

Mucormycosis is a severe infection that requires treatment with antifungal medications such as amphotericin B, posaconazole, or isavuconazole. Amphotericin B, posaconazole, and isavuconazole are administered intravenously (amphotericin B, posaconazole, and isavuconazole) or orally (posaconazole, isavuconazole) (posaconazole, isavuconazole).

Fluconazole, voriconazole, and echinocandins are not effective against the fungi that cause mucormycosis. Mucormycosis sometimes necessitates surgery to remove contaminated tissue.

PROGNOSIS :

Previously, cases of rhinocerebral mucormycosis were almost consistently fatal . Although the mortality rate of rhinocerebral disease remains high, the infection can be cured when diagnosed early and treated with aggressive surgery and antifungal agents (discussed further below).

Recent series have described a mortality of approximately 40% in diabetics with rhinocerebral mucormycosis.and a similar survival rate for rhinocerebral disease in patients with hematological malignancies.Of note, the prognosis is much better if the disease has not penetrated beyond the sinus prior to surgical debridement; in local sinonasal disease, the mortality has been reported to be <10%.

The nature of the underlying disease and the reversibility of the immune dysfunction are also important determinants of survival.

One study showed that 75% of patients with rhinocerebral disease who had no underlying immune compromise survived, while 60% of those with diabetes and only 20% of patients with other immunocompromised states were cured

CONCLUSIONS :

Mucormycosis is an increasingly common infection in immunocompromised patients. The central role of iron in the organism’s pathogenesis has only recently been appreciated.

The interaction between the Mucorales and endothelial cells is also beginning to be understood. Both of these pathogenetic features of disease may be amenable to novel therapeutic intervention in the future.

Currently, novel regimens for the treatment of mucormycosis include combination lipid-based amphotericin plus either an echinocandin or itraconazole or both. As well, compassionate-use posaconazole is currently available, and its potential for combination therapy with a polyene, caspofungin, or both is meritorious for study. In the future, novel iron chelator therapy may be useful as an adjunct to standard antifungal therapy. Finally, prompt diagnosis, reversal of predisposing conditions, and aggressive surgical debridement remain cornerstones of therapy for this deadly disease.

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