Mucormycosis and Entomophthoramycosis: a Review of the Clinical Manifestations, Diagnosis and Treatment R

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Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment R. M. Prabhu1 and R. Patel1,2

1Division of Infectious Diseases and 2Division of Clinical Microbiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

ABSTRACT The class Zygomycetes is divided into two orders, Mucorales and Entomophthorales. These two orders produce dramatically different infections. Genera from the order Mucorales (Rhizopus, Mucor, Rhizomucor, Absidia, Apophysomyces, Cunninghamella and Saksenaea) cause an angioinvasive infection called mucormycosis. Mucormycosis presents with rhino-orbito-cerebral, pulmonary, disseminated, cutaneous, or gastrointestinal involvement. Immunocompromising states such as haematological malignancy, bone marrow or peripheral blood stem cell transplantation, neutropenia, solid organ transplantation, diabetes mellitus with or without ketoacidosis, corticosteroids, and deferoxamine therapy for iron overload predispose patients to infection. Mucormycosis in immunocompetent hosts is rare, and is often related to trauma. Mortality rates can approach 100% depending on the patient’s underlying disease and form of mucormycosis. Early diagnosis, along with treatment of the underlying medical condition, surgery, and an amphotericin B product are needed for a successful outcome. Genera from the order Entomophthorales produce a chronic subcutaneous infection called entomophthoramycosis in immunocompetent patients. This infection occurs in tropical and subtropical climates. The genus Basidiobolus typically produces a chronic subcutaneous infection of the thigh, buttock, and ⁄ or trunk. Rarely, it has been reported to involve the gastrointestinal tract. The genus Conidiobolus causes a chronic infection of the nasal submucosa and subcutaneous tissue of the nose and face. This paper will review the clinical manifestations, diagnosis and treatment of mucormycosis and entomophthoramycosis. Keywords Mucormycosis, entomophthoramycosis, zygomycetes, Mucorales, Entomophthorales, Mucor, Rhizopus, Apophysomyces, Conidiobolus, Basidiobolus

Clin Microbiol Infect 2004; 10 (Suppl. 1): 31–47

The terms phycomycosis and zygomycosis have INTRODUCTION previously been used to describe both forms of The class Zygomycetes is divided into two orders, infection. Given their distinct clinical presenta- Mucorales and Entomophthorales (Table 1). Mem- tions, the term ‘mucormycosis’ should be reserved bers of these two orders produce dramatically for those infections caused by Mucorales, and the different infections. In general, members of the term ‘entomophthoramycosis’ for those caused by order Mucorales cause acute, angioinvasive infec- Entomophthorales [2]. This paper will review the tions in immunocompromised patients with mor- clinical manifestations, diagnosis and treatment of tality rates exceeding 60% [1]. In contrast, members mucormycosis, and brieﬂy, those of entomoph- of the order Entomophthorales cause chronic thoramycosis. subcutaneous infections in immunocompetent patients from subtropical and tropical regions. MUCORMYCOSIS After aspergillosis and candidiasis, mucormycosis Corresponding author and reprint requests: R. Patel, Division is the third most common invasive fungal infection of Infectious Diseases, Mayo Clinic College of Medicine, 200 [3]. It represents 8.3–13% of all fungal infections First Street SW, Rochester, Minnesota 55905, USA encountered at autopsy in haematology patients Tel: + 1 507 255 6482 Fax: + 1 507 255 7767 [4,5]. The most commonly recovered genera in- E-mail: [email protected] clude Mucor, Rhizopus, Rhizomucor, Absidia,

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases 32 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004

Table 1. Fungi from the class Class: Zygomycetes Zygomycetes reported as causing Order: Mucorales Entomophthorales infections in humans (older nomen- Genus: Mucor Basidiobolus clature in parentheses) M. racemosus, B. ranarum,(B. haptosporus) M. circinelloides M. ramosissimus Conidiobolus M. indicus C. coronatus M. hiemalis (Entomopthora coronata) C. incongruus Rhizopus R. arrhizus (R. oryzae) R. rhizopodiformis R. azygosporus R. stolonifer R. schipperae R. microsporus var. microsporus var. rhizopodiformis var. oligosporus Rhizomucor R. pusillus Absidia A. corymbifera Apophysomyces A. elegans Cunninghamella C. bertholletiae Saksenaea S. vasiformis Cokeromyces C. recurvatus

Adapted from Ribes et al. [9].

Apophysomyces, Cunninghamella, and Saksenaea [3,6]. Table 2. Major risk factors for mucormycosis Mortierella wolﬁ and Syncephalastrum racemosum Haematological malignancy play questionable roles as human pathogens [7–9]. Leukaemia Five major forms of infection exist—rhino- Lymphoma orbito-cerebral, pulmonary, disseminated, cuta- Multiple myeloma neous, and gastrointestinal. Mucorales enter the Neutropenia Pharmacologic immunosuppression human host through inhalation, percutaneous Antineoplastic chemotherapy inoculation or ingestion [9]. Mucormycosis typ- Corticosteroid therapy ically affects patients with at least one of the Antirejection therapy following immunocompromising states—haema- Diabetes mellitus (Types I and II) with or without tologic malignancy, neutropenia, receipt of high- diabetic ketoacidosis Solid organ transplantation dose corticosteroids, diabetes mellitus, diabetic Bone marrow and peripheral blood stem cell ketoacidosis, organ transplantation, deferoxamine transplantation therapy, trauma and burns (Table 2) [10,11]. Deferoxamine therapy Immunocompetent patients rarely develop Burns Trauma mucormycosis [12]. Malnutrition in children The diagnosis of mucormycosis is challenging. Intravenous drug use In a review of 185 cases of disseminated mucormycosis, Ingram et al. found that an ante mortem diagnosis was made in only 9% of cases reported single institutional series of mucormy- [13,14]. The site of infection inﬂuences physicians’ cosis cases [129 over a 10-year period (1990–99)], abilities to make a diagnosis. In pulmonary Chakrabarti et al. observed that rhino-orbito-cer- mucormycosis, 28–74% of cases were diagnosed ebral (91%) and cutaneous (100%) mucormycosis while patients were alive [5,10,11,15]. In the largest were most reliably diagnosed ante mortem,

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 Prabhu and Patel Mucormycosis and entomophthoramycosis 33 compared to pulmonary (31%), renal (44%), liver transplants from 11 to 42%, with heart gastrointestinal (0%) and disseminated (0%) transplants from 2.2 to 6.3%, and with lung forms [16]. A high index of clinical suspicion transplants from 9 to 27.5% [24–39]. Singh et al. and biopsy accessibility influence physicians’ reported that 80% of cases in solid organ trans- diagnostic abilities as well. plant recipients occurred within 6 months of transplantation [40]. Mucormycosis has been reported from all Epidemiology corners of the world. A few papers have com- The clinical presentation of mucormycosis mented on a possible seasonal variation in Mu- depends on the patient’s underlying medical con- corales infection [5,41]. In Israel, Talmi et al. noted dition. Overall, rhino-orbito-cerebral mucormyco- that 16 of their 19 cases of rhino-orbito-cerebral sis is the most common form (44–49%), followed by mucormycosis occurred between August and cutaneous (10–16%), pulmonary (10–11%), dis- November [41]. In Japan, Funada and Matsuda seminated (6–11.6%) and gastrointestinal (2–11%) noted a similar seasonal variation among haema- presentations [2,17,18]. In patients with haem- tology patients, with six of seven cases of pul- atological malignancy, pulmonary, followed monary mucormycosis having developed by disseminated and rhino-orbtio-cerebral pres- between August and September [5]. entations, are the most common [6]. Diabetics usually develop rhino-orbito-cerebral or pulmon- Microbiological diagnosis ary mucormycosis [11,18]. Some studies have suggested a rising incidence Mucorales are ubiquitous saprophytes found in of mucormycosis. At M. D. Anderson Cancer soil and decaying organic matter [42,43]. They Center in Texas, for example, the number of cases grow on most routine bacterial (i.e. sheep blood increased from eight per 100 000 admissions agar, chocolate agar) and fungal culture media during 1989–93 to 17 per 100 000 admissions (i.e. Sabouraud dextrose agar, inhibitory mould during 1994–98 [6]. The overall incidence of agar, potato dextrose agar) at a wide range of mucormycosis at autopsy at M. D. Anderson temperatures, 25–55 C [44]. Mucorales present in Cancer Center was 0.7% (12 of 1765 autopsies) clinical specimens will grow at 37 C [45] and during the period 1989–98 [6]. Among those with form fluffy white, grey, or brownish colonies that haematological malignancies it was 1.9% (12 of rapidly fill the Petri dish within 1–7 days [9,18]. 624 autopsies) [6]. In Japan, Funada and Matsuda Mechanical homogenization of tissue specimens found a similar incidence of 2.1% at autopsy in can lower the yield of cultures [9,11,46]. patients with acute leukaemia [5]. At the Memor- Several different techniques (e.g. treatment with ial Sloan-Kettering Cancer Center in New York, 20% potassium hydroxide, Gomori’s methenam- Meyer et al. reported an incidence of 4% at ine silver staining, haematoxylin & eosin staining, autopsy among patients with leukaemia from periodic acid-Schiff staining) can be used for direct the period 1962–71. These investigators reported a microscopic detection of Mucorales. Although on higher incidence during the last 2 years (1970–1) microscopy Mucorales have been classically compared to the first 2 years (1962–3), 8% vs. described as having broad (10–50 lm), ribbon-like 1.1%, respectively [19]. Mucormycosis afflicts aseptate hyphae with right-angle branching, approximately 0.9–1.9% of allogeneic bone mar- the hyphae are actually pauciseptate, and the row transplant patients [13,20–23]. angle of hyphal branching can vary from 45 to 90 Mucormycosis constitutes a small proportion of [44,47–51]. Histopathologically, angioinvasion invasive fungal infections in solid organ trans- with surrounding tissue infarction are often ob- plant recipients. The incidence of mucormycosis served. Frater et al. noted perineural invasion in in patients with renal transplants ranges from 0.2 90% of biopsies, a phenomenon that may explain to 1.2%, with liver transplants from 0 to 1.6%, why Mucorales causes rhino-orbital-cerebral dis- with heart transplants from 0 to 0.6%, and with ease [48,52,53]. Mucorales produce a variable lung transplants from 0 to 1.5% [24–36]. The inflammatory response. In a single institutional corresponding incidence of all invasive fungal review of 20 cases, Frater et al. noted a neutrophilic infections (same institutions) in patients with inflammatory response in 50% of cases, a mixture renal transplants ranges from 3.5 to 6.1%, with of neutrophils and granulomas in 25% of cases,

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 34 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004 granulomas alone in 5% of cases, and no inflam- of mucormycosis [32,56,57]. In liver transplant matory response in 20% of cases [48]. recipients, high intraoperative blood transfu- sion requirements, bacterial infections and retransplantation for graft failure place Risk factors patients at greater risk for mucormycosis [24,26, Haematological malignancy is a major risk factor 32,36,37,56,58,59]. for mucormycosis, with leukaemia or lymphoma Deferoxamine therapy for iron or aluminium being the underlying diagnosis in the majority of overload, especially in haemodialysis patients, is patients [14]. Other haematological conditions associated with mucormycosis [60,61]. Over 75% associated with infection include multiple myel- of reported dialysis patients with mucormycosis oma, myelodysplastic syndrome, aplastic anae- had received deferoxamine at the time of diagno- mia and sideroblastic anaemia [1,6,54,55]. Patients sis [62]. Patients with other iron-overload condi- with solid tumours rarely develop mucormycosis tions requiring deferoxamine therapy such as [14]. At M. D. Anderson Cancer Center, Kontoyi- myelodysplastic syndrome, b-thalassaemia and annis et al. found no cases of mucormycosis sideroblastic anaemia have also developed among patients with solid tumours over a 10-year mucormycosis [61,63]. The long half-life of defe- period; all positive cultures represented colonisa- roxamine in haemodialysis patients may uniquely tion [6]. predispose them to infection. The mean duration Malignancy relapse, neutropenia (< 500 neu- of deferoxamine therapy before infection has trophils ⁄ mm3), graft-versus-host disease, and ranged from 8 to 9.3 months (range, 19 days to immunosuppressive therapy (steroids and ⁄ or 20 months) [60,61]. Rhizopus spp. have been the chemotherapy) received in the month before predominant organism recovered on culture diagnosis have been identified as risk factors for [60,61]. Daly et al. found that more than one-half mucormycosis [4,6]. Morrison and McGlave of the patients had disseminated infection, and found that among 13 bone marrow transplant one-quarter had isolated rhinocerebral disease patients (10 allogeneic and three autologous), five [61]. Mortality rates approached 90% in experienced relapse of their underlying disease at these patients [60,61]. Today, far fewer cases of diagnosis, including all autologous transplant mucormycosis are expected in dialysis patients, recipients [22]. In a retrospective review of inva- given that therapeutic erythropoietin has reduced sive mould infections, Baddley et al. found that the need for frequent blood transfusions. graft-versus-host disease, corticosteroids and Iron overload, in itself, is also a risk factor for receipt of an allogeneic bone marrow transplant mucormycosis [3,21,64]. McNab and McKelvie from a matched unrelated, haplotype-identical or reported a diabetic patient with myelodysplasia umbilical cord blood donor were risk factors for receiving monthly blood transfusions and 25 mg mucormycosis by univariate analysis. Only corti- of prednisolone per day who developed rhino- costeroid use remained a significant risk factor by orbito-cerebral mucormycosis; autopsy revealed multivariate analysis (p ¼ 0.018, odds ratio > 20) haemochromatosis [64]. Maertens et al. reported [20]. that severe iron overload in bone marrow trans- Among studies from various institutions, plant recipients was a risk factor for mucormyco- 40–100% of haematology patients with mucormy- sis. In their retrospective review of 263 allogeneic cosis had been neutropenic at diagnosis [6,20–22]. bone marrow transplants, five cases of mucormy- Nosari et al. reported the median duration of cosis were identified. All demonstrated iron neutropenia before diagnosis as 10 days (range, overload compared to a control group—mean 5–18 days) while Kontoyiannis et al. found a ferritin 2029 lg ⁄ L vs. 608 lg ⁄ L(p ¼ 0.0185), trans- mean duration of 16 days (range, 5–54 days) [4,6]. ferrin saturation 92% vs. 63% (p ¼ 0.0001), and Patients who undergo solid organ transplan- number of transfused units of blood 52 vs. 26 units tation are at risk for mucormycosis as well, (p ¼ 0.0001), respectively [21]. Most infections particularly if they are treated for acute rejection occurred in the late post-transplant period, median with high-dose corticosteroids, OKT3, or anti- 343 days post-transplant (range, 90–534 days) [21]. thymocyte globulin [27,36,39,56]. Cytomegalovi- Other studies, however, reported earlier develop- rus infection in solid organ transplant recipients ment of mucormycosis, median 102–126 days post- has been associated with the development transplant (range, 12–470 days) [20,22].

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Deferoxamine, which acts as a siderophore, Cirrhosis, congenital heart disease, malnutri- was originally isolated from Streptomyces pilosus tion, carcinoma, anaemia, hepatitis, glomerulo- [65]. Iron is a necessary growth factor for many nephritis, uraemia, amoebiasis, typhoid fever micro-organisms. In animal models of mucor- and gastroenteritis have been associated with mycosis, iron and deferoxamine promote the mucormycosis [76]. growth and increase the virulence of Rhizopus oryzae and Rhizopus microsporus [62,65]. Clinical manifestations Diabetics, especially those with ketoacidosis, are predisposed to rhino-orbito-cerebral All species of Mucorales produce similar clinical mucormycosis. In vitro, serum acidosis permits pictures [3]. The underlying medical condition the growth of Rhizopus spp. Normal serum inhib- and associated risk factors determine which form its the growth of Mucorales [62]. The capacity of of mucormycosis develops. serum to bind iron falls significantly when the pH drops below 7.4 [66]. Artis et al. and Boelaert et al. Rhino-orbital-cerebral have shown that acidosis inhibits transferrin’s Mucorales infects the head and neck region in well- capacity to bind iron, thus allowing Rhizopus spp. defined stages. Infection begins in the palate or the to utilize it for growth in vitro. Artis et al. found paranasal sinuses, progresses to the orbit, and, if that the serum of four of seven diabetic ketoac- not diagnosed early, to the brain. For simplicity the idosis patients (pH 6.74–7.27) incubated with term ‘rhino-orbito-cerebral mucormycosis’ will be R. oryzae spores supported profuse growth, but used to refer to any stage of this type of infection. inhibited growth when the pH was titrated to 7.4. Rhino-orbito-cerebral mucormycosis is the most The three serum samples that did not support common form of infection [10]. Rhizopus spp. growth, compared to those that did, had signifi- account for 70% of culture-positive cases reported cantly lower iron levels, 13 lg ⁄ dL vs. 69 lg ⁄ dL, in the literature [77]. respectively. The serum glucose level did not Signs and symptoms can include fever, leth- affect growth irrespective of pH [66]. Impaired argy, headache, orbital pain, abrupt loss of vision, neutrophil and macrophage function in diabetics ophthalmoplegia, proptosis, ptosis, dilated pupil, may also contribute to a risk of mucormycosis corneal anaesthesia and clouding, chemosis, peri- [47,67–69]. orbital cellulitis, sinusitis, epistaxis, facial palsy, Human immunodeficiency virus (HIV) infec- trigeminal nerve distribution sensory loss and tion does not appear to increase the risk of seizures [10,77–79]. Cavernous sinus and internal developing mucormycosis probably because neu- carotid artery thrombosis are also reported com- trophils, as opposed to T lymphocytes, play a plications [10,41,76–78]. Cerebrospinal fluid find- major role in defence against Mucorales ings are usually normal or nonspecific [41,76]. [3,11,70,71]. When mucormycosis does occur in Rhino-orbito-cerebral mucormycosis has been an HIV patient, it usually occurs in the context of described classically in patients with diabetic intravenous drug use. In a review of HIV patients ketoacidosis or poorly controlled diabetes mellitus with mucormycosis, Van den Saffele and Boelaert [50,76]. It develops in leukaemia patients, usually reported that 73% were intravenous drug users. as a result of concomitant diabetes mellitus, or The majority developed cerebral, cutaneous, arti- high-dose corticosteroids [19,50,76]. Rhino-orbito- cular, or renal infection [70]. The majority of cerebral mucormycosis has developed in many intravenous drug users (80–85%) who develop other situations, such as following solid organ isolated cerebral mucormycosis are HIV negative and bone marrow transplant, b-thalassaemia, [70,72]. trauma, burns, deferoxamine therapy, and even Other infections (e.g. malaria) may predispose polypous rhinosinusitis [49,50,80]. Rhino-orbito- patients to Mucorales infection. Wilson et al. cerebral mucormycosis has been rarely reported reported a patient with severe Plasmodium falci- in HIV patients [71]. When rhino-orbito-cerebral parum malaria who developed disseminated Absi- mucormycosis develops after trauma in an immu- dia corymbifera and Aspergillus flavus infection. nocompetent host, one should consider Apophy- Possible predisposing factors include severe hae- somyces elegans as the possible pathogen [49]. Early molysis, metabolic acidosis and immune suppres- on, paranasal sinus involvement may manifest sion from malaria itself [73–75]. as benign mucosal thickening on computed

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 36 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004 tomography. Bone destruction occurs later [80]. [41,50,77,78,85]. Anecdotally, nebulized ampho- Mucorales invades the retro-orbital region and tericin B has been used as an adjunct to surgery frontal lobes by extending through the ethmoid or and intravenous liposomal amphotericin B in sphenoid sinuses [76,81,82]. It can also invade the sinonasal mucormycosis [80,86]. brain through the superior orbital fissure, ophthal- mic vessels, perineural route, cribiform plate or the Pulmonary carotid artery [10,41]. This is the second most common site of involve- Black necrotic eschar visualized on the palate or ment of Mucorales infection [10,76]. Inhalation of nasal mucosa has been the classically described spores is the primary route of infection [9,87]. Its clinical clue of infection, however this lesion is not clinical presentation is indistinguishable from that invariably there on presentation. Ferry and Abedi of invasive pulmonary aspergillosis [87]. Males noted a black eschar on the skin, nasal mucosa or appear to be over-represented in the medical palate in 19% (three of 16) of patients at presen- literature, with a male to female ratio of 2.3–3 : 1 tation, but the majority (68%) eventually devel- [11,15]. oped this sign [78]. Yohai et al. noted nasal or Patients with leukaemia have traditionally been palatal ulceration, or necrosis in only 52% of considered to represent the majority of cases; patients within 72 h of onset of signs and symp- however, recent papers have suggested diabetes toms [77]. The absence of this finding should not mellitus to be the most prevalent underlying con- preclude considering the diagnosis. dition [16,76]. Chakrabati et al. found that among Patients can develop a slowly progressive form 13 pulmonary cases, diabetes was the predispos- of rhino-orbito-cerebral mucormycosis with signs ing factor in 23.1%, renal transplantation in and symptoms of more than 4 weeks duration 15.4%, malignancy in 7.7%, and corticosteroid [41,79,81]. Harrill et al. reviewed 18 cases of administration in 7.7% [16]. Tedder et al. re- chronic mucormycosis, and found a median viewed 255 cases of mucormycosis that involved duration of symptoms of 7 months. Sixty-seven at least the lungs; 39% had underlying haema- per cent of the patients had diabetes mellitus, and tological malignancy, 32% had diabetes mellitus, 83% had evidence of internal carotid artery or 8% had undergone organ transplantation, and cavernous sinus thrombosis. Despite this, the 18% had renal failure [15]. In a recent review of 87 overall survival rate was 83% [81]. cases of isolated pulmonary mucormycosis, Lee Intravenous drug use places patients at risk for et al. found that diabetics compromised the isolated cerebral mucormycosis. The basal ganglia majority [49 (56%)] of cases, followed by 28 were involved in 92% of cases reviewed by patients (32%) with haematological malignancy, Hopkins et al. [72]. Computed tomography of 11 (13%) with renal insufficiency, 10 (11%) with the head reveals a variety of enhancement prior organ transplantation, and 11 (13%) had no patterns, from ring, to homogeneous, to none apparent underlying disease [11]. These figures [72]. The lesions may show minimal enhancement do not, however, reflect the incidence of disease. on magnetic resonance imaging with gadolinium Patients with leukaemia, lymphoma and severe contrast [72]. Such patients have been treated neutropenia remain at greater risk of developing successfully with a combination of surgery and pulmonary mucormycosis compared to other amphotericin B, and even amphotericin B alone forms of mucormycosis [19,47,76]. The apparent [72,83,84]. equal or greater prevalence of diabetics with Indicators of poor prognosis include delay in pulmonary mucormycosis may be related treatment (> 6 days), symptomatic intracranial more to the greater number of patients with involvement with hemiplegia or hemiparesis, diabetes compared to haematological malignan- bilateral sinus involvement, palatal involvement, cies [47,76,88]. Patients with lymphoma may need underlying leukaemia, deferoxamine therapy, the added risk factor of diabetes to place them at facial necrosis, or orbital involvement [41,77,85]. risk for infection. In a review by Meyer et al. Effective therapy includes early diagnosis, all mucormycosis patients with lymphoma had correction of any underlying reversible med- diabetes, while only 29% of those with acute ical condition, antifungal therapy, and surgical leukaemia had concomitant diabetes [19]. Patients debridement. In rhino-orbito-cerebral mucormy- with solid tumours rarely develop pulmonary cosis, mortality rates vary from 30% to 69% mucormycosis [2,12,49].

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 Prabhu and Patel Mucormycosis and entomophthoramycosis 37

Patients can present with cough, fever, haem- infection [4,5,11,22,88]. Subacute pulmonary optysis and ⁄ or pleuritic chest pain [5,11,87]. mucormycosis may be more responsive to med- Leukocytosis need not be present [11,89]. Haema- ical therapy alone [4,47,95,99]. A combined surgi- tology patients can have coexisting infection with cal and medical approach is the most common Aspergillus species, Candida species, bacteria, or method of treatment. cytomegalovirus [5,11,19,21]. Lee et al. found Mucorales can produce an asymptomatic coinfection, mostly bacterial, in 32% of cases. mycetoma, similar to Aspergillus [8,76,87]. Hyper- This could explain the initial response to antibac- sensitivity pneumonitis to Rhizopus has been terial therapy occasionally noted [11]. reported in Scandinavian sawmill workers Diabetics have an apparent predilection for (so-called woodtrimmer’s disease) and in farm developing endobronchial lesions [87,90–92]. workers [100]. These patients represent 82–85% of endobronchial cases in the literature [11,93]. Signs of endo- Cutaneous bronchial involvement include a hoarse voice, Cutaneous mucormycosis can develop after a haemoptysis, mediastinal widening on chest break in the skin’s integrity from surgery, burns, radiograph, lobar collapse and postobstructive soiled trauma, motor vehicle accidents, bone pneumonia [87,92]. These lesions can invade fractures, intravenous lines, insect bites, cactus major pulmonary blood vessels; patients usually spine injuries, abrasions, lacerations, biopsy sites, die from massive haemoptysis [92]. Surgical allergen patch testing, contaminated adhesive resection is a necessity. tapes and intramuscular injections [13,17,56,101– Pulmonary mucormycosis has a similar radio- 109]. graphic appearance to aspergillosis. Both infec- Predisposing factors include diabetes, leukae- tions have a propensity to invade blood vessels mia and organ transplantation [24,42,56,110]. and produce thrombosis. Radiographic presenta- Cutaneous mucormycosis is the form of infection tions include inﬁltrate, wedge-shaped consolid- least likely to be associated with underlying ation, nodule, cavitation, mycetoma, lobar collapse disease [17,103]. In a review by Adam et al. and, rarely, pleural effusion [5,10,11,88,94]. The air diabetes was present in only 26% of cutaneous crescent sign, which typically suggests invasive cases, compared to 67% of rhinocerebral, 21% of pulmonary aspergillosis, was present in 12% of 32 disseminated, and 20% of pulmonary cases. cases of mucormycosis reviewed by McAdams Leukaemia and ⁄ or neutropenia were found in et al. [90,95]. In the same review of mucormycosis 16% of cutaneous, 16% of rhinocerebral, 42% of cases, 66% had consolidation and 41% had disseminated, and 48% of pulmonary cases cavitation on chest radiograph [90]. Crescentic [102]. cavitation can develop either during the neutrop- Cutaneous mucormycosis can manifest as a enic or postneutropenic phase [5,11,95]. superﬁcial or deep infection [102]. It can appear Pulmonary mucormycosis in immunocompe- as pustules, blisters, nodules, necrotic ulcera- tent hosts is not common [96,97]. When infections, echthyma gangrenosum-like lesions or tion in an apparently immunocompetent host necrotizing cellulitis [107,111,112]. Skin biopsy does occur, symptoms can be present for several is required for diagnosis. Cultures and fungal months before diagnosis. For example, Zeilender stains of wound swabs are not sensitive, and et al. reported an immunocompetent patient may give misleading microbiological results with Cunninghamella bertholletiae pulmonary [111,113]. infection who presented with a 4-month history Of particular note, infections with A. elegans of productive cough, fever, chills and night and Saksenaea vasiformis occur predominantly in sweats [98]. tropical and subtropical climates (Australia, India, Subacute (> 4–6 weeks of symptoms) pulmon- Mexico, Venezuela, Aruba, South Carolina, Mis- ary, and even disseminated mucormycosis, cases sissippi, Florida, Arizona, Texas, Caribbean) in diabetic patients have been reported [47,89]. Lee [9,49,102,104,105,108,109,114,115]. They are both et al. found that 18% of pulmonary mucormycosis thermophilic fungi that grow at warm incubation cases had symptoms for > 30 days [11]. temperatures (i.e. 43 C) [46]. Infection typically Mortality rates of 60–100% have been reported develops in the extremities after trauma or in the in haematology patients with focal pulmonary context of prior skin lesions [105].

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 38 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004

Historically, contaminated dressings have malnutrition, meningococcaemia and prematurity caused hospital outbreaks of cutaneous have developed gastrointestinal mucormycosis mucormycosis. Keys et al. reported a hospital [10,43,118,120–124]. outbreak of R. oryzae skin infection from contam- Gastrointestinal mucormycosis has rarely inated nonsterilized Elastoplast tape. Samples of occurred after renal, liver and heart transplanta- unused Elastoplast tape from the hospital and tion [118,125–127]. Oliver et al. reported a bone the manufacturing plant both grew R. oryzae marrow transplant patient with graft-versus-host [113,116]. Gartenberg et al. reported a similar disease who developed Mucor indicus hepatic series of Rhizopus rhizopodiformis-contaminated mucormycosis after consuming naturopathic Elastoplast tape related infections [113]. Cutane- medicine. M. indicus was recovered from the ous mucormycosis from contaminated dressings hepatic abscess and naturopathic medicine. Both has not been reported recently [102]. were identical by arbitrary-primed polymerase Cutaneous mucormycosis portends a better chain reaction analysis [128]. prognosis than other forms of mucormycosis. In One third of the cases of gastrointestinal mu- a review of 11 cases of cutaneous mucormycosis cormycosis occur in infants and children [10,43]. from one institution over a 25-year period, Adam In children less than 1 year of age, the stomach et al. found that all patients survived. In a review (59%) and colon (53%) have been the most of the medical literature, cutaneous involvement commonly involved sites, followed by the small had the lowest mortality (16%), compared to 67% bowel (24%) [43]. In children aged 2–18 years the for rhinocerebral, 83% for pulmonary, and 100% stomach has been involved in 85% of cases, for disseminated and gastrointestinal mucor- oesophagus in 38% of cases, small bowel in 31% mycosis [102]. Complete resection of necrotic of cases, and colon in 31% of cases [43]. Mal- and infected tissue is the key to successful nutrition has been present in 50% of cases [43]. therapy. Cutaneous mucormycosis presentation Overall, the most frequent segments involved are varies from indolent to a rapidly progressive the stomach, followed by the large bowel [10,76]. infection requiring surgical debridement, antifun- Intestinal mucormycosis is rare in the normal gal therapy, or even amputation [102]. host. Calle and Klatsky described a case in an apparently immunocompetent 23-year-old Disseminated African-American woman [119]. The autopsy, Disseminated mucormycosis involves two or more however, demonstrated haemosiderosis of the noncontiguous organs. Neutropenic patients with liver and spleen, raising the possibility of iron leukaemia or lymphoma comprise the majority of overload. Gastric mucormycosis has developed patients with disseminated mucormycosis [4,89]. after nasogastric intubation and in the presence of Dissemination occurs in 23–62% of cases with known gastric ulcers [21,43,116,123,129]. haematological malignancy [3,4,6,19,22,117]. Other Surgical intervention is usually necessary given risk factors for dissemination include organ trans- the high risk of gastrointestinal perforation and plantation, chemotherapy, corticosteroids and def- exsanguination [122]. eroxamine therapy [4,6,16,61]. Many patients are coinfected with other bacterial, viral or fungal Miscellaneous pathogens [6,76]. The mortality rate for dissemin- Mucormycosis is a rare cause of prosthetic valve ated disease approaches 100% [3,15,117]. endocarditis [63,130,131]. Native valve endocarditis with C. bertholletiae and S. vasiformis has been Gastrointestinal reported [12,132]. The signs and symptoms of gastrointestinal Kalayjian et al. reported an unusual case of mucormycosis are nonspeciﬁc, and include Mucorales causing aortic thrombosis in a patient abdominal pain, haematemesis and melena with myelodysplastic syndrome. At autopsy, [40,118,119]. Patients who have undergone organ, hyphal invasion throughout the entire thickness bone marrow or peripheral blood stem cell of the aortic wall, with no organ involvement, was transplantation, and those with acute myelogen- noted [54]. ous leukaemia, lymphoma, diabetic ketoacidosis, Isolated renal mucormycosis has developed in nonketotic diabetes mellitus, amoebic colitis, intravenous drug users. It has also occurred in typhoid fever, pellagra, kwashiorkor, malaria, patients who have undergone renal transplanta-

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 Prabhu and Patel Mucormycosis and entomophthoramycosis 39 tion in warmer climates and developing countries tial to therapy [87]. Diabetics may have a more such as India, Egypt, Saudi Arabia, Kuwait and favourable outcome than nondiabetics. Yohai Singapore [26,57,133]. et al. reported an overall survival rate for rhino- Osteomyelitis usually occurs after traumatic orbito-cerebral mucormycosis of 77% in diabetics inoculation or surgical intervention (i.e. tibial pin and 34% in nondiabetics [77]. Blitzer et al. made a placement, anterior cruciate ligament repair) similar observation in rhino-orbito-cerebral [134–136]. Osteomyelitis of the tibia, cuboid, mucormycosis patients with a 60% survival rate calcaneus, femur, humerus, scapula, metacarpals, among diabetics and 20% in nondiabetics [85]. phalanges and sternum have been reported Those with severe underlying diseases, such as [94,114,135–138]. Haematogenous osteomyelitis leukaemia and lymphoma, tend to have poorer is extremely rare [138]. outcomes [76]. The mortality rate for isolated pulmonary mucormycosis varies from 9.4 to 27% with a combined surgical and medical approach, Diagnosis compared to 50–55% for those treated only A diagnosis of mucormycosis is rarely suspected medically [11,15]. Notably, there is inherent selec- among haematology patients as most physicians tion bias in reported cases, and in candidates for presume a diagnosis of invasive aspergillosis. In types of therapy [11]. haematology patients an ante mortem diagnosis The mainstay of treatment is antifungal therapy of mucormycosis is made in only 23–50% of cases with an amphotericin B preparation (Table 3), [4–6,21,117]. Computed tomography of the chest surgery, and correction of the underlying medical might identify infiltrates suggestive of mucor- condition if possible. Amphotericin B is the only mycosis not documented by standard chest radio- available antifungal agent with significant in-vitro graph [4,90]. The poor sensitivity of sputum activity against Zygomycetes. Caspofungin and culture (25%) makes diagnosis challenging [6]. 5-flucytosine are resistant in vitro to Mucorales The yield of bronhoalveolar lavage is not higher [150,193]. Amphotericin B and its lipid formula- [6,88,90]. Direct microscopy of bronchoalveolar tions have been successfully used to treat mu- lavage together with transbronchial biopsy may cormycosis [1,99,141,192]. increase the yield [87,88]. It may be difficult to Certain Mucorales species have variable sus- obtain a transbronchial biopsy given that many ceptibilities to amphotericin B. Garey et al. found haematology patients are thrombocytopenic. A that the mean inhibitory concentrations (MIC) of positive finding from bronchoalveolar lavage Cunninghamella clinical isolates ranged from from a neutropenic or immunocompromised host <1 lg ⁄ mL to 100 lg ⁄ mL. They reported a case would be highly suggestive of infection, and of C. bertholletiae infection in an allogeneic bone should be treated as such [87,88,99]. Histological marrow transplant recipient unsuccessfully trea- examination of biopsied tissue is the preferred ted with two different lipid formulations of method of diagnosis. Invasion seen on histo- amphotericin B (amphotericin B liposomal and pathology is needed to confirm a diagnosis [10]. lipid complex). The MIC according to National Polymerase chain reaction may become a diag- Committee for Clinical Laboratory Standards nostic modality to identify these organisms [139]. Rickerts et al. diagnosed disseminated C. bertholletiae infection in a leukaemic patient using a Table 3. Most frequently used antifungal agents to treat polymerase chain reaction assay targeting 18S mucormycosis and entomophthoramycosis ribosomal DNA in blood. The diagnosis was Mucormycosis confirmed by positive cultures from bronchoalvel- Amphotericin B deoxycholate (Fungizone) [5,22] olar lavage and pleural fluid. Such an approach Amphotericin B cholesterol sulfate complex also holds promise for the diagnosis of invasive (Amphotec, Amphocil) [1] Liposomal amphotericin B (AmBisome) [49,59,99,109] aspergillosis [139,140]. Amphotericin B lipid complex (Abelcet) [83,190] Entomophthoramycosis Potassium iodide [167,174,175] Treatment Itraconazole [169,171,176,179] Ketoconazole [175] Treating a patient’s underlying medical condi- Miconazole [181,183] tion and reducing immunosuppression are essen-

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 40 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004

(NCCLS) guidelines was 4 lg ⁄ mL. Amphotericin marrow transplantion for non-Hodgkin’s lym- B lung concentrations from surgically removed phoma by using amphotericin B lipid complex tissue were on average 9.5 lg ⁄ mL after having (5 mg ⁄ kg daily) and itraconazole (200 mg twice received more than 10 g of liposomal amphoter- daily) alone. Re-induction of remission through icin. Amphotericin B may not achieve satisfactory donor lymphocyte infusion and neutropenia reso- levels at the site of involvement because of tissue lution appeared to play critical roles for his survival infarction and thrombosis [142]. [141]. Anecdotal case reports exist concerning the Granulocyte–macrophage colony-stimulating treatment of mucormycosis with fluconazole and factor (GM-CSF) and granulocyte colony-stimula- itraconazole [143–145]. Funada et al. reported a ting factor (G-CSF) have been used adjunctively to 29-year-old woman with acute myelogenous treat mucormycosis in neutropenic and non-neu- leukaemia with pulmonary mucormycosis who tropenic patients [49,99,153–156]. Anecdotally, appeared to respond clinically and radiographi- granulocyte transfusions have been used as an cally to fluconazole. The response, however, may additional treatment measure in neutropenic have been secondary to a recovering neutrophil patients [141, 194]. count [146]. Most in-vitro and animal studies have There are multiple reports on the use of shown poor efficacy of azoles [51,145,147–150]. adjunctive hyperbaric oxygen [49,50,157–163]. A Azoles were not effective against Rhizopus typical regimen uses 100% oxygen at two atmos- infection in guinea-pig and murine models [145]. pheres for 90 min twice a day [50]. In vitro, there Itraconazole was inferior to amphotericin B in is no effect of pressure alone on the growth of murine models of disseminated Absidia and fungi [164]. In vitro, R. oryzae is inhibited by a 2-h Rhizopus infection [145,147]. There is some exposure to 100% oxygen at one atmosphere experimental murine data to suggest activity [50,165]. In a deferoxamine-treated mouse model of fluconazole in combination with ciprofloxa- of mucormycosis, Barratt et al. found no benefit of cin or trovafloxacin in pulmonary mucormycosis adjunctive hyperbaric oxygen compared to ampho- [151]. Voriconazole, in vitro, shows no useful tericin B alone [166]. activity against Mucorales [148,150]. Posacona- In a retrospective review, Ferguson et al. zole, a new triazole under development, shows observed that hyperbaric oxygen, amphotericin promise as an effective alternative agent against therapy, and surgical debridement were associ- Mucorales [191]. ated with a statistically insignificant lower mor- Correction of the underlying medical condi- tality than were amphotericin B therapy and tion is essential for successful therapy, as dem- surgical debridement alone. In a retrospective onstrated by a rare case of documented cavitary review of mucormycosis, Yohai et al. found a pulmonary mucormycosis by Rhizopus sp. that higher survival rate with standard therapy and resolved without antifungal therapy after correc- hyperbaric oxygen compared to standard therapy tion of diabetic ketoacidosis [152]. Abraham et al. alone, 83% (five of six patients) vs. 22% (four of 18 reported a case of asymptomatic pulmonary patients) (p ¼ 0.0285) [77]. Such studies are limited mucormycosis in a man with Graves’ thyrotoxi- by their small sample size and the lack of random- cosis that resolved without antifungal therapy isation [50]. A randomised trial is unlikely to be [148–150]. performed, given the rarity of this infection, and Recovery of neutrophils plays a significant role patients’ variable comorbidities and severity of in successful resolution of this infection in neu- illness [50]. tropenic patients [95,141]. Funada et al. reported a patient with acute myelogenous leukaemia with ENTOMOPHTHORAMYCOSIS documented pulmonary mucormycosis who was successfully treated with amphotericin B and Infection with fungi from the order Entomophtho- 5-flucytosine alone. Recovery from neutropenia rales, Conidiobolus coronatus, Conidiobolus incongru- was considered of vital importance for this us and Basidiobolus ranarum, typically occurs in patient’s recovery [95]. Roy et al. successfully immunocompetent patients residing in subtropical treated disseminated (brain, lung, skin) Mucor and tropical climates [167]. Unlike Mucorales, and Aspergillus species infection in a patient who Entomophthorales do not cause angioinvasive had relapsed 10 months after allogeneic bone disease [9,168–171].

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 Prabhu and Patel Mucormycosis and entomophthoramycosis 41

The most common symptoms include nasal Basidiobolomycosis obstruction, nasal discharge or chronic sinusitis. Basidiobolomycosis is a chronic infection of the Surgery alone is usually not curative [183]. subcutaneous tissue caused by B. ranarum. This Invasive infection is rare. Jaffey et al. described organism resides in decaying plant material, soil, a case of a cocaine abuser who developed dis- leaves from deciduous trees, and the intestines of seminated Conidiobolus sp. infection with endo- fish, frogs, toads, insects, reptiles and insectivor- carditis and fungal vasculitis. The species was not ous bats [167,172,173]. Many case reports and consistent with C. congruus or C. coronatus [186]. series of subcutaneous basidiobolomycosis come Walsh et al. reported a case of pulmonary and from Africa (especially Uganda and Nigeria), cardiac involvement with angioinvasion in a India, and South-east Asia [167,169]. B. ranarum patient with lymphoma [187]. usually infects children [172,174,175]. Mugerwa reviewed 80 cases from Uganda and found that Diagnosis 76% of patients were under 10 years of age, and 88% under 20 years of age [172]. Histopathologic examination usually shows Basidiobolomycosis mainly involves the thigh, dense eosinophilic granular infiltrates surround- buttock or trunk [172,174,175]. Mugerwa sugges- ing hyphal elements, the so-called Splendore– ted that the use of ‘toilet leaves’ to clean after Hoeppli phenomenon. The inflammatory infil- defecation might explain the observed distribu- trate is mixed with eosinophils, histiocytes, tion of lesions and source of infection [172]. neutrophils, lymphocytes, plasma cells and giant Painless erythematous firm indurated plaques of cells [167–169,172,174,175]. This reaction is not the subcutaneous tissue are characteristic [167]. seen in mucormycosis. Patients may have leuko- Significant nonpitting oedema of the involved cytosis and peripheral eosinophilia [174]. extremity may occur. Skin ulceration and lymph Serology testing is not widely available. Khan node enlargement have been reported [174,175]. et al. detected B. ranarum antibodies with immuno- B. ranarum are pauciseptate on histopathology, diffusion and ELISA tests [178]. Kaufman et al. but more septate than are Mucorales. also devised an immunodiffusion test to detect B. ranarum rarely involves the gastrointesti- both Conidiobolus and Basidiobolus. The assay was nal tract, as has been described in Arizona, 100% sensitive and specific [188]. Florida, Utah, Nigeria, Brazil and Kuwait [169–171,176–179]. Patients can present with Treatment abdominal pain, constipation, diarrhoea, nausea, vomiting, bloody mucous discharge, fever and Potassium iodide, miconazole, cotrimoxazole, weight loss [167,169–171,177]. Gastrointestinal ketoconazole, itraconazole, amphotericin B, terbin- basidiobolomycosis is associated with mural afine, hyperbaric oxygen and surgical debridement thickening, nodular masses, and ulcerations of have been used in various combinations with the intestine that resemble Crohn’s disease. It can variable success (Table 3) [167,173–176,181, involve the stomach, small intestine, colon or 183–185]. Guarro et al. performed susceptibility rectum [179]. Invasive sinusitis has also been testing on nine Basidiobolus spp. and eight Conid- reported rarely [180]. iobolus spp. isolates. The geometric mean MIC values for Basidiobolus spp. were lower than for Conidiobolus spp.: itraconazole, 1.8 vs. 11.3 lg ⁄ mL; Conidiobolomycosis ketconazole, 1.0 vs. 20.7 lg ⁄ mL; miconazole, 3.9 vs. Conidiobolus spp. typically cause a chronic, indolent 11.3 lg ⁄ mL; amphotericin B, 2.7 vs. 3.1 lg ⁄ mL; infection of the face [173,175,181]. Cases have been fluconazole, 14.8 vs. 107.5 lg ⁄ mL; and flucytosine, reported from West Africa, South America, India, 165.9 vs. 234.6 lg ⁄ mL [189]. There is no clinical Saudi Arabia, Oman and Taiwan [173,175,181– experience in treating entomophthoramycosis 185]. Conidiobolus spp. cause a progressive swelling with voriconazole. Krishnan et al. had good mass over the nasal submucosa, nose, eyelids, and success with potassium iodide at 40 mg ⁄ kg ⁄ day over the malar and frontal regions of the face. in 9 of 10 patients seen with either conidiobolomy- Conidiobolomycosis has been rarely reported to cosis or basidiobolomycosis over a 4-year period involve the nasolacrimal duct and orbit [182,183]. [175]. Clinical failure has been reported with

2004 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 10 (Suppl. 1), 31–47 42 Clinical Microbiology and Infection, Volume 10 Supplement 1, 2004 amphotericin B [171,181]. Itraconazole or potas- 4. Nosari A, Oreste P, Montillo M et al. Mucormycosis in sium iodide seem reasonable ﬁrst-line choices hematologic malignancies: an emerging fungal infection. Haematologica 2000; 85: 1068–71. [171,179]. No single agent has reliable consistent 5. Funada H, Matsuda T. Pulmonary mucormycosis in a antifungal activity [181]. In-vitro susceptibility hematology ward. Intern Med 1996; 35: 540–4. testing may be helpful in guiding therapy [181]. 6. Kontoyiannis DP, Wessel VC, Bodey GP, Rolston VI. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis 2000; 30: 851–6. CONCLUSIONS 7. Kamalam A, Thambiah AS. Cutaneous infection by Syncephalastrum. Sabouraudia 1980; 18: 19–20. Infections with fungi from the orders Muco- 8. 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