Postgrad Med J: first published as 10.1136/pgmj.62.733.985 on 1 November 1986. Downloaded from Postgraduate Medical Journal (1986) 62, 985-996

Review Article

Systemic

E.W. Benbow and R.W. Stoddart Department ofPathology, University ofManchester, Oxford Road, Manchester M13 9PT, UK.

Introduction Two families of the class of fungi known as zygomycetes not within the order of can Zygomycetes contain most of those members which cause systemic zygomycosis (King & Jong, 1976; de are reported to cause human disease. The Entomoph- Aguiar et al., 1980; Scholer et al., 1983). Deep thoraceae are particularly associated with infection of infection is often only diagnosed on histological the and subcutaneous tissue, whereas the examination: the species cannot then be identified by typically cause systemic disease. The any method in general use, and the genus can only be species most often associated with such systemic guessed at. It is, in such circumstances, not possible to infections include oryzae, Rhizopus be sure of anything other than that a zygomycete is rhizopodiformis, corymbifera and Rhizomucor present, and so the term 'zygomycosis' is safest. When pusillus; a number ofother species are also occasional- a suitable adjective, such as 'systemic' or 'subcutan- ly implicated (Scholer et al., 1983), and it is clear that eous' is appended, all examples can be unambiguously

the number ofidentified pathogenic species is increas- labelled (Ajello et al., 1976). by copyright. ing. The Zygomycetes are typically found in soil and In clinical nomenclature, there is a terminological dung (Emmons, 1962). Members of the genera quagmire, within which '', 'phycomy- associated with human disease are part of the soil cosis' and 'zygomycosis' are sometimes used as if mycoflora in many parts of the world (Warcup, 1951; they were synonymous (Medical Research Council, Miller et al., 1957; Moubasher & Abdel-Hafez, 1978), 1977). '' appears to have been rendered including the United Kingdom (Warcup, 1951; obsolete by taxonomic changes (Ajello et al., Nichols, 1956); they are frequent contaminants of 1976; Emmons et al., 1977), though it was the term animal fodder (Ainsworth & Austwick, 1955) and of preferred by the nomenclature committees of the tobacco (Papavassiliou et al., 1971). Their spores are

British Society for Mycopathology (Medical Research widespread in the air (Agarwal et al., 1969; Hudson, http://pmj.bmj.com/ Council, 1977) and the International Society for 1973; Sorensen et al., 1974), are present in house dust Human and Animal Mycology (Vanbreuseghem et al., (Davies, 1960) and were found in the atmosphere in a 1980), as well as the authors of a standard text in ward in a London teaching hospital (Noble & Clayton, mycology (Emmons et al., 1977). Other major texts, 1963). They may be cultured from the sputum of a however, prefer 'mucormycosis' (Rippon, 1982) or minority ofhealthy men (Kahanpiiii, 1972; Comstock 'zygomycosis' (Chandler et al., 1980). The organisms et al., 1974). Pathogenic species were found in the causing cutaneous and subcutaneous infections can warm effluent from a power station and in the soil of often be identified by culture, and it may then be the immediate vicinity, though no significant on September 30, 2021 by guest. Protected logical to refer to the resulting clinical condition as associated increase in the air spore count could be '' or ''. detected (Rippon et al., 1980). Zygomycetes do not 'Mucormycosis' should strictly be limited to cases often cause human disease; their most common effects proven by culture to be caused by a member of the on our lives result from their ability to cause decay in Mucorales (Meyers et al., 1979; Hawksworth et al., many kinds offruit and vegetables (Harter & Weimer, 1983), but the term is established by long usage, and is 1922). customary where a diagnosis by biopsy only is availa- They are facultative necrotrophs, able to invade and ble. This usage is potentially misleading, for kill living tissue, and to then withdraw nutrients from it (Cooke, 1977). They require previous damage to the Correspondence: E.W. Benbow B.Sc., M.B., Ch.B., skin of most fruits, either by trauma (Harter & M.R.C.Path. Weimer, 1922) or initial attack by another agent Accepted: 12 May 1986 (Stevens, 1914), before they can invade. Intact peach t) The Fellowship of Postgraduate Medicine, 1986 Postgrad Med J: first published as 10.1136/pgmj.62.733.985 on 1 November 1986. Downloaded from 986 E.W. BENBOW & R.W. STODDART skin may be breached (Harter & Weimer, 1922), and especially India, usually of single cases. European economically significant decay may result (Heaton, publications follow this latter pattern, with the excep- 1980). They may harm other soft fruit crops, such as tion ofa Swiss report offour cases (Stahel et al., 1983), strawberries (Stevens, 1914), but they can also cause a Czech report of 11 cases (Vorreith, 1969), and four significant post-harvest loss of thick-skinned fruit, cases in a Spanish hospital, presented in two overlap- such as Cantaloupe melons (Wade & Morris, 1982). ping reports (Guttierez Diaz et al., 1981; del Palacio They are often found in peanuts (Moubasher et al., Hernanz, 1983). 1979), and may reduce the useable oil content of Symmers (1966) has seen 'many' examples in re- cotton seeds (Abdel-Rahman, 1981). They are even ferred histological material originating within the present in dried pasta products (Christensen & Ken- British Isles, but does not describe them in detail. nedy, 1971). Various Zygomycetes are used, often as Detailed reports are all of single cases (Kurrein, 1954; components of mixed cultures, in several culinary La Touche et al., 1963; Winston, 1965; Hanley, 1978; processes in the Far East and the Indian subcontinent. Helenglass et al., 1981; Benbow et al., 1985; Flood et They are used to promote the fermentation of various al., 1985). substrates, including soybeans and rice, to foods and It is the general experience that the incidence of drinks which are more palatable or interesting than the systemic zygomycosis is increasing, though the disease original material. Some of these techniques even remains a minority of opportunistic infections. This increase the nutritional value of the raw material by increase may be a consequence of the increased use of making its components more readily digestible (Hes- antibiotics, the development ofmore potent chemoth- seltine, 1965; Fukushima, 1981). erapeutic agents, and their devolvement in an increas- Systemic disease is not confined to man, and may ing number of conditions (Meyer et al., 1972). It is arise in a variety of domestic animals (Ainsworth & clear that particular susceptibility occurs during Austwick, 1955), including sheep (Angus et al., 1971), periods of leukopenia in treated leukaemics, and in cattle (Spratling et al., 1968; Nielan et al., 1982), pigs those with diabetes mellitus while they are acidotic. (Mahanta & Chaudhury, 1985), dogs (Ader, 1979) and Modern supportive techniques in haematology are cats (Ader, 1979; Loupal, 1982), and has been des- able to maintain severely leukopenic patients for cribed in non-human et primates (Migaki al., 1982). longer, and diabetics are able to survive a greaterby copyright. One feline case was mistaken for rabies (Ravisse et al., number of ketoacidotic episodes. In both groups, 1978). Ader (1979) reviews cases in a variety of more therefore, each individual sufferer may be susceptible exotic species, including birds, reptiles, amphibians to opportunistic infection for a greater total amount of and fish. time. The four main systemic forms of the disease in man are the rhinocerebral, pulmonary, gastrointestinal and disseminated types. There is also a miscellaneous Clinical forms category of involvement of single organs not within the main categories (Baker, 1957; Lehrer et al., 1980). Rhinocerebral zygomycosis Systemic zygomycosis is usually an opportunistic infection, and each of the main forms is associated This type, with its association with diabetes mellitus, is http://pmj.bmj.com/ with a characteristic group of underlying conditions. the most characteristic form (Gregory et al., 1943; Pillsbury & Fischer, 1977; Meyers et al., 1979; del Real Mora et al., 1983; Abedi et al., 1984). It usually, but Geography and incidence not always, occurs when diabetic control is poor, and acidosis is an important predisposing factor (Baker, Although the earliest recorded cases are of European 1960). There is destructive inflammation within the

origin (Hutter, 1959; Rippon, 1982), the majority of nasal cavity, with erosion ofthe bony walls ofthe nasal on September 30, 2021 by guest. Protected modem published reports are North American. These sinuses. Palatal necrosis may occur, and the lesion has began with three classic cases described by Gregory et usually penetrated to the cranial cavity by the time its al. in 1943, and now include many substantial series significance has been realised. The has a (Straatsma et al., 1962; Meyers et al., 1979; Blitzer et predilection for growth within blood vessels, and so al., 1980; Marchevsky et al., 1980; Abedi et al., 1984). this leads to infarction and fungal invasion of the Systemic zygomycosis is clearly relatively common in frontal lobes. Less common consequences of this Mexico (Rangel-Carrillo et al., 1982; del Real Mora, cerebral involvement include cerebral abscess (Berth- 1983; Rangel-Guerra et al., 1985), and not infrequent ier et al., 1982), intracerebral haemorrhage (Ho, 1979) in Japan (Hotchi et al., 1980) and Southern Africa or subarachnoid haemorrhage (Baker, 1957). Further (Neame & Rayner, 1960; Deal & Johnson, 1969; spread to the tissues of the orbit is also usual, either Dannheimer et al., 1974; Lawson & Schmaman, 1974). from the cranium, via the lacrimal duct, or by direct Reports have come from many other countries, invasion (Diamond & Proppe, 1982), and in a few SYSTEMIC ZYGOMYCOSIS 987 Postgrad Med J: first published as 10.1136/pgmj.62.733.985 on 1 November 1986. Downloaded from cases has lead to severe disruption ofthe globe (Blatrix sometimes seen. In a number of cases, death has et al., 1970; Albert et al., 1979). followed infiltration of a major vessel, such as the This progression of lesions gives a characteristic superior vena cava (Helenglass et al., 1981; Marwaha clinical picture, with swelling and distortion of the et al., 1985) or a pulmonary artery (Reich & Renzetti, face, marked proptosis and ptosis and early visual loss, 1970; Johnson & Baldwin, 1981). all typically unilateral (Fleckner & Goldstein, 1969; Pillsbury & Fischer, 1977; Diamond & Proppe, 1982). Gastrointestinal zygomycosis There is often severe unilateral facial pain, sometimes initially believed to be odontogenic (Diamond & Malnutrition is often associated with this form, and a Proppe, 1982; Webb et al., 1984), together with a considerable proportion of cases have occurred in persistent serosanguinous nasal discharge (Smith & neonates and infants (Neame & Rayner, 1960; Kirschner, 1958; Ferry & Abedi, 1977). Examination Michalak et al., 1980). Published cases of gastrointes- of the nasal cavity, or a palatal lesion if one exists, tinal zygomycosis suggest a particular association with usually reveals a black crusting ulcer (Smith & Kirsch- southern Africa (Neame & Rayner, 1960; Deal & ner, 1958; Pillsbury & Fischer, 1977). Neurological Johnson, 1969; Lawson & Schmaman, 1974; Gwavava signs are often present, but are usually non-specific & Gelfand, 1983), a finding which might suggest some and masked by the underlying condition, or misinter- subtle difference in the predominant organisms, but preted because of it. Multiple cranial nerve defects which is more probably the consequence of the may occur because of involvement at the orbital apex juxtaposition of a malnourished population with (Diamond & Proppe, 1982), but local tissue destruc- sophisticated modern diagnostic services. Gastroin- tion in the face and orbit may complicate their testinal zygomycosis may also occur in diabetes, and interpretation. Cavernous sinus is a recog- like the pulmonary form, there may be few clues to the nized complication (Ferry & Abedi, 1983; Meyers et specific diagnosis of zygomycosis. The most usual site al,. 1979; Anaissie & Shikhani, 1985), but internal of involvement is the (Hutter, 1959; Lawson carotid artery thrombosis is much more characteristic, & Schmaman, 1974), where there may be a large and typically occurs in over a third ofcases (Landau & necrotic ulcer; presentation may be with gastric per-

Newcomer, 1962). It is usually unilateral, but may be foration (Michalak et al., 1980). Large intestinal by copyright. bilateral (Wilson et al., 1979). disease causes a severe diarrhoea with plentiful blood Rhinocerebral zygomycosis is not limited to those and mucus in the stool (Neame & Rayner, 1960; Agha with diabetes mellitus, and may, for example, follow et al., 1985). the immunosuppression of anti-tumour chemoth- erapy. Such patients are, however, more likely to Disseminated zygomycosis progress to the disseminated form, and the prognosis is correspondingly poorer. The craniofacial signs This form, like the pulmonary type, usually occurs in remain the same. those with haematological malignancy, but may on occasion complicate other diseases, including con- Pulmonary zygomycosis taminated skin wounds. Of particular interest are those nosocomial cases which followed the use of http://pmj.bmj.com/ Pulmonary zygomycosis is the predominant form contaminated dressings (Dennis et al., 1980; Garten- complicating haematological malignancy (Keye & berg et al., 1978). Magee, 1956; Hutter & Collins, 1962; Meyer et al., Disseminated zygomycosis in leukaemics usually 1972), and is thus more often a precursor ofdissemin- follows chemotherapy, and may in many cases only be ated disease than is the rhinocerebral form. It typically relevant in that it hastens an already imminent death. occurs in the patient who has been treated with Other cases occur in patients with a better prognosis, chemotherapy, and who is already critically ill (Hutter and appropriate therapy may prolong life. A diversity on September 30, 2021 by guest. Protected & Collins, 1962). The clinical findings are non-specific, of non-specific symptoms occurs, but these are often and many cases remain unsuspected until necropsy overshadowed by the poor general condition of the (Mills & Wolfe, 1980). Retrospective examination of patient. the notes and radiographs of such individuals reveals that death typically followed a rapidly progressive, but Miscellaneous forms of systemic zygomycosis patchy, pneumonic process. When other conditions, such as diabetes mellitus or chronic renal failure Zygomycosis of single organs or single body systems, underlie this form of the disease, the disease may apart from those discussed already, is rare. When remain more localized, but its features are still non- zygomycosis involves the brain alone, the underlying specific, with cough and chest pain; radiological cause is often intravenous drug abuse, usually with findings suggest pulmonary infarction or focal heroin (Hameroff et al., 1970; Masucci et al., 1982; pneumonia (Bigby et al., 1986). A solitary lesion is Pierce et al., 1982) or, rarely, amphetamines (Micozzi 988 E.W. BENBOW & R.W. STODDART Postgrad Med J: first published as 10.1136/pgmj.62.733.985 on 1 November 1986. Downloaded from

& Wetli, 1985). The clinical, radiological and path- zygomycosis may result from contamination of air ological findings are those ofmultiple cerebral absces- conditioning (England et al., 1981; del Palacio Her- ses. nanz, 1983). A rhinofacial form of zygomycosis, usually caused Transplant patients form another important sub- by a member of the Entomophthorae, typically group, and a number of cases have followed renal progresses slowly (Emmons et al., 1977), and is best transplantation (Gallis et al., 1975; Hammer et al., classified with the subcutaneous zygomycoses. A 1975; Abedi et al., 1984; Carbone et al., 1985). Cardiac syndrome intermediate between it and classical rhin- (Schober & Herman, 1973) and bone marrow (Mysk- ocerebral zygomycosis has recently been described, owski et al., 1983) transplantation are also risk factors. wherein a more aggressive nasal zygomycotic Zygomycosis is not included among the fungal osteomyelitis presents with multiple cranial nerve infections associated with acquired palsies of sudden onset, but with characteristic early syndrome (Jaffe et al., 1983), and no examples were sparing of the VIlIth nerve (Bahna et al., 1980). found among the infectious complications of that Involvement of the heart is unusual, and may be disease in a recent major series (Gold & Armstrong, endocardial, myocardial or both. Solitary cardiac 1984). A suggested association with the acquired involvement seems limited to endocarditis complicat- immunodeficiency syndrome in two recent cases ing open heart (Virmani et al., 1982). Solitary (Micozzi & Wetli, 1985) is clearly entirely speculative. renal zygomycosis is even rarer, and has only been Several of the reported cases have been in people discovered on examination ofnephrectomy specimens without any apparent pre-disposing condition. These (Prout & Goddard, 1960; Flood et al., 1985). Isolated have usually suffered from the rhinocerebral form bony involvement is also very unusual (Echols et al., (Muresan, 1960; Baum, 1967; Blodi et al., 1969; 1979). Kurrasch et al., 1982), though the pulmonary (Record Wound infections with Zygomycetes may also & Ginder, 1976) and gastrointestinal (Horowitz et al., occur. Examples have been described at the site of 1974) varieties have also been seen in previously repeated injections (Symmers, 1968), in needle biopsy healthy people. The significance of such cases is not tracts (Gartenberg et al., 1978; Dennis et al., 1980), easily understood, for few appear to have been adjacent to colostomies (Wilson et al., 1976) or in followed-up for a significant period, and little atten- surgical incisions (Gartenberg et al., 1978). Other tion has been paid to the more subtle defects ofby copyright. examples have complicated accidental peripheral leucocyte function that may arise from specific genetic trauma (Boyce et al., 1981; Potvliege et al., 1983) and anomalies. Blankenberg & Verhoeffis (1959) report is diabetic leg ulcers (Tomford et al., 1980). Some of interesting, for they saw localized pulmonary these infections have been indolent, with a well-de- zygomycosis in a girl who was otherwise healthy at fined granulomatous response (Symmers, 1968), initial presentation, but who was found to have whereas others have caused extensive local tissue diabetes mellitus one year later. destruction (Wilson et al., 1976; Tomford et al., 1980). Other underlying conditions Diagnosis http://pmj.bmj.com/ The majorunderlying causes have already been discus- Confirmation of the presence of zygomycosis should sed. These have been reviewed by McNulty (1982), ideally be by culture (Smith, 1984), but this is often not who also describes other important predisposing possible. Even with the characteristic appearances of states, including antibiotic or steroid usage, chronic the rhinocerebral form, the significance ofthe changes renal failure, pancreatitis, burns, malnutrition and is often not appreciated, and any material removed by trauma. Single cases and small series are associated the surgeon placed in histological fixative without with many other conditions. reserving a portion for culture. Attempts to culture on September 30, 2021 by guest. Protected Many infections are nosocomial, as with any oppor- material from necropsy specimens often fails because tunist. A number of cases have followed the use of of bacterial overgrowth, and if a zygomycete is grown contaminated dressings (Gartenberg et al., 1978; Bot- when its presence was not anticipated, it may be tone et al., 1979; Dennis et al., 1980), and may be discarded as a contaminant (Sands et al., 1985). associated with the sites ofinjection (Symmers, 1968), Cultures of sputum (Bogard, 1972; Bhaduri et al., needle biopsy (Gartenberg et al., 1978; Dennis et al., 1983), bronchial brushings (Fahey et al., 1981) and 1980) or cannula insertion (Fisher et al., 1980). A few stool (Agha et al., 1985) have been used to confirm the cases of the rhinocerebral form appear to have been presence ofthe pulmonary and gastrointestinal forms, precipitated by dental extraction (Eilderton, 1974; though the risk ofcontamination makes interpretation Ristow et al., 1979), though it is difficult to be sure that difficult. Blood cultures have on rare occasions been facial pain caused by pre-existing zygomycosis was positive (Bhaduri et al., 1983). not misinterpreted. Rhinocerebral or pulmonary Histological examination is therefore of greater Postgrad Med J: first published as 10.1136/pgmj.62.733.985 on 1 November 1986. Downloaded from SYSTEMIC ZYGOMYCOSIS 989 significance than it is with many other infections, both Serological changes occur in infected laboratory because it may be the only means of diagnosis and animals, and so attempts have been made to develop because it may be needed to confirm that a positive tests to diagnose human disease (Jones & Kaufman, culture is significant. It has the further advantage that 1978; Yankey & Abraham, 1983). Such tests remain it may provide faster confirmation of this rapidly too insensitive, and too prone to cross-reaction, to progressive disease than is possible with culture. allow confident diagnosis of human disease (Lehrer et Microscopic examination of crushed tissue may al., 1980). However, serological confirmation has been provide strong evidence ofthe correct diagnosis within claimed to have been useful in a few recent cases a few hours (Meyers et al., 1979). (Valicenti & Conti, 1980; Pierce et al., 1982; Vincent et In tissue, the Zygomycetes have hyphae which are of al., 1984). variable diameter, though they are characteristically broad. Septa are scanty or absent, and the hyphae divide at irregular intervals at an angle of approx- Treatment and prognosis imately 900. These features generally distinguish them from the slender hyphae of species, with Rapid and effective control of the underlying condi- their regular dichotomous branching and frequent tion is, if feasible, an important and often crucial septation, though zygomycetes growing within a con- prerequisite to therapeutic success (Blitzer et al., fined space may somewhat resemble aspergilli. The 1980). Indeed, cases complicating diabetes mellitus fungus is usually visible on routine haematoxylin and have recovered with no other therapy (Harris, 1955). eosin stains, though the extent of the eosinophilic The only anti-fungal agent with a proven usefulness hyphae, embedded within eosinophilic thrombus or against zygomycosis is (Blitzer et al., necrotic tissue, is much more easily appreciated using 1980; Eng et al., 1981), and even with this drug, periodic acid-Schiff or methenamine silver stains. sensitivity is highly variable (Watson & Neame, 1960; Radiologically, opacification of the nasal sinuses Utz, 1980). Resistance is rapidly inducible, at least in without fluid levels, irregular erosion of their bony vitro (Leathers & Sypherd, 1985). The drug should be walls and nodular soft tissue thickening are a combin- used promptly, and the dose should be increased to its ation which is highly suggestive of rhinocerebral maximum level as soon as possible. The total dose that by copyright. zygomycosis (Green et al., 1967). Internal carotid may be given is limited by the predictable onset of thrombosis is a frequent angiographic finding (Lazo et renal failure. Newer agents, such as ketoconazole, are al., 1971), and obstruction of smaller, more distal of no value (Medoff & Kobayashi, 1980), and a claim vessels may be observed (Courey et al., 1972). Com- that exposure to hyperbaric oxygen is beneficial seems puterized axial tomography (CT) may demonstrate premature (Price & Stevens, 1980). that the lesion crosses fascial planes, and the carotid Surgical debridement of necrotic tissue is also vascular bundles may become indistinct (Bohman et important (Ferry & Abedi, 1983; Blitzer et al., 1980). It al., 1981; Raji et al., 1981). CT scans of the orbit may may be necessary to remove the orbital contents be more characteristic, however, with distortion and (Lazzaro & Sloan, 1982), with much of the nose,

displacement of the extraocular muscles and enlar- nasopharynx and the face (Eden & Santos, 1979; http://pmj.bmj.com/ gement of the optic nerve (Centeno et al., 1981; Rangel-Guerra et al., 1985). Where appropriate, lung Diamond & Proppe, 1982). Cerebral changes resemble or gut resection may be valuable (Eden & Santos, infarcts or abscesses. CT scans may be particularly 1979; Gribetz et al., 1980; Wright et al., 1980). useful in the assessment of therapeutic response Adequate surgery to the face may leave a substantial (England et al., 1981). Radioisotope brain scans show defect, and since such patients may have, on recovery, increased uptake in the characteristic sites in the a good life expectancy, there is a major challenge to the frontal lobes and the basal zones (Zwas & Czerniak, skills of prosthetists (Kurrasch et al., 1982). Cures

1975). have followed medical treatment alone (Hauch, 1977; on September 30, 2021 by guest. Protected Chest radiographs usually show either diffuse shad- Hamill et al., 1983), but adequate debridement as well owing or focal lesions (Bartrum et al., 1973), though provides a much better prognosis (Anaissie & well-developed zygomycotic pneumonia may be inv- Shikhani, 1985). isible on repeated radiographic examination (Aderka Systemic zygomycosis has a considerable mortality et al., 1983). Focal lesions may be either single or in all groups, even with treatment. When disease is multiple (Pagani & Libshitz, 1981). Such changes are limited to the head, the mortality of those with non-specific, but in the right context, they would diabetes mellitus is about 40%, and rises to 80% where justify commencement of therapy (Libshitz the underlying condition is a haematological malig- & Pagani, 1981). Barium studies of the intestines have nancy (Blitzer et al., 1980). The best prognosis is in occasionally been useful (Lyon et al., 1979; Agha et al., that small group who were previously well, but even in 1985), and typical hyphae have been seen on sub- this relatively favourable circumstance, about a fifth sequent endoscopic biopsy. will die. Internal carotid thrombosis is an indicator of Postgrad Med J: first published as 10.1136/pgmj.62.733.985 on 1 November 1986. Downloaded from 990 E.W. BENBOW & R.W. STODDART poor prognosis (Anaissie & Shikhani, 1985). alloxan (Bauer et al., 1955). It can be shown that the A few may develop a more chronic condition, with inflammatory response is qualitatively similar in persistent signs over several weeks or months (Helder- diabetic mice, but less intense (Sheldon & Bauer, man et al., 1974; Finn & Farmer, 1982). In some cases, 1959). Subcutaneous injection of cultures in healthy this is related to the species involved, but chronicity mice leads to focal granulomatous inflammation; may follow infection with a type which is usually subsequent induction of diabetes by alloxan permits aggressive (Symmers, 1968; Leong, 1978). An early, recrudescence of active (Sheldon & Bauer, apparently spontaneous, 'cure' (Hoagland et al., 1961) 1958). Acidosis may be a component of other predis- was followed by fatal recrudescence some years later posing states in humans, including renal failure (Ferstenfeld et al., 1977). (McNulty, 1982) and chronic salicylate poisoning, (Espinoza & Halkias, 1983). Iron is known to be necessary for fungal growth, Experimental studies and serum from iron-deficient patients is less able to support fungal growth than that from those with This unusual disease, with its striking association with normal iron saturation (King et al., 1975). Transferrin diabetes mellitus, has long attracted the interest of releases iron as the pH drops (Lestas, 1976; Artis et al., those wishing to study opportunistic infection. The 1982), and acidosis may therefore modify conditions rarity of the disease is in marked contrast to its to encourage fungal growth; serum from patients with devastating nature once established, and to the diabetic ketoacidosis will only fail to support hyphal frequency of the causative organisms in the environ- growth if its iron saturation is low (Artis et al., 1982). ment. Further, there is a well-recognized phagocytic and Clinical observations ofleukaemics suggest that the microbicidal defect in diabetes mellitus (Bybee & primary disease is a less important factor than leuk- Rogers, 1964; Bagdade, 1976). openia following therapy (Hutter, 1959; Baker, 1962). Steroid-induced susceptibility may also be ex- Further, mice with inherited lymphocyte deficiency perimentally investigated (Bauer et al., 1957; Baker & (Corbel & Eades, 1976), or experimentally rendered Linares, 1974). Cortisone administration enhances lymphopenic (Corbel & Eades, 1975), are no more spore germination (Waldorfet al., 1984b), and greatlyby copyright. susceptible than their normal counterparts to ex- reduces the lethal dose (Kitz et al., 1983). perimental infection. Most human cases have followed Spore germination must precede hyphal growth. non-specific causes of immunosuppression, but may The organs in which invasive hyphal growth occurs complicate inherited defects of neutrophil killing correlate poorly with the sites of maximum spore mechanisms (Bruun et al., 1976; Marx et al., 1982). deposition following intravenous injection (Smith & Zygomycete hyphae produce a chemotactic agent in Jones, 1973), suggesting that local tissue factors are vitro (Chinn & Diamond, 1982), and neutrophils significant. The relation between Zygomycete spore become attached to them, causing damage demonstra- germination and immunosuppression has been less ble on electron microscopy (Diamond et al., 1978). extensively studied than the interaction between Neutrophils reduce uptake of radioactive metabolic hyphal growth and underlying immune defects. substrates by Zygomycete hyphae in vitro (Diamond et Recent experimental studies are therefore important, http://pmj.bmj.com/ al., 1982), an effect reduced by inhibitors of both for they show that spores germinate with much greater oxidative and non-oxidative microbicidal activity facility in diabetic animals (Waldorf et al., 1984a), or (Diamond & Clark, 1982). Normal monocytes have a in those given steroids (Waldorf et al., 1984b). similar inhibitory effect on hyphal metabolism to that Our primary defences, therefore, are the of neutrophils (Diamond et al., 1982), but those from phagocytes, which may have two opportunities to patients with chronic granulomatous disease of child- repel any zygomycotic invasion. They may prevent hood are ineffective, suggesting that the oxidative spore germination, and if this fails, they can inhibit on September 30, 2021 by guest. Protected mechanisms of microbe damage (Ramasarma, 1982) hyphal growth. are more important than the non-oxidative ones. Macrophages from diabetics bind zygomycete hyphae less avidly than do those from normal patients (Wal- Conclusion dorf et al., 1984a). Isolated lymphocytes, on the other hand, have no effect on the metabolism ofthe cultured Systemic zygomycosis is relatively uncommon in the hyphae (Diamond et al., 1982). United Kingdom, though in other parts ofthe world it Systemic zygomycosis complicates diabetes when causes a substantial minority of opportunistic fungal control is poor, particularly in phases of acidosis; infections (Bodey, 1966; Hart et al., 1969; Marchevsky hyperglycaemia is probably less important (Baker, et al., 1980). The first case recognized in this depart- 1960). This phenomenon has long been studied in ment was found at necropsy in 1984 (Benbow et al., animals rendered diabetic by the administration of 1985), and four cases were seen in 1985 (unpublished Postgrad Med J: first published as 10.1136/pgmj.62.733.985 on 1 November 1986. Downloaded from SYSTEMIC ZYGOMYtOSIS 91 observations). This increase reflects world-wide ex- of sufferers if recognized early in its development. perience; systemic zygomycosis may remain unusual, Diabeticians, oncologists, haematologists and general but is no longer a rarity. It can be cured in a proportion physicians must beware its devastating potential.

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