Central Annals of Otolaryngology and Rhinology

Cite this article: Malhotra S (2017) Zygomycetes and Neck Cancer- An Update. Ann Otolaryngol Rhinol 4(8): 1196.

*Corresponding author

Shalini Malhotra, Department of Microbiology, Dr Ram Manohar Lohia Hospital, New Delhi, India, Email:

Submitted: 01 August 2017

Accepted: 28 October 2017

Published: 30 October 2017

ISSN: 2379-948X

Copyright© 2017 Malhotra

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Keywords•Zygomycosis•Diagnosis•Mortality•Co-infection

Review Article

Zygomycetes and Neck Cancer- An UpdateShalini Malhotra*Department of Microbiology, Dr Ram Manohar Lohia Hospital, India

Abstract

Zygomycosis has an angio-invasive pathology with high morbidity and mortality rates and mainly affects immunocompromised patients. Rhizopus species is the most common known cause and Rhizomucor, Cunninghamella, Saksenaea, and Apophysomyces species occur less frequently. The diagnosis is difficult and done in the terminal stage of the disease or even postmortem except for the rhinocerebral and cutaneous forms. However, with the development of diagnostic tools that allowed earlier diagnosis, better surgical and newer antifungal interventions, more patients are surviving these previously fatal infections. This review briefly describes about the newer classification, clinical manifestations, co-infection with other organisms and development in treatment strategy of zygomycosis.

INTRODUCTIONZygomycosis has emerged as a major infection caused by fungi

belonging to the order Mucorales (subphylum Mucormycotina) [1]. It has an angio-invasive pathology with high morbidity and mortality rates and mainly affects immunocompromised patients [2,3]. The fungal hyphae invade skin, mucosae, and tissues causing thrombosis in blood vessels, infarction, haemorrhage and necrosis [4]. Numerous fungi within zygomycetes have been associated with human disease, Rhizopus species is the most common known cause and Rhizomucor, Cunninghamella, Saksenaea, and Apophysomyces species occurring less often. Severe infection of the sinuses may extend into the brain. Less common manifestations are pulmonary, cutaneous, gastrointestinal (GI) and disseminated infections [3,5]. The diagnosis is difficult and done in the terminal stage of the disease or even postmortem except for the rhinocerebral and cutaneous forms. Infection usually progresses rapidly and the case fatality rate is very high. The mortality rate is ≥40% despite aggressive surgical and antifungal therapy [6-8]. However, with the development of diagnostic tools that allowed earlier diagnosis, better surgical and newer antifungal interventions, more patients are surviving these previously fatal infections. This review briefly describes about the newer classification, clinical manifestations, co-infection with other organisms and development in treatment strategy of zygomycosis.

Newer Classification of Zygomycetes

The kingdom Fungi is divided into three phyla on the basis of differences in the mode of sexual reproduction of the organisms and on the basis of morphologic features into Basidiomycota, Zygomycota and Ascomycota. Those species that reproduced only by asexual spores were grouped in the class Deuteromycetes, or Fungi Imperfecti. The phylum Zygomycota contained Mucorales,

Entomophthorales, and 8 other orders [9]. Changes in fungal taxonomy will continue to evolve as new species are discovered and whole genome sequencing unfolds, which will make nomenclature changes within the zygomycetes inevitable. Zygomycota underwent further taxonomic changes and it is proposed to eliminate Zygomycota and named phylum Glomeromycota and 4 subphyla include Mucoromycotina, Entomophthoromycotina, Kickxellomycotina, and Zoopagomycotina [1]. Present taxonomy includes zygomycetes in the subphylum Mucoromycotina without a class designation within the order Mucorales. This order is composed of 12 families with 6 of them containing the 20 species that have been described as causing human zygomycosis (Cunninghamellaceae, Lichtheimiaceae, Mucoraceae, Saksenaeaceae, Syncephalastraceae, and Thamnidiaceae) [1]. Also there is reclassification of Mucor pusillus into the genus Rhizomucor and Absidia corymbifera into the genus Lichtheimia [10]. Other notable changes are the renaming of Cunninghamella bertholletia as C. elegans and Rhizopus oryzae as R. arrhizus.

Zygomycetes species associated with human infections

Organisms are mostly identified on the basis of morphologic tissue findings of coenocytic, angioinvasive hyphae suggesting infection with one of the Mucorales. Majority of cases reported had no culture identification; instead, the infection was identified as a “mucormycosis,” or Mucor infection, despite this lack of culture confirmation. Also most of the pathogenic zygomycetes were originally classified as members of the genus Mucor. These organisms were later reassigned, into different genera and families within the order Mucorales. The variety of organisms causing disease has also expanded. In addition to Rhizopus, Mucor, and Absidia, human diseases due to Rhizomucor, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum

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spp. have all been confirmed. The disease manifestations have also evolved from primarily rhinocerebral, pulmonary, and disseminated disease to include gastrointestinal, cutaneous/subcutaneous, allergic disease, and even asymptomatic colonization [5,11]. There is usually a fulminant course with considerable tissue necrosis. In rhinocerebral disease there is unilateral, retro-orbital headache, nasal stuffiness progressing to a black discharge followed by invasion of the orbital nerves and vessels include diplopia and visual field loss. Pulmonary mucormycosis presents nonspecifically with fever, dyspneoa, and cough. Cutaneous mucormycosis produces cellulitis that progresses to dermal necrosis and black eschar formation. Gastrointestinal (GI) mucormycosis occurs with severe malnutrition and presentation is nonspecific, with abdominal pain, abdominal distension, nausea, and vomiting [12].

Risk factors associated with Zygomycetes

Immunocompromised neutropenic patients and patients with impaired phagocytosis are at higher risk for developing mucormycosis [3]. Rhinocerebral mucormycosis is often associated with diabetic ketoacidosis [3,6] and cerebral mucormycosis has been diagnosed in AIDS patients and drug addicts [4,6]. Other factors include long term corticosteroid therapy, organ or hematopoietic stem cell transplant recipients, malignancy, those with burn wounds or trauma, deferoxamine treatment or iron overload [5]. Other important predisposing factors of zygomycetes include illicit intravenous drug use, neonatal prematurity, malnourishment and broad-spectrum antimicrobial agents, as well as antifungal agents with no activity against zygomycetes, such as voriconazole and echinocandins [6, 7].

Diagnosis of Zygomycetes

The clinical diagnosis of zygomycetes is notoriously difficult because of the similarity with aspergillosis or other mycoses caused by filamentous fungi. When clinical presentation suggests mucormycosis, imaging techniques are helpful, but cultures and histopathology are required for confirmation. In case of rhinocerebral involvement, MRI brain helps in early detection of orbital, sinus, meningeal, bone, and cerebral lesions as well as intracranial vascular occlusion even before clinical signs develop. In pulmonary mucormycosis, lung biopsies (endoscopic, CT-guided or surgical) should be performed, depending on the radiological findings obtained by CT scans [13]. The laboratory diagnosis of mucormycosis is challenging and requires expertise and proper sampling. Proper clinical samples include scrapings and aspirates from sinuses, nasal discharges, BAL, needle biopsies from pulmonary lesions, skin scrapings from cutaneous lesions and biopsy tissues. They are commonly encountered as contaminants hence histopathologic evidence of fungal invasion of tissue is required to confirm clinical or radiological diagnosis and/or reliability of culture. The direct microscopic examination of biopsy material in 10%-20% shows characteristic broad (6–15 μm in diameter), mostly aseptate, ribbon-like hyaline hyphae with almost right –angle branching at irregular intervals. In histopathological examination, they are better stained by H&E, GMS, or Periodic-acid Schiff stain. Hyphae within necrotic tissue and signs of

angioinvasion and infarction are seen in these patients [14]. Identification of zygomycetes at the genus and species levels requires culture studies (SDA with antibiotics without cycloheximide), because all members of this group are morphologically similar in tissue [15]. In culture negative cases, molecular identification of zygomycetes to species level can be confirmed using DNA probes targeting the ribosomal 18S subunit, ITS1 sequencing after PCR with pan-fungal primers, 18S-targeted semi-nested PCR and real-time PCR targeting cytochrome b gene [16-18]. Molecular typing is most useful for characterizing zygomycete epidemiology in outbreak situation to rule out clonal spread or a common infecting source.

Treatment strategy for Zygomycetes

The successful treatment of mucormycosis requires four steps: 1) early diagnosis; 2) reversal of underlying predisposing risk factors, if possible; 3) surgical debridement and 4) prompt antifungal therapy [19]. Primary antifungal therapy for mucormycosis should be based on a polyene, i.e. amphotericin B deoxycholate (AmB) or liposomal amphotericin B (LAmB). LAmB is less toxic and has better survival compared to patients treated with AmB [20]. Fluconazole, voriconazole, and itraconazole do not have reliable activity against mucormycosis [21-23]. The reported in vitro MIC90 of posaconazole against the Mucormycotina has ranged from 1 μg/mL to ≥4 μg/mL [24, 25]. However, in patients with febrile neutropenia or invasive fungal infections, posaconazole levels in serum were less than 1 μg/mL, with considerable variability [26,27]. Furthermore, posaconazole is relatively ineffective for the treatment of mucormycosis in pre-clinical animal models [28,29]. Hence, posaconazole cannot be recommended as a first-line treatment for mucormycosis but it can be used as an option for salvage therapy for these infections. In a recent retrospective study, combination polyenecaspofungin therapy was associated with significantly improved outcomes in patients with rhino-orbital and rhino-orbital-cerebral mucormycosis compared to polyene monotherapy [30]. Addition of the iron chelators deferiprone and deferasirox to treat iron overload in mucormycosis improved survival in such patients [31]. Hence deferasirox can be used as an adjunctive therapy for mucormycosis patients. However according to clinical studies, posaconazole does not have a clear role as adjunctive therapy in combination with lipid polyenes [32]. Posaconazole or deferasirox are reasonable salvage options for patients with mucormycosis refractory to or intolerant of polyene therapy. Recently colistin, has reported activity against the Mucorales, as it involves disruption of the cytoplasmic and intracellular vacuolar membrane integrity. However, its potential role as a second agent in a combination regimen merits further study [33]. Proinflammatory cytokines, such as interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), enhance the ability of granulocytes to damage the agents of mucormycosis when used in conjunction with lipid formulations of amphotericin B [34,35]. G-CSF-mobilized granulocyte transfusions may provide additional support for persistently neutropenic patients until recovery from neutropenia. Administration of GM-CSF or IFN-γ may further augment host response and antifungal effect in non-neutropenic patients with refractory infection [36].

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Co-infection of Zygomycetes with other infections

Dual fungal infections like zygomycosis with candidiasis were reported from immunocompromised patients, rhinocerebral zygomycosis with invasive pulmonary aspergillosis has also been reported in various studies [37,38]. A single case of combined zygomycosis and aspergillosis at a single site, i.e. the oropharyngeal region, has been reported from a patient with Castleman’s disease [39]. Binder and Ruchel described a case of combined infection with Aspergillus and Zygomycetes sp. involving the lungs, spleen, and the brain in a patient of acute myeloid leukemia and leading to fatal outcome inspite of early antimycotic treatment [40]. In a review of 929 cases of zygomycosis by Roden et al., coinfection with Aspergillus sp., proven or probable was noted in 44% cases [5]. Co-infection with Aspergillus (probable or proven invasive aspergillosis) was also a feature in 50% of the patients with proven pulmonary mucormycosis in a review of 18 cases by Saegeman et al [6]. Also coinfection of pulmonary mucormycosis with tuberculosis was reported by Aggarwal et al [41].

CONCLUSION Zygomycosis is an important emerging infectious disease

especially in compromised patients hence complete knowledge regarding the changing nomenclature, changing clinical features along with better methods for diagnosis and treatment is required. The availability of reliable molecular assays to diagnose this devastating infection and newer therapeutic options with heightened awareness and better cooperation between clinicians, microbiologists, and pathologists in recent years are the key ingredients for reducing the spread of this devastating disease.

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Malhotra S (2017) Zygomycetes and Neck Cancer- An Update. Ann Otolaryngol Rhinol 4(8): 1196.

Cite this article

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