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Home , Mucormycosis, Mycosis, Phycomycosis, Zygomycosis

S Afr Optom 2008 67(1) 36-41

Mucormycosis

‡ SD Mathebula

Department of Optometry, University of Limpopo, Private Bag x 1106, Sovenga, 0727 South Africa

Received 8 December 2007; revised paper accepted 31 March 2008

Abstract of uniformity in this text, although and The zygomycoses are caused by are also accepted. is a fungi of the class zygomycetes, comprised of the rare but fatal or aggressive, opportunistic of orders and . Fungi of the sinuses and caused by saprophytic aerobic this order are causes of mucormycosis, an acute op- fungi of the , order Mucora- portunistic infection occurring mostly in immuno- les.3 − 5 Among the Mucorales, and are compromised individuals, particularly in patients the common causes of human infections. with . The purpose of this Phycomycetes (Zygomycetes) are common through- paper is to present an academic perspective on the out the environment and in bread mould, soil, ma- pathophysiology, presentation and management of nure, decaying fruit and vegetables, and are frequent- mucormycosis. Possible management strategies are ly found colonizing the oral mucosa, nose, paranasal provided. sinuses and throat, where massive formation occurs.7 , 8 Inhalation is the natural route of infection. Keywords: amphotericin, ketoacidosis, Infection progresses as the hyphae begin to invade mucormycosis, phycomycosis, zygomycosis blood vessels and causes erosion of the bone through walls of the nasal and maxillary sinuses. Extension to Introduction ethmoid sinuses can lead to orbital and retro-orbital Mucormycosis 1 , also known as zygomycosis or involvement. Intracranial involvement also occurs phycomycosis was first described by Paultauf in from invasion by way of the superior orbital fissure, 1885. He documented involvement of the central ophthalmic vessels and cribriform plate, through the nervous system for the first time, and coined the term carotid artery or possibly via a perineural route. 7− 10 “ mucorina” which later became “mucormy- cosis.” In 1959, Lie-Kian-Joe, et al. 2 proposed that the be designated “phycomycosis” rather than “mucormycosis”, since they found that fungi belong- Host defences ing to orders other than the Mucorales (such as En- Both mononuclear and polymorphonuclear phago- tomophthorales, Zoopagales and Kickxellales) were cytes of the normal host are the major defence mecha- pathogenic to man. Since then the term phycomycosis nism against mucormycosis. They kill Mucorales by has become widely accepted. The term “zygomyco- the generation of oxidative metabolities and the sis” includes both mucormycosis and entomophtho- cationic peptides defensins. 11 − 14 Organisms of this ramycosis, the latter being a tropical infection of the family of saprophytic fungi are ubiquitous, infecting subcutaneous tissue or paranasal sinuses caused by humans whose systemic health is compromised (dys- of Basidiobolus or . 3 − 5Mucormy- functional phagocytes). Several predisposing cosis is the terminology that will be used for the sake

‡ BOptom(UNIN) MOptom(UNIN) 36 The South African Optometrist S Afr Optom 2008 67(1) 36-41 SD Mathebula - Mucormycosis conditions, such as diabetes, , , even when appropriate treatment has been instituted. AIDS, , severe , and Based on clinical presentation and the involvement of uremia have been reported in the literature.1 − 10 a particular site, mucormycosis can be divided into Human infection is felt to be caused by asexual various clinical categories (rhinocerebral, pulmonary, spore formation. 1 The tiny become airborne cutaneous, gastrointestinal, disseminated and miscel- and land on the oral or nasal mucosal of humans. In laneous). the vast majority of immunologically competent in- Rhinocerebral mucormycosis is the most com- dividuals, these spores will be contained through mon form of the infection and predominantly occurs phagocytic response. If this fails (for example, in im- in patients with poorly controlled diabetes mellitus. munocompromised or metabolic abnormalities), ger- The high iron, glucose-rich acid milieu facilitates mination will ensue and hyphae will develop. Because fungal growth. 1 ,, 4 10 ,, 25 26 Pulmonary mucormycosis polymorphonuclear leukocytes are less effective in occurs most commonly in leukemic patients who removing hyphae, the infection can then become es- are receiving chemotherapy and patients undergoing tablished. Hyperglycemia and are known to hematopoietic stem cell transplants. 27 − 29 Pulmonary impair the ability of phagocytes to move toward and mucormycosis may develop as a result of inhalation kill the invading organism by both oxidative and non- or by hematogenous or lymphatic spread. Symptoms oxidative mechanisms (they provide an excellent en- include dyspnea, and chest pain. 29 Gastrointes- vironment for fungi to grow).14 tinal mucormycosis is rare but it is believed to occur in extremely malnourished children. The , Role of iron colon and ileum are the most commonly involved Iron appears to be an important element in the sites.30 Hepatic mucormycosis has been associated growth factor of Mucorales. Reduced ability of the with ingestion of herbal . 31 Nonspecific serum to bind iron at low pH may be the basic defect , nausea, vomiting, and hema- in the body defense mechanism. 1 ,, 1 1 1 5 − 1 7 Human re- tochezia are the common symptoms. The agents of sistance to fungal infection rests on the ability to re- cutaneous mucormycosis are typically incapable of strict the availability of iron to an invading by penetrating intact . Patients who develop cutane- binding it to proteins such as apotransferrin. Fungal ous mucormycosis are those with disruption of the hyphae produce a substance called rhizoferrin which normal protective cutaneous barrier. However, burns binds iron avidly. This iron-rhizoferrin complex is and traumatic disruption of skin enable the organisms then taken up by the fungus and becomes available to penetrate into deeper tissues. Hematologenously for vital intracellular processes, further reducing iron disseminated mucormycosis may originate from any availability for the host. primary site of infection. 8 , 11 Pulmonary mucormyco- Deferoxamine is used as a chelating agent for iron sis in severely neutropenic patients has the highest and aluminum in patients undergoing hemodialysis incidence of dissemination. Less commonly, dis- and has been associated with a fulminant form of mu- semination can arise from the , cormycosis. 1 ,, 11 1 8 − 2 3 While deferoxamine is an iron sinuses or cutaneous lesions. The most common site chelator from the perspective of the host, Rhizopus of dissemination is the brain, but metastatic lesions spp. actually utilizes deferoxamine as a rhizoferrin may also be found in the spleen, heart, skin and other to supply previously unavailable iron to the fungus. organs. Cerebral infection following dissemination is Patients with diabetic ketoacidosis are at high risk distinct from rhinocerebral mucormycosis and results of developing mucormycosis due to an elevation in in abscess formation and infarction, patients present available serum iron. 24 with sudden onset of focal neurological deficits or . 11 Agents of the Mucorales may cause infection Clinical presentation in virtually any body site.1,, 8 11 The clinical hallmark of mucormycosis is vascular Other at-risk populations include immunosup- invasion resulting in and tissue infarction pressed patients with organ transplants, possibly due (). Because of its lethal (aggressive) nature to from repeated blood transfusion death can occur within several days to a few weeks,

37 The South African Optometrist S Afr Optom 2008 67(1) 36-41 SD Mathebula - Mucormycosis and graft-versus-host disease treated with steroids, pa- Imaging techniques may be suggestive of mu- tients undergoing hematological stem cell transplan- cormycosis but are rarely diagnostic because the ini- tation and patients with severe . 1, 4, 10, 32-40 Other tial imaging study is frequently negative or has subtle immunocompromised hosts, such as patients with findings. 11 Diagnosing mucormycosis almost always AIDS, rarely have been reported with this disease. requires histopathologic evidence of fungal invasion of the tissues. Culturing organisms from a potential Symptoms infected site is rarely sufficient to establish the diag- Infection is acquired through the respiratory tract. nosis of mucormycosis. The causative agent is ubiqui- In this text, only the infection occurring via the tous, may colonize a normal person, and is a relatively respiratory tract is discussed. Once the infection is frequent laboratory contamination. Additionally, the established in the paranasal sinuses, the infection can organism may be killed during tissue grinding, which easily spread to and enter the orbit via the nasolac- is routinely used to process tissue specimens for cul- rimal duct and medial orbit. 1 The ease of spread may ture, 1, 8, 11 thus a sterile culture does not rule out the be due to the thinness of the lamina papyracea and infection. Furthermore, waiting for the results of the perforation of the medial wall by arteries and veins. fungal culture may delay the institution of the appro- Spread to the brain may occur via the orbital apex, priate therapy, where time is critical. orbital vessels or via the cribiform plate. 1, 9 There are no reliable serologic, PCR-based or The initial symptoms are low-grade fever, sinusi- skin tests for mucormycosis. Therefore, the diagno- tis and and facial pain, followed by the onset of sis should be made by of infected tissues. The conjunctival suffusion, blurry vision and chemosis, biopsy should demonstrate the characteristic wide, superior orbital fissure syndrome (unilateral sen- ribbon-like, unseptate hyphae of uneven diameters sory deficit of the first and second divisions ofthe that branch at right angles with long sporangiophores trigeminal nerve and ophthalmoplegia), proptosis due attached. 26, 32 Other fungi (, or to vascular compromise and infection of the orbital Scedosporium) may look similar to the Mucorales contents. 26, 32−34 Fungal invasion of the globe or reti- on biopsy, however, they have septate, thinner and nal artery leads to blindness. 32, 35-37 When the orbital branching at acute angles. 40 apex becomes involved, extension into the cavernous sinus and involvement of the internal carotid artery Treatment can result in cerebral ischaemia, brain infarction and Four factors are critical for treating mucormyco- ultimately death. 9 sis:

Diagnosis Rapidity of diagnosis Diagnosis of mucormycosis is established by clini- Early diagnosis is important because small, fo- cal picture revealing the invasive course of the dis- cal lesions can often be surgically excised before they ease and by demonstrating fungal elements in smear, progress to involve critical structures or disseminate. culture and . 35 Imaging studies play an 26, 37 A high index of clinical suspicion is critical and to important role in defining the extent of involvement aggressively pursue diagnostic biopsy. Given the rap- and presence of intracranial disease. 38, 39 The most idly progressive nature of mucormycosis and marked common finding on computerized tomography (CT) increase in mortality when the fungus penetrates the scanning of the head or sinuses is the soft tissue swell- cranium, any diabetic patient with a , visual ing, sinus mucosal thickening, bone erosion, thicken- changes and eye pain is a candidate for prompt evalu- ing of extraocular muscles, intracranial/ cavernous ation with imaging studies and nasal endoscopy to sinus thrombosis, enhancement of vessels and central rule out mucormycosis. 10 nervous system lesions. Magnetic resonance imaging (MRI) can add diagnostic information by showing the Reversal of the underlying predisposing factors extension of the infection into the surrounding blood Correcting or controlling predisposing problems vessels, orbital fat and intracranial invasion before is also essential for improving the treatment outcome. clinical signs develop. In diabetic ketoacidotic patients, hyperglycemia and acidemia should be corrected.

38 The South African Optometrist S Afr Optom 2008 67(1) 36-41 SD Mathebula - Mucormycosis Discontinuation of deferoxamine or immuno- Orbital exenteration may be life-saving in the pres- suppressive therepy, particularly steroids, should be ence of an active fungal invasion of the orbit and strongly considered when the diagnosis of mucormy- should be considered for an actively infected orbit cosis is made. with a blind and immovable eye.

Appropriate therapy Novel therapies The current available antifungal agents lack sig- The central role of iron metabolism in the - nificant clinical trial data because it is impractical esis of mucormycosis suggests the possibility of uti- to conduct prospective interventional study. Even lizing effective iron chelators as adjunctive antifungal though the disease is unusually deadly, it occurs at a therapy. The potential for this iron chelator to serve low frequency relative to other opportunistic infec- as adjunctive therapy with other antifungal agents tions. Given the lack of controlled clinical trials for should be investigated. Hyperbaric oxygen should mucormycosis, clinicians have been forced to rely be used to treat mucormycosis because higher oxy- on anecdotal case reports and limited retrospective gen pressure improves the ability of the reviews in determining the first-line therapy for mu- to kill the organisms. High oxygen pressure inhibits cormycosis. Until recently, only members of the poly- the germination of fungal spores and growth of myce- ene antimicrobial class demonstrated activity against lia. 43 that activate phagocytic activity (such the agent of mucormycosis. 1 ,, 8 1 1 , 32 These include Am- as gamma interferon and granulocyte-macrophage photericin B deoxycholate (AmB), Liposomal am- colony-stimulating factor) increase the ability of photericin B (LAmB) and lipid com- phagocytes to kill. 11 , 44 Whether these therapies could plex (ABLC). improve the outcomes of patients with mucormycosis AmB acts by binding to sterols (primarily ergos- need to be established through appropriate controlled terol) in the fungal cell membrane with a resulting prospective clinical trials. change in membrane permeability. LAmB is highly protein bound and poorly dialyzed. Small doses ad- ministered over a long period help to minimize toxic- Despite advances in diagnosis and treatment, a ity and side effects. Recognized side effects are fever, high mortality still exists for this disease. Death may chills, headache, malaise, nausea, vomiting, phlebitis occur within two weeks if untreated or unsuccessfully and nephrotoxic. 1 ,, 8 11 , 37 ABLC is a formulation de- treated. Although the mortality rate is high, the infec- signed to be less toxic than AmB, while enhancing tion can be cured when diagnosed early and treated the therapeutic index of the drug.1 with antifungal agents and aggressive .

Appropriate surgical and of infected tis- Conclusion sue Early recognition and treatment are essential for Fungi strive in necrotic tissue and surgery is nec- this disease. The management demands a multidis- essary due to the massive amount of tissue necrosis ciplinary approach. ophthalmologists, optometrists, occurring during mucormycosis. Early surgical exci- physicians, maxillofacial surgeons, oculoplastic sur- sion of the infected sinuses and appropriate debride- geons, neurosurgeons and otolaryngologists. Current ment of the retro-orbital space can often prevent the regimen for the treatment of mucormycosis is ampho- infection from extending into the eye. Repeated surgi- tericin and surgery. In the future, iron chelator, hyper- cal debridement may be necessary to ensure that all baric oxygen and therapies may be useful as necrotic tissue has been debrided and the infection adjunctive to standard antifungal has not progressed.26 therapy.

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