Opportunistic Mold Infections

7/24/2019 Opportunistic Mold Infections

1/12

2 Opportunistic Mold Infections

RONALDG. WASHBURN1

CONTENTS

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 21 II. Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . . . 21

A. Mycology . . . . . . . . . . . . . . . . . . . . . . . . . . 21B. Epidemiology . . . . . . . . . . . . . . . . . . . . . . 22C. Clinical Manifestations . . . . . . . . . . . . . . 23

1. Invasive Pulmonary Aspergillosisand Disseminated Infection . . . . . . . . 23

2. InvasiveAspergillusSinusitis . . . . . . . 233. Noninvasive Mycelial Mass

of the Lung . . . . . . . . . . . . . . . . . . . . . . 234. Noninvasive Mycelial Mass

of the Paranasal Sinuses . . . . . . . . . . . 245. Bronchopulmonary Aspergillosis . . . 246. AllergicAspergillusSinusitis . . . . . . . 24

D. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . 24E. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . 25

III. Mucormycosis. . . . . . . . . . . . . . . . . . . . . . . . . 25A. Mycology . . . . . . . . . . . . . . . . . . . . . . . . . . 26B. Epidemiology . . . . . . . . . . . . . . . . . . . . . . 26C. Clinical Manifestations . . . . . . . . . . . . . . 26

1. Rhinocerebral Mucormycosis . . . . . . 26

2. Invasive Pulmonary Mucormycosisand Disseminated Infection . . . . . . . . 263. Gastrointestinal Mucormycosis . . . . . 264. Skin and Wound Mucormycosis . . . . 27

D. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . 27E. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . 27

IV. Infections Caused by Fusariumspp. . . . . . . 27 V. Infections Caused by Pseudallescheria

boydii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 VI. Dematiaceous Molds . . . . . . . . . . . . . . . . . . . 28 VII. Rare Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . 28 VIII. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . 28 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

I. Introduction

This chapter provides an overview of opportunisticmold infections, including aspergillosis, mucormy-cosis, infections caused by Fusariumspp. and Pseu-dallescheria boydii, and infections caused by the

dematiaceous molds (Table 2.1). Although eachof these agents is also capable of causing diseasein normal individuals, special emphasis has beenplaced on infections in compromised hosts.

II. Aspergillosis

Species of Aspergillusare responsible for a widevariety of different clinical syndromes, includ-ing saprophytic colonization of the pulmonaryairspaces in patients with chronic lung disease,chronic noninvasive mycelial masses of the lungsor paranasal sinuses, and rapidly-progressivelife-threatening invasive infections of the lungsor paranasal sinuses in neutropenic hosts. Inaddition, Aspergillus spp. produce a number ofdifferent allergic syndromes, including extrinsicallergic alveolitis, bronchopulmonary aspergillo-sis, and allergicAspergillussinusitis.

A. Mycology

Aspergillusspp. are ascomycetes that are ubiquitousin nature, and most species can be recovered fromsoil. One hundred and thirty-two species are listedby Raper and Fennell (1965); the species most com-monly responsible for human disease areA. fumiga-tus,A. flavus(Miloshev et al. 1967; Green et al. 1969;

Young et al. 1972), and A. niger, with fewer casescaused by relatively nonpathogenic species suchasA. avenaceus(Washburn et al. 1988),A. nidulans(Redmond et al. 1965; Bujak et al. 1974; White et al.1988),A. oryzae(Ziskind et al. 1958), andA. terreus(Moore et al. 1988; Hara et al. 1989). The organismgrows at temperatures ranging over 455 C, withmost abundant growth at 3037 C.

Aspergillusgrows in air conditioning conduits,fire-proofing material, and decaying vegetation;since it is thermophilic, the organism grows in

almost pure culture in compost heaps.Aspergillus

Human and Animal Relationships, 2nd EditionThe Mycota VIA.A. Brakhage and P.F. Zipfel (Eds.) Springer-Verlag Berlin Heidelberg 2008

1Overton Brooks Veterans Administration Medical Center and

Louisiana State University Health Sciences Center, 510 East Stoner

Avenue, Shreveport, LA 71101, USA; e-mail: ronald.washburn@

med.va.gov


2/12

22 Ronald G. Washburn

spp. possess a wide array of different degrada-tive and biosynthetic enzymes, and therefore theorganisms are able to grow on many differentsubstrates, including not only rich media (e.g. Sab-ourauds agar), but also chemically defined mediacomprised solely of low molecular weight compo-nents (e.g. CzapekDox agar).

The infectious particles are airborne conidia(25m diameter) produced by phialides that are

borne on conidiophores. When these tiny spheresare inhaled, they are capable of reaching the pul-monary alveoli. In normal hosts, the organisms areeffectively cleared by mucociliary mechanisms andphagocytic killing (Waldorf et al. 1984a; Levitz andDiamond 1985; Washburn et al. 1987); however, insusceptible hosts, severe invasive pneumonia mayensue (discussed below). The elongated hyphaethat invade tissue are narrow (25m), regular,septate, and dichotomously branching (ca. 45-degree angles). In invasive disease, hyphae invade

blood vessels, producing distal tissue infarction.

B. Epidemiology

Conidia are continuously inhaled, but typicallycause infection only in immunocompromisedindividuals; e.g. those with prolonged neutro-penia (Young et al. 1970), supraphysiologicglucocorticoid therapy, chronic granulomatousdisease (Bujak et al. 1974), or AIDS (Pursell et al.1990; Woods and Goldsmith 1990; Denning et al.

1991). Concentrations of airborne conidia increaseduring construction and there is some evidenceto support a link between hospital constructionand nosocomial outbreaks of invasive pulmonaryaspergillosis. Thus, the recommendation has beenmade that susceptible hosts (e.g. bone marrowtransplant recipients) should be housed in roomswith high-efficiency particulate air (HEPA) filters(Sherertz et al. 1987).

Less commonly, infection can result from directpercutaneous inoculation in susceptible hosts; e.g.

by intravenous catheters or contaminated tape

Table 2.1. Clinical syndromes caused by opportunistic molds

Aspergillusspp.

Invasive disease Invasive pulmonary aspergillosis disseminated infection InvasiveAspergillussinusitis Skin and wound invasive aspergillosis Keratomycosis

Noninvasive disease Noninvasive mycelial mass of lung or paranasal sinus Bronchopulmonary aspergillosis Extrinsic allergic alveolitis AllergicAspergillussinusitisAgents of mucormycosis

Rhinocerebral mucormycosis Invasive pulmonary mucormycosis disseminated infection Gastrointestinal mucormycosis Skin and wound mucormycosisFusariumspp.

Disseminated infection Keratomycosis Mycetoma

OnychomycosisPseudallescheria boydiiPneumonia

Brain abscess Invasive sinusitis Noninvasive mycelial mass of lung or paranasal sinus MycetomaDematiaceous moldsInvasive disease Brain abscess Localized subcutaneous infection Disseminated infection Invasive sinusitisNoninvasive disease Allergic bronchopulmonary disease Allergic sinusitis


3/12

Opportunistic Mold Infections 23

(Prystowsky et al. 1976; Carlile et al. 1978; McCartyet al. 1986; Googe et al. 1989). Invasive disease ofthe eye (Cameron et al. 1991) or deep structures(e.g. vertebrae or endocardium) can follow surgicalprocedures even in previously normal individuals,presumably due to direct inoculation (Corrall

et al. 1982; Mawk et al. 1983; Weber and Washburn1990). Rarely, Aspergillus endocarditis may beencountered in intravenous drug abusers. There isno documented human-to-human transmission.

C. Clinical Manifestations

1. Invasive Pulmonary Aspergillosisand Disseminated Infection

The most lethal form of aspergillosis is invasive

disease in the neutropenic host with leukemia orlymphoma. The disease is characterized by fever,dyspnea, pleuritic chest pain, cough, and rapidlyprogressive pulmonary infiltrates after ca. 24weeks of neutropenia. Invasive pulmonary aspergil-losis usually progresses rapidly during severalweeks. Even in the face of appropriate antifungaltherapy the infection is almost uniformly fatalunless bone marrow function returns. Vascularinvasion and pulmonary infarction may lead tohemoptysis. In approximately one-third of cases

the infection disseminates to distant organs; e.g.brain (Boon et al. 1990), kidneys, liver, and spleen.Gastrointestinal (GI) lesions may produce bleed-ing and perforation (Meyer et al. 1973b).

In patients with abnormal phagocyte function(e.g. those with chronic granulomatous disease;CGD) or those taking daily high-dose glucocorti-coids (e.g. bone marrow transplant patients withgraft versus host disease) the infection is moreslowly progressive than that seen in patients withprolonged neutropenia. In CGD, invasive pulmo-nary aspergillosis typically presents with multiple

nodules and the infection often invades contiguousstructures such as mediastinum, ribs, vertebrae, orclavicle (Altman 1977). Hyphae are scarce, but thegranulomatous inflammation is exuberant.

Several cases of invasive pulmonary aspergillo-sis have been reported in small children followinginhalation of large inoculae of conidia or in alco-holics with chronic liver disease (Zellner et al. 1969;Blum et al. 1978; Brown et al. 1980). Spontaneousresolution is the rule in the childhood form of thedisease, whereas invasive aspergillosis in alcoholics

carries a poor prognosis.

2. InvasiveAspergillusSinusitis

Invasive sinusitis can be either acute (e.g. in theneutropenic host) (Young et al. 1970; Swerdlowand Deresinski 1984) or chronic (e.g. in immu-nologically normal individuals) (Washburn et al.

1988; Washburn 1998). In general, the acute formof the disease resembles rhinocerebral mucormy-cosis (McGill et al. 1980), but acute Aspergillussinusitis is most commonly encountered in the set-ting of prolonged neutropenia, and rhinocerebralmucormycosis usually occurs in poorly controlleddiabetics.

Acute Aspergillus spp. sinusitis typicallybegins in the maxillary or ethmoid sinuses andrapidly invades blood vessels, producing tissuenecrosis and violating anatomic barriers (Peter-son and Schimpff 1989; Dyken et al. 1990; Talbot

et al. 1991). Thus, the disease may be recognizedbecause of a black eschar on the hard palate due toinferior extension through the floor of the maxil-lary sinus. Unilateral proptosis and chemosis mayoccur because of superior erosion through the roofof the maxillary sinus or lateral extension throughthe ethmoid sinus into the lamina papyracea. Focalneurological findings and altered mental statusare signs that the disease has already extendedinto the brain and such involvement in neutopenicindividuals usually predicts a fatal outcome. How-

ever, patients with chronic granulomatous diseasehave more indolent brain involvement that mayrespond to antifungal therapy.

Aspergillusmay produce a more chronic formof invasive sinusitis in apparently normal hosts(Washburn 1998). Patients typically present withpainless unilateral proptosis, and they are not sys-temically ill. The infection is endemic in the aridportion of the Sudan where A. flavus is the pre-dominant causative organism presumably becauseof high ambient concentrations of airborne

A. flavus conidia. It has been postulated thatchronic upper respiratory mucosal fissuring due tothe arid climate facilitates passage of the organisminto submucosal tissue. In this disease erosionthrough anatomic barriers requires months oryears and produces granulomatous inflammation.

3. Noninvasive Mycelial Mass of the Lung

Aspergillus spp. may grow as noninvasive myc-elial masses in preexisting lung cavities causedby emphysema, tuberculosis, cancer, or sarcoido-

sis (Varkey and Rose 1976; Jewkes et al. 1983).


4/12


The fungus ball is usually mobile and not attachedto the wall of the cavity. Radiographically, a crescentof air can often be seen above the mass. Aspergil-lusspp. may be recovered repeatedly from expec-torated sputum, and whenAspergillus nigeris thecausative organism calcium oxalate crystals may

be observed (Wilson and Wilson 1961). Patientswith noninvasive pulmonary mycelial masses maydevelop life-threatening hemoptysis (Jewkes et al.1983). Repeated severe hemoptysis is an indicationfor surgery (discussed below).

4. Noninvasive Mycelial Mass of the ParanasalSinuses

Patients with chronic bacterial sinusitis andimpaired sinus drainage (e.g. due to polypoid

obstruction) may accumulate inspissated mucus thatsupports noninvasive mycelial growth. Intermittentunilateral maxillary sinus pain, vertex headachesdue to sphenoid sinus pressure, and cacosmia arecommon complaints (Washburn 1998). In this dis-ease the mucosa and submucosa may be chroni-cally thickened and infiltrated by lymphocytes andplasmacytes but hyphae do not invade tissue.

5. Bronchopulmonary Aspergillosis

Bronchopulmonary aspergillosis represents an

allergic response that is usually seen in patientswith preexisting asthma. The syndrome is charac-terized by bronchospasm, fleeting pulmonary infil-trates, bronchiectasis, mucus plugging, repeatedrecovery of Aspergillus spp. from sputum, andeosinophils and CharcotLeyden crystals in spu-tum (Washburn 1996). Additional features includeimmediate cutaneous hypersensitivity toAspergil-lusantigens, peripheral eosinophilia, elevations oftotal IgE, and specific anti-Aspergillusprecipitins,including IgE and IgG.

6. AllergicAspergillusSinusitis

AllergicAspergillussinusitis shares many featureswith bronchopulmonary aspergillosis, exceptthat the inflammation is located in the parana-sal sinuses instead of the lungs (Katzenstein et al.1983; Waxman et al. 1987). These individuals havechronic sinusitis with positive cultures and visiblehyphae in direct smears of mucus. The character-istic mucus is termed allergic mucin because itcontains eosinophils and CharcotLeyden crystals.

There may be mucosal and submucosal thicken-ing, with eosinophilic inflammation. Eventually,patients may have bony rearrangement, probablydue to sustained increases in intrasinus pressure.By definition, the infection does not cross anatomicbarriers and thus, for example, extension into the

brain has not been described in carefully definedcases of allergic Aspergillus sinusitis. Similar topatients with bronchopulmonary aspergillosis,those with allergic Aspergillus sinusitis exhibitperipheral eosinophilia, immediate-type hyper-sensitivity to Aspergillus antigens, elevated totalIgE, and specific anti-Aspergillus precipitins,including IgE and IgG.

D. Diagnosis

Diagnosis of invasive pulmonary aspergillosis isusually made at autopsy. To firmly establish the diag-nosis antemortem, biopsies must demonstrate inva-sive hyphae; cultures are confirmatory. Diagnosticyield of transbronchial biopsy is low, so open-lungbiopsy is the gold standard. Unfortunately, throm-bocytopenia or coagulopathy often render biopsyinadvisable. In that setting a low attenuation halosurrounding a nodule visualized by computerizedtomography (CT) is suggestive of invasive fungaldisease. In nonsmokers a presumptive diagnosis

can be established by repeated recovery ofAspergil-lus from expectorated sputum, bronchoalveolarlavage fluid, or nasopharyngeal cultures. In contrast,smokers are so frequently colonized that recoveryofAspergillusspp. from these same sources carriesless diagnostic weight (Yu et al. 1986).

New cerebral mass lesions in the setting ofneutropenia and progressive pulmonary infiltratesraise the specter of central nervous system dissem-ination; and GI hemorrhage raises suspicions forGI dissemination. Unfortunately, blood cultures

are virtually always negative, but galactomannandetection by enzyme immunoassay is now gainingpractical diagnostic value.

InvasiveAspergillusspp. sinusitis is diagnosedby visualizing characteristic hyphae in mucosa anddeeper structures, and cultures are confirmatory.In the neutropenic host with thrombocytopenia,the ability to safely obtain deep biopsy specimensmay be limited. However, in immunologicallyintact hosts biopsies are helpful for defining theinvasive nature of the infection and delineatingthe associated inflammatory response.


5/12


Noninvasive mycelial mass of the lung is diag-nosed by the appearance of a fungus ball on chestroentgenograms, combined with repeated recov-ery ofAspergillusspp. from expectorated sputumand/or bronchoalveolar lavage specimens; moreinvasive procedures would rarely be warranted.

Many patients have circulating anti-Aspergillusprecipitins, usually IgG (Kurup and Fink 1978).

Noninvasive mycelial mass of the paranasalsinus is diagnosed by sinoscopic visualizationof a greasy or friable mass that shows entangledhyphae limited to the airspace, and thickenedsubmucosa that may contain lymphocytic inflam-mation. Occasionally, conidiophores may be seenwithin the mycelial mass, providing a clue aboutthe causative species; cultures are confirmatory.

Diagnostic criteria for bronchopulmonary

aspergillosis and allergic Aspergillussinusitis areoutlined in the respective sections concerningclinical manifestations (discussed above).

E. Treatment

Therapy for invasive pulmonary aspergillosiswith or without dissemination is vorizonazole4 mg/kg every 12 h (Steinbach and Stevens 2003)or amphotericin B deoxycholate to a total doseof at least 12 g. Liposomal amphotericin B is

approved as salvage therapy and has the advan-tage of being less nephrotoxic than amphotericinB deoxycholate. There is some evidence to supportadjunctive use of 5-fluorocytosine or rifampinwith amphotericin B-based regimens in espe-cially difficult cases (Kitahara et al. 1976; Arroyoet al. 1977; Hughes et al. 1984). Additionally, caspo-fungin is approved for invasive aspergillosis inpatients who are refractory or intolerant of othertherapy (Patterson 2005). Some authorities advo-cate surgical resection of infected lung tissue for

patients in whom hemostasis can be achieved(Weiland et al. 1983). Unfortunately the diseaseremains highly lethal unless bone marrow func-tion returns and immunosuppression is reduced.For those patients in whom the infection comesunder control, a course of oral voriconazole oritraconazole 400 mg/day could be considered forfollow-up therapy (Denning et al 1994; Patterson2005). Posaconazole also has useful clinical activityagainst invasive aspergillosis (Walsh et al. 2007).

The same antifungal options are available forinvasive Aspergillussinusitis. Aggressive surgical

extirpation of necrotic tissue is recommendedwhen hemostasis can be achieved, and follow-uptherapy with oral voriconazole, itraconazole, orposaconazole would be an option for patients whocan be discharged from the hospital.

Noninvasive mycelial masses of the lung do

not require therapy except when severe hemop-tysis ensues, and in those cases surgical excisioncan be life-saving (Jewkes et al. 1983). Noninva-sive mycelial masses of the paranasal sinuses canbe cured with complete surgical removal of thefungus ball (Washburn et al. 1988). No antifungalchemotherapy is required for noninvasive massesof lung or sinuses.

For patients with bronchopulmonary aspergil-losis, bronchodilation with cromolyn sodiumfacilitates clearance of infected secretions. Oral

steroid therapy may also be required for controlof acute exacerbations; dosage recommendationsare reviewed elsewhere (Washburn 1996). A fewpatients become steroid dependent. There is nowsome evidence to support the use of itraconazoleto prevent recurrent episodes of bronchopulmo-nary aspergillosis.

There is no controlled data to guide therapyof allergic Aspergillus sinusitis. However, accu-mulating evidence suggests that a reasonableapproach would be surgical removal of inspissatedmucus and inflamed mucosa, combined with post-

operative topical steroids, e.g. beclomethasone(Washburn 1998). The roles of systemic antifun-gal agents and systemic glucocorticoids remaincontroversial.

III. Mucormycosis

Mucormycosis is caused by zygomycetous fungiof the order Mucorales. There are several different

clinical forms of mucormycosis, including acuterhinocerebral disease, invasive pulmonary disease(often accompanied by disseminated infection),GI infection, and locally invasive cutaneousdisease arising from direct inoculation. Patientsat risk include poorly controlled diabeticsand individuals with prolonged neutropenia(e.g. leukemia or lymphoma), chronic renal insuf-ficiency, kidney transplantation, deferoxaminechelation therapy for iron- or aluminum-overload,metabolic acidosis, burns, malnutrition, andintravenous drug abuse.


6/12


A. Mycology

Three different genera account for the majorityof mucormycosis cases: Rhizopus (R. oryzae andR. microsporusvar. rhizopodiformis; Bottone et al.1979), Cunninghamella bertholletiae(Boyce et al.

1981; Sands et al. 1985; Rex et al. 1988; Mostaza andBarbado 1989; Zeilender et al. 1990), andSaksenaeavasiformis(Pierce et al. 1987; Kaufmann et al. 1988;Goldschmied-Reouven et al. 1989). The infectiousparticles, tiny sporangiospores measuring 23min diameter, are produced within sporangia borneon sporangiophores. Alveolar macrophages bindto the spores and inhibit germination (Waldorfet al. 1984a, b). Coenocytic hyphae are the tissue-invasive form of the organism. Those structures aremorphologically distinct fromAspergillushyphae,because they are aseptate or only sparsley septate,broad and irregular (up to 15m wide), and theyexhibit right-angle branching. The broad hyphaeof mucormycosis invade blood vessels and pro-duce extensive tissue infarction similar to invasiveaspergillosis. Neutrophils kill Rhizopus hyphae(Schaffner et al. 1986). Deferoxamine enhancesgrowth of the fungus (Boelaert et al. 1993, 1994).

B. Epidemiology

The airborne spores are ubiquitious; for example,the mold grows on decaying vegetation, stalebread, and fruit. Infection is acquired by inhala-tion, or rarely by direct inoculation into skin e.g.by Elastoplast bandages (Gartenberg et al. 1978;Hammond and Winkelmann 1979; Sheldon andJohnson 1979), or by intravenous and perito-neal dialysis catheters (Baker et al. 1962; Brantonet al. 1991), or into the eye, e.g. by lens insertion(Orgel and Cohen 1989). In severely malnourishedchildren GI infection is believed to be acquired by

oral ingestion (Watson 1957; Isaacson and Levin1961; Washburn and Bennett 1995). There is nodocumented human-to-human transmission.

C. Clinical Manifestations

1. Rhinocerebral Mucormycosis

Rhinocerebral mucormycosis is a catastrophic ill-ness, usually seen in patients with poorly control-led diabetes mellitus; it may also be encountered in

renal allograft recipients and patients with other

forms of severe immunocompromise. The infectionrepresents a true medical and surgical emergencybecause it can progress rapidly to death. Patientstypically present with unilateral nasal discharge,headache, and fever. As the disease progresses,an eschar may form over the hard palate due to

erosion through the floor of the maxillary sinus.Unilateral proptosis and chemosis are indicatorsof superior extension through the roof of the max-illary sinus or lateral extension through the eth-moid. Contiguous areas of involved skin progressrapidly from erythematous to violaceous, and ulti-mately become necrotic.

Lateral extension from the sphenoid sinus canlead to cavernous sinus thrombosis and cranialnerve palsies (cranial nerves IIIVI). Brain inva-sion presents with focal neurological deficits and

altered mental status progressing to coma anddeath. Central nervous system lesions may be visu-alized by CT scan or magnetic resonance imaging,but cerebrospinal fluid (CSF) cultures are almostuniformly negative and other CSF parameters maybe normal. Intravenous drug abusers may presentwith brain abscesses, presumably due to infectedemboli (Pierce et al. 1982; Smith et al. 1989; Staveet al. 1989; Fong et al. 1990).

2. Invasive Pulmonary Mucormycosis

and Disseminated InfectionInvasive pulmonary mucormycosis is a life-threateninginfection usually found in patients with prolongedneutropenia (Meyer et al. 1972), diabetes mellitus,or deferoxamine therapy. Clinical presentationsof the disease are similar to those of invasivepulmonary aspergillosis; the infection may extendlocally into the mediastinum (Connor et al. 1979) oracross the diaphragm, and hemoptysis may resultfrom vascular invasion and pulmonary infarction(Murray 1975). Disseminated disease most com-

monly affects the brain and GI tract.

3. Gastrointestinal Mucormycosis

GI mucormycosis is principally a disease of neu-tropenic and kidney transplant patients and isusually a manifestation of disseminated infection(Lyon et al. 1979; Washburn and Bennett 1995).The disease typically produces localized tissueinfarction and thus presents with abdominal painand GI bleeding. The stomach is most commonly

involved, but infection of the colon (Agha et al.


7/12


1985) and esophagus have also been described.Small children with protein-calorie malnutritionmay develop gastric mucormycosis (Ismail et al.1990; Thomson et al. 1991).

4. Skin and Wound Mucormycosis

In susceptible patients (e.g. those with diabetesmellitus or immunosuppression), skin and under-lying structures may become infected by inocu-lation with tape (e.g. Elastoplast), intravenous orintraperitoneal catheters, or minor trauma (e.g.spider bite), leading to extensive localized tis-sue destruction. Even in previously normal hosts,tissue that becomes devitalized through crushinjury or burns can become locally infected byagents of mucormycosis (Pierce et al. 1987; Vainrub

et al. 1988). Rarely, disseminated mucormycosisproduces skin lesions that resemble echthymagangrenosa (Meyer et al. 1973a).

D. Diagnosis

Blood and urine cultures are almost uniformlynegative and there is no readily available serologictest for invasive mucormycosis, so diagnosis relieson documentation of tissue-invasive hyphae withcharacteristic morphologic features. Positive tis-

sue cultures are confirmatory but the yield isextremely low. Unfortunately, thrombocytopeniaand coagulopathy often render biopsy proceduresinadvisable, so most cases of invasive pulmonarymucormycosis evade diagnosis until autopsy.Patients with rhinocerebral or skin disease havemore accessible lesions, so biopsy is safer.

E. Treatment

Therapy for all forms of mucormycosis includes

amphotericin B deoxycholate or lipid formula-tions of amphotericin B to reduce nephrotoxic-ity. Reduction of immunosuppression and controlof diabetic ketoacidosis contribute to likelihoodof successful outcome. The recommended dailydosage of amphotericin B deoxycholate is at least1 mg/kg for life-threatening disease until the infec-tion has been brought under control; the dailydose may then be reduced to 0.5 mg/kg duringcompletion of an 8-week course of therapy. Lipidformulations of amphotericin B reduce nephro-

toxicity. Posaconazole has clinical activity against

mucormycosis, but at present there is less experi-ence to support its use compared with amphoter-icin B-based regimens (Sugar 2005).

Surgical extirpation of necrotic tissue is helpfulwhen hemostasis can be achieved, and is stronglyadvised for diabetic patients with acute sinusitis if

intracranial extension has not yet occurred. Mortalityfor all forms of invasive mucormycosis is significant,with the exception of localized skin, wound, and eyedisease. With appropriate therapy, mortality fromrhinocerebral mucormycosis can be limited to 1524%(Meyers et al. 1979; Lehrer et al. 1980).

IV. Infections Caused by Fusariumspp.

Fusariumspp. are soil saprophytes that are respon-

sible for a number of different clinical syndromes,including disseminated infection in neutropenichosts or patients with burns (Anaissie et al. 1988;Merz et al. 1988; Richardson et al. 1988; Vendittiet al. 1988; Gamis et al. 1991; Robertson et al.1991) and localized disease in normal hosts; e.g.mycetoma, onychomycosis (DiSalvo and Fickling1980), and keratomycosis (Zapater and Arrechea1975). The species most commonly responsiblefor human disease are F. solani, F. oxysporum, andF. moniliforme.

Hyphae of Fusarium spp. appear similar

to those of Aspergillus spp. in tissue. However,three key features help to distinguish dissemi-nated fusariosis from invasive aspergillosis: (1)unlike aspergillosis, a majority of patients withdisseminated fusariosis have painful skin lesionsresembling echthyma gangrenosa that can pro-vide diagnostic tissue (6070%), (2) the major-ity of patients with fusariosis have positive bloodcultures (60%), and (3) fusariosis is even morerefractory to antifungal chemotherapy than isaspergillosis. Because of the highly lethal nature

of fusariosis (Anaissie et al. 1988), it is recom-mended that patients should be treated with highdaily doses of amphotericin B (1.01.5 mg/kgdaily; Merz et al. 1988). Voriconazole is approved assecond-line therapy (Hospenthal 2005).

V. Infections Caused by Pseudallesche-ria boydii

Pseudallescheria boydii, a fungus found in soil and

water, gives rise to a number of clinical entities,


8/12


including pneumonia following near-drowning(often complicated by brain abscess; Fisher et al.1982; Dubeau et al. 1984; Hachimi-Idrissi et al.1990), invasive sinusitis in normal or immunocom-promised hosts (Bryan et al. 1980; Winn et al. 1983;Schiess et al. 1984; Salitan et al. 1990), noninvasive

pulmonary mass (Louria et al. 1966; Arnett andHatch 1975; Rippon and Carmichael 1976), para-nasal sinus mass (Washburn et al. 1988), andmycetoma (Green and Adams 1964). The courseof Pseudallescheria infections in compromisedhosts is usually more rapidly progressive than inpreviously normal individuals (Winston et al.1977; Gumbart 1983; Shih and Lee 1984; Smithet al. 1985).

In tissue, hyphae of P. boydiiappear similar tothose ofAspergillusspp., and cultures are required

to make a positive identification. However, in non-invasive mycelial masses P. boydiican sometimesbe presumptively identified even without cultureconfirmation, on the basis of fascicle-like struc-tures called coremia (Gluckman et al. 1977), andteardrop-shaped conidia.

Since P. boydii is resistant to amphoter-icin B but susceptible to imidazoles in vitro, andsince clinical successes also support the use ofimidazoles, most authorities agree that intrave-nous miconazole is preferable to amphotericin Bfor treatment of Pseudallerscheria infections in

patients that require intravenous therapy (Lutwicket al. 1979; Anderson et al. 1984; Collignon et al.1985; Berenguer et al. 1989). Oral itraconazole(Piper et al. 1990) or ketoconazole (Schiesset al. 1984) have been used successfully to com-plete therapy. More recently voriconazole (Neskyet al. 2000) and posaconazole have been shown topossess clinical activity and voriconazole has beenapproved for treatment of patients who are refrac-tory to or intolerant of other antifungal therapy.Surgical debridement of infected tissue improves

the chances for a permanent cure.

VI. Dematiaceous Molds

Dematiaceous molds are soil- and plant-fungithat produce brown pigments in vitro and some-times in vivo. Human infection caused by theseorganisms is termed phaeohyphomycosis. Generaproducing human infections include species of

Alternaria, Bipolaris, Cladosporium, Curvularia,

Drechslera, Exophiala, Exserohilum, and Phialo-phora (Adam et al. 1986; Washburn et al. 1988).

Clinical syndromes that affect compromisedhosts include brain abscess (Seaworth et al. 1983;Anandi et al. 1989; Aldape et al. 1991), localizedsubcutaneous inoculation disease (Fincher et al.1988), and disseminated disease. Syndromesfound principally in previously normal hosts

include chronic invasive fungal sinusitis (Wash-burn 1998), allergic fungal sinusitis with clinicalfeatures paralleling those of allergic Aspergillussinusitis (Brummund et al. 1986; MacMillanet al 1987; Bartynski et al. 1990; Gourley et al. 1990;Friedman et al. 1991), and allergic bronchopul-monary disease (Dolan et al. 1970; Halwig et al.1985). In tissue, the septate branching hyphaeof dematiaceous fungi are irregular in diameter,and may contain globose swellings. Therapy forchronic invasive fungal sinusitis includes surgi-

cal extirpation of infected tissue combined witha prolonged course of antifungal chemotherapy,usually amphotericin B to a total dose of ca. 2 gm.Therapy for allergic fungal sinusitis includes sur-gical removal of inspissated mucus and inflamedmucosa, combined with topical steroids; in con-trast, roles of systemic steroids and antifungalchemotherapy remain to be defined. Anecdotalliterature concerning allergic bronchopulmo-nary disease suggests that combined therapy withbronchodilators and systemic steroids is effective.Disseminated disease in normal hosts or immu-

nocompromised patients is treated with a pro-longed course of amphotericin B.

Itraconazole has been used successfully innonlife-threatening disease and there is anecdotalevidence for posaconazole as salvage therapy afteramphotericin B failure (Hospenthal 2005). The invitro activity of voriconazole against dematiaceousmolds is more potent than that of itraconazole.

VII. Rare Agents

The following molds only rarely cause infection inhumans: Acremonium, Paecilomyces, Penicillium,Schizophyllum, and Scopulariopsis. For a full dis-cussion of those organisms, the reader is referredto Kwon-Chung and Bennett (1992).

VIII. Conclusions

The molds discussed in this chapter are those that

take opportunistic advantage of an immunocom-promised host.


9/12


Aspergillosis is an infection caused by one oranother species in the genus Aspergillus. Thesemolds produce pigmented colonies in culture. Theconidia produced are phialoconidia arranged in acharacteristic fashion on the conidiophore (Raperand Fennell 1965). Aspergillus spp. appear in the

tissues of an infected host as septate hyphae withbranches occurring at acute angles. Mycelial fungisuch as Fusariumspp. and Pseudallescheria boydii,among others, resembleAspergillusspp. in tissue.

The disease mucormycosis is caused by zygo-mycetes of the order Mucorales. Both deep-seated,systemic diseases and inoculation mycoses maybe produced. These zygomycetes produce asexualspores called sporangiospores. The myceliumis composed of nonseptate hyphae, and thismorphologic form is observed in tissues of an

infected host.There are a large number of fungi other thanspecies ofAspergillusand mucoraceous zygomyc-etes that can cause infections in an immunosup-pressed host.

References

Adam RD, Paquin ML, Petersen EA, Saubolle MA, RinaldiMG, Corcoran JG, Galgiani JN, Sobonya RE (1986)Phaeohyphomycosis caused by the fungal generaBipolarisand Exserohilum. Medicine 65:203217

Agha FP, Lee HH, Boland CR, Bradley SF (1985) Mucormy-coma of the colon: early diagnosis and successfulmanagement. Am J Roentgenol 145:739741

Aldape KD, Fox HS, Roberts JP, Ascher NL, Lake JR, RowleyHA (1991) Cladosporium trichoidescerebral phaeohy-phomycosis in a liver transplant recipient. Am J ClinPathol 95:499502

Altman AR (1977) Thoracic wall invasion secondary topulmonary aspergillosis: a complication of chronicgranulomatous disease of childhood. Am J Roentge-nol 129:140142

Anaissie E, Kantarjian H, Ro J, Hopfer R, Rolston K,Fainstein V, Bodey G (1988) The emerging role of

Fusariuminfections in patients with cancer. Medicine67:7783Anandi V, John TJ, Walter A, Shastry JCM, Lalitha MK,

Padhye AA, Ajello L, Chandler FW (1989) Cerebralphaeohyphomycosis caused by Chaetomium globo-sum in a renal transplant recipient. J Clin Microbiol27:22262229

Anderson RL, Carroll TF, Harvey JT, Myers MG (1984)Petriellidium (Allescheria) boydii orbital and brainabscess treated with intravenous miconazole. Am JOphthalmol 97:771775

Arnett JC, Hatch HB (1975) Pulmonary allescheriasis:report of a case and review of the literature. ArchIntern Med 135:12501253

Arroyo J, Medoff G, Kobayashi GS (1977) Therapy ofmurine aspergillosis with amphotericin B in combi-

nation with rifampin or 5-fluorocytosine. AntimicrobAgents Chemother 11:2125

Baker RD, Seabury JH, Schneidau JD (1962) Subcutaneousand cutaneous mucormycosis and subcutaneous phy-comycosis. Lab Invest 11:10911102

Bartynski JM, McCaffrey TV, Frigas E (1990) Allergicfungal sinusitis secondary to dematiaceous fungi:

Curvularia lunataand Alternaria. Otolaryngol HeadNeck Surg 103:3239Berenguer J, Diaz-Mediavilla J, Urra D, Munoz P (1989)

Central nervous system infection caused by Pseudal-lescheria boydii: case report and review. Rev Infect Dis11:890896

Blum J, Reed JC, Pizzo SV, Thompson WM (1978) Miliaryaspergillosis associated with alcoholism. Am J Roent-genol 131:707709

Boelaert JR, deLocht M, Van Cutsem J, Kerrels V (1993)Mucormycosis during deferoxamine therapy is asiderophore-mediated infection. In vitro and in vivoanimal studies. J Clin Invest 91:19791986

Boelaert JR, Van Cutsem J, deLocht M, Schneider YJ,

Crichton RR (1994) Deferoxamine augments growthand pathogenicity of Rhizopus while hydroxypyridi-none chelators have no effect. Kidney Int 45:667671

Boon AP, Adams DH, Buckels J, McMaster P (1990) Cere-bral aspergillosis in liver transplantation. J Clin Pathol43:114118

Bottone EJ, Weitzman L, Hanna BA (1979) Rhizopus rhizo-podiformis: emerging etiological agent of mucormy-cosis. J Clin Microbiol 9:530537

Boyce JM, Lawson LA, Lockwood WR, Hughes JL (1981)Cunninghamella bertholletiae wound infectionof probable nosocomial origin. South Med J 74:11321135

Branton MH, Johnson SC, Brooke JD, Hasbargen JA (1991)Peritonitis due to Rhizopus in a patient undergoingcontinuous ambulatory peritoneal dialysis. Rev InfectDis 13:1921

Brown E, Freedman S, Arbeit R, Come S (1980) Invasivepulmonary aspergillosis in an apparently nonimmu-nocompromised host. Am J Med 69:624627

Brummund W, Kurup VP, Harris GJ, Duncavage JA, ArkinsJA (1986) Allergic sino-orbital mycosis. J Am MedAssoc 256:32493253

Bryan CS, DiSalvo AF, Kaufman L, Kaplan W, Brill AH,Abbott DC (1980) Petriellidium boydiiinfection of thesphenoid sinus. Am J Clin Pathol 74:846851

Bujak JS, Kwon-Chung KJ, Chusid MJ (1974) Osteomyelitis

and pneumonia in a boy with chronic granulo-matous disease of childhood caused by a mutantstrain of Aspergillus nidulans. Am J Clin Pathol 61:361367

Cameron JA, Antonios SR, Cotter JB, Habash NR (1991)Endophthalmitis from contaminated donor corneasfollowing penetrating keratoplasty. Arch Ophthalmol109:5459

Carlile JR, Miller RE, Cho CT, Vats TS (1978) Primary cuta-neous aspergillosis in a leukemic child. Arch Derma-tol 114:7880

Collignon PJ, Macleod C, Packham DR (1985) Miconazoletherapy in Pseudallescheria boydii infection. Aust JDermatol 26:129132

Connor BA, Anderson RJ, Smith JW (1979) Mucor medias-tinitis. Chest 75:524526


10/12


Corrall CJ, Merz WG, Rekedal K, Hughes WT (1982)Aspergillus osteomyelitis in an immunocompetentadolescent: a case report and review of the literature.Pediatrics 70:455461

Denning DW, Follansbee SE, Scolaro M, Norris S, Edelstein H,Stevens DA (1991) Pulmonary aspergillosis in theacquired immunodeficiency syndrome. N Engl J Med

324:654662Denning DW et al (1994) NIAID Mycoses Study Groupmulticenter trial of oral itraconazole therapy for inva-sive aspergillosis. Am J Med 97:135144

DiSalvo AF, Fickling AM (1980) A case of nondermato-phytic toe onychomycosis caused by Fusarium oxyspo-rum. Arch Dermatol 116:699700

Dolan CT, Weed LA, Dines DE (1970) Bronchopulmonaryhelminthosporiosis. Am J Clin Pathol 53:235242

Dubeau F, Roy LE, Allard J, Laverdiere M, Rousseau S,Duplantis F, Boileau J, Lachapelle J (1984) Brainabscess due to Petriellidium boydii. Can J Neurol Sci11:395398

Dyken ME, Biller J, Yuh WTC, Fincham R, Moore SA, Justin E

(1990) Carotid-cavernous sinus thrombosis caused byAspergillus fumigatus: magnetic resonance imagingwith pathologic correlation a case report. Angiology41:652657

Fincher RME, Fisher JF, Padhye AA, Ajello L, Steele JC Jr(1988) Subcutaneous phaeohyphomycotic abscesscaused by Phialophora parasiticain a renal allograftrecipient. J Med Vet Mycol 26:311314

Fisher JF, Shadomy S, Teabeaut R, Woodward J, MichaelsGE, Newman KA, White E, Cook P, Seagraves A, YaghmaiF, Rissing JP (1982) Near-drowning complicated bybrain abscess due to Petriellidium boydii. Arch Neurol39:511513

Fong KM, Seneviratne EME, McCormack JG (1990) Mucorcerebral abscess associated with intravenous drugabuse. Aust N Z J Med 20:7477

Friedman GC, Hartwick WJ, Ro JY, Saleh GY, Tarrand JJ,Ayala AG (1991) Allergic fungal sinusitis. Report ofthree cases associated with dematiaceous fungi. Am JClin Pathol 96:368372

Gamis AS, Gudnason T, Giebink GS, Ramsay NK (1991) Dis-seminated infection with Fusarium in recipients ofbone marrow transplants. Rev Infect Dis 13:10771088

Gartenberg G, Bottone EJ, Keusch GT, Weitzman I (1978)Hospital acquired mucormycosis (Rhizopus rhizo-

podiformis) of skin and subcutaneous tissue. N EnglJ Med 299:11151118

Gluckman SJ, Ries K, Abrutyn E (1977)Allescheria (Petriel-lidium) boydiisinusitis in a compromised host. J ClinMicro 5:481484

Goldschmied-Reouven A, Shvoron A, Topaz M, Black C(1989) Saksenaea vasiformis infection in a burnwound. J Med Vet Mycol 27:427429

Googe PB, DeCoste SD, Herold WH, Mihm MC Jr (1989)Primary cutaneous aspergillosis mimicking dermato-phytosis. Arch Lab Med 113:12841286

Gourley DS, Whisman BA, Jorgensen NL, Martin ME, ReidMJ (1990) Allergic Bipolaris sinusitis: clinical andimmunopathologic characteristics. J Allergy ClinImmunol 85:583591

Green WO, Adams TE (1964) Mycetoma in the United

States. Am J Clin Pathol 42:7591

Green WR, Font RL, Zimmerman LE (1969) Aspergillosisof the orbit: report of ten cases and review of the lit-erature. Arch Ophthalmol 82:302313

Gumbart CH (1983) Pseudallescheria boydii infectionafter bone marrow transplantation. Ann Intern Med99:193194

Hachimi-Idrissi S, Willemsen M, Desprechins B, Naessens A,

Goossens A, De Meirleir L (1990) Pseudallescheria boy-diiand brain abscesses. Pediatr Infect Dis J 9:737741Halwig JM, Brueske DA, Greenberger PA, Dreisin RB, Sommers

HM (1985) Case reports: allergic bronchopulmonarycurvulariosis. Am Rev Respir Dis 132:186188

Hammond DE, Winkelmann RK (1979) Cutaneous phyco-mycosis: report of three cases with the identificationof Rhizopus. Arch Dermatol 115:990992

Hara KS, Ryu JH, Lie JT, Roberts GD (1989) DisseminatedAspergillus terreusinfection in immunocompromisedhosts. Mayo Clin Proc 64:770775

Hospenthal DR (2005) Uncommon fungi. In: Mandell GL,Bennnett JE, and Dolin R (eds) Principles and prac-tice of infectious diseases, vol 2. Elsevier, Philadelphia,

pp 30683079Hughes CE, Harris C, Moody JA, Peterson LR, Gerding DN

(1984) In vitro activities of amphotericin B in com-bination with four antifungal agents and rifampinagainst Aspergillus spp. Antimicrob Agents Chem-other 25:560562

Isaacson C, Levin SE (1961) Gastro-intestinal mucormyco-sis in infancy. S Afr J Med 35:581584

Ismail MHA, Hodkinson HJ, Setzen G, Sofianos C, HoleMJ (1990) Gastric mucormycosis. Trop Gastroenterol11:103105

Jewkes J, Kay PH, Paneth M, Citron KM (1983) Pulmonaryaspergilloma: analysis of prognosis in relation to hae-moptysis and survey of treatment. Thorax 38:572578

Katzenstein A-LA, Sale SR, Greenberger PA (1983) Aller-gic Aspergillussinusitis: a newly-recognized form ofsinusitis. J Allerg Clin Immunol 72:8993

Kaufman L, Padhye AA, Parker S (1988) Rhinocerebralzygomycosis caused by Saksenaea vasiformis J MedVet Mycol 26:237246

Kitahara M, Seth VK, Medoff G, Kobayashi GS (1976) Activ-ity of amphotericin B, 5-fluorocytosine, and rifampinagainst six clinical isolates ofAspergillus. AntimicrobAgents Chemother 9:915919

Kurup VP, Fink JN (1978) Evaluation of methods to detectantibodies against Aspergillus fumigatus. Am J ClinPathol 69:414417

Kwon-Chung KJ, Bennett JE (1992) Medical Mycology. Leaand Febiger, MalvernLehrer RI, Howard DH, Sypherd PS, Edwards JE, Segal GP,

Winston DJ (1980) Mucormycosis. Ann Intern Med93:93108

Levitz SM, Diamond RD (1985) Mechanisms of resistanceof Aspergillus fumigatus conidia to killing by neu-trophils in vitro. J Infect Dis 152:3342

Louria DB, Lieberman PH, Collins HS, Blevins A (1966)Pulmonary mycetoma due toAllescheria boydii. ArchIntern Med 117:748751

Lutwick LI, Rytel MW, Yaez JP, Gaigiani JN, Stevens DA(1979) Deep infections from Petriellidium boy-dii treated with miconazole. J Am Med Assoc 241:

272273


11/12


Lyon DT, Schubert TT, Mantia AG, Kaplan MH (1979) Phy-comycosis of the gastrointestinal tract. Am J Gastro-enterol 72:379394

MacMillan RH, Cooper PH, Body BA, Mills AS (1987) Aller-gic fungal sinusitis due to Curvularia lunata. HumPathol 18:960964

McCarty JM, Flam MS, Pullen G, Jones R, Kassel SH (1986)

Outbreak of primary cutaneous aspergillosis relatedto intravenous arm boards. J Pediatr 108:721724McGill TJ, Simpson G, Healy GB (1980) Fulminant aspergil-

losis of the nose and paranasal sinuses. Laryngoscope90:748754

Mawk JR, Erickson DL, Chan SN, Seljeskog EL (1983)Aspergillus infections of the lumbar disc spaces.J Neurosurg 58:270274

Merz WG, Karp JE, Hoagland M, Jett-Goheen M, JunkinsJM, Hood AF (1988) Diagnosis and successful treat-ment of fusariosis in the compromised host. J InfectDis 158:10461055

Meyer RD, Rosen P, Armstrong D (1972) Phycomycosiscomplicating leukemia and lymphoma. Ann Intern

Med 77:871879Meyer RD, Kaplan MH, Ong M, Armstrong D (1973a) Cuta-

neous lesions in disseminated mucormycosis. J AmMed Assoc 225:737738

Meyer RD, Young LS, Armstrong D, Yu B (1973b) Aspergil-losis complicating neoplastic disease. Am J Med54:615

Meyers BR, Wormser G, Hirschman SZ, Blitzer A (1979)Rhinocerebral mucormycosis: premortem diagnosisand therapy. Arch Intern Med 139:557560

Miloshev B, Davidson CM, Gentles JC, Sandison AT (1967)Aspergilloma of paranasal sinuses and orbit in north-ern Sudanese. Sabouraudia 6:57

Moore CK, Hellreich MA, Coblentz CL, Roggli VL (1988)Aspergillus terreus as a cause of invasive pulmonaryaspergillosis. Chest 94:889891

Mostaza JM, Barbado FJ (1989) Cutaneoarticular mucormy-cosis due to Cunninghamella bertholletiaein a patientwith AIDS. Rev Infect Dis 11:316318

Murray HW (1975) Pulmonary mucormycosis with mas-sive fatal hemopytsis. Chest 68:6568

Nesky MA, McDougal EC, Peacock JE Jr (2000) Pseudalle-scheria boydiibrain abscess successfully treated withvoriconazole and surgical drainage: case report andliterature review of central nervous system pseudal-lescheriasis. Clin Infect Dis 31:673677

Orgel IK, Cohen KL (1989) Postoperative zygomycetes

endophthalmitis. Ophthalm Surg 20:584587Patterson TF (2005) Aspergillus species. In: Mandell GL,Bennett JE, Dolin R (eds) Principles and practice ofinfectious diseases, vol 2. Elsevier, Philadelphia, pp29582973

Peterson DE, Schimpff SC (1989) Aspergillus sinusitis inneutropenic patients with cancer: a review. BiomedPharmacother 43:307312

Pierce PF Jr, Solomon SL, Kaufman L, Garagusi VF, ParkerRH, Ajello L (1982) Zygomycetes brain abscesses innarcotic addicts with serological diagnosis. J Am MedAssoc 248:28812882

Pierce PF, Wood MB, Roberts GD, Fitzgerald RH Jr, Robert-son C, Edson RS (1987) Saksenaea vasiformisosteo-

myelitis. J Clin Microbiol 25:933935

Piper JP et al (1990) Successful treatment of Scedosporiumapiospermumsuppurative arthritis with itraconazole.Pediatr Infect Dis J 9:674675

Prystowsky SD, Vogelstein K, Ettinger DS, Merz WG, KaizerH, Sulica VI, Zinkham WH (1976) Invasive aspergil-losis. N Engl J Med 295:655658

Pursell KJ, Telzak EE, Armstrong D (1990) Aspergillus

species colonization and invasive disease in patientswith AIDS. Clin Infect Dis 14:141148.Raper KB, Fennell DI (1965) The genus Aspergillus.

Williams & Wilkins, BaltimoreRedmond A et al (1965)Aspergillus(Aspergillus nidulans)

involving bone. J Pathol Bacteriol 89:391Rex JH, Ginsberg AM, Fries LF, Pass HI, Kwon-Chung KJ

(1988) Cunninghamella bertholletiae infection asso-ciated with deferoxamine therapy. Rev Infect Dis10:11871194

Richardson SE, Bannatyne RM, Summerbell RC, Milliken J,Gold R, Weitman SS (1988) Disseminated fusarialinfection in the immunocompromised host. Rev InfectDis 10:11711181

Rippon JW, Carmichael JW (1976) Petriellidiosis (allesche-riosis): four unusual cases and review of literature.Mycopathologia 58:117124

Robertson MJ, Socinski MA, Soiffer RJ, Finberg RW,Wilson C, Anderson KC, Bosserman L, Sang DN,Salkin IF, Ritz J (1991) Successful treatment of dis-seminated Fusarium infection after autologous bonemarrow transplantation for acute myeloid leukemia.Bone Marrow Transplantation 8:142145

Salitan MD, Lawson W, Som PM, Bottone EJ, Biller HF (1990)Pseudallescheriasinusitis with intracranial extensionin an immunocompromised host. Otolaryngol HeadNeck Surg 102:745780

Sands JM, Macher AM, Ley TJ, Nienhuis AW (1985) Dis-seminated infection caused by Cunninghamellabertholletiae in a patient with beta-thalassemia. AnnIntern Med 102:5963

Schaffner A, Davis CE, Schaffner T, Markert M, Douglas H,Braude AI (1986) In vitro susceptibility of fungi tokilling by neutrophil granulocytes discriminatesbetween primary pathogenicity and opportunism.J Clin Invest 78:511524

Schiess RJ, Coscia MF, McClellan GA (1984) Petriellidiumboydiipachymeningitis treated with miconazole andketoconazole. Neurosurgery 14:220224

Seaworth BJ, Kwon-Chung KJ, Hamilton JD, Perfect JR(1983) Brain abscess caused by a variety of Cladospo-

rium trichoides. Am J Clin Pathol 79:747752Sheldon DL, Johnson WC (1979) Cutaneous mucormycosis.J Am Med Assoc 241:10321034

Sherertz RJ, Belani A, Kramer BS, Elfenbein GJ, Weiner RS,Sullivan ML, Thomas RG, Samsa GP (1987) Impactof air filtration on nosocomial Aspergillus infections.Unique risk of bone marrow transplant recipients. AmJ Med 83:709718

Shih L, Lee N (1984) Disseminated petriellidiosis (allesche-riasis) in a patient with refractory acute lymphoblas-tic leukemia. J Clin Pathol 37:7882

Smith AG, Crain SM, Dejongh C, Thomas GM, VigoritoRD (1985) Systemic pseudallescheriasis in a patientwith acute myelocytic leukemia. Mycopathologia

90:8589


12/12


Smith AG, Bustamante CI, Gilmor GD (1989) Zygomycosis(absidiomycosis) in an AIDS patient. Mycopathologia105:710

Stave GM, Heimberger T, Kerkering TM (1989) Zygomyco-sis of the basal ganglia in intravenous drug users. AmJ Med 86:115117

Steinbach WJ, Stevens DA (2003) Review of newer antifun-

gal and immunomodulatory strategies for invasiveaspergillosis. Clin Infect Dis 37[Suppl 3]:S157S187Sugar AM (2005) Agents of mucormycosis and related spe-

cies. In: Mandell GL, Bennett JE, Dolin R (eds) Princi-ples and practice of infectious diseases, vol 2. Elsevier,Philadelphia, pp 29732984

Swerdlow B, Deresinski S (1984) Development ofAspergil-lussinusitis in a patient receiving amphotericin B. AmJ Med 76:162166

Talbot GH, Huang A, Provencher M (1991) InvasiveAspergillus rhinosinusitis in patients with acuteleukemia. Rev Infect Dis 13:219232

Thomson SR, Bade PG, Taams M, Chrystal V (1991) Gas-trointestinal mucormycosis. Br J Surg 78:952954

Vainrub B, Macareno A, Mandel S, Musher D (1988) Woundzygomycosis (mucormycosis) in otherwise healthyadults. Am J Med 84:546548

Varkey B, Rose HD (1976) Pulmonary aspergilloma: arational approach to treatment. Am J Med 61:626631

Venditti M, Micozzi A, Gentile G, Polonelli L, Morace G,Bianco P, Avvisati G, Papa G, Martino P (1988) Inva-sive Fusarium solaniinfections in patients with acuteleukemia. Rev Infect Dis 10:653660

Waldorf AR, Levitz SM, Diamond RD (1984a) In vivobronchoalveolar macrophage defense against Rhizo-

pus oryzae and Aspergillus fumigatus. J Infect Dis150:752760

Waldorf AR, Ruderman N, Diamond RD (1984b) Specificsusceptibility to mucormycosis in murine diabetesand bronchoalveolar macrophage defense againstRhizopus. J Clin Invest 74:150160

Walsh TJ et al (2007) Treatment of invasive aspergillosiswith posaconazole in patients who are refractory toor intolerant of conventional therapy: an externallycontrolled trial. Clin Infect Dis 44:212

Washburn RG (1996) Bronchopulmonary aspergillosis. In:Kelley WN et al (eds) Textbook of internal medicine.Lippincott, Philadelphia, pp 20002001

Washburn RG (1998) Fungal sinusitis. In: Remington JS,Swartz MN (eds) Curr Clin Top Infect Dis 18:6074

Washburn RG, Bennett JE (1995) Deep mycoses. In: Blaser

MJ et al (eds) Infections of the Gastrointestinal Tract.Raven, New York, pp 957966Washburn RG, Gallin JI, Bennett JE (1987) Oxidative

killing of Aspergillus fumigatus conidia pro-ceeds by parallel myeloperoxidase-dependent and

myeloperoxidase-independent pathways. Infect Immun55:20882092

Washburn RG, Kennedy DW, Begley MG, Henderson DK,Bennett JE (1988) Chronic fungal sinusitis in appar-ently normal hosts. Medicine 67:231247

Watson KC (1957) Gastric perforation due to the fungusMucor in a child with kwashiorkor. S Afr J Med 31:

99101Waxman JE, Spector JG, Sale SR, Katzenstein A-LA (1987)Allergic Aspergillus sinusitis: concepts in diagnosisand treatment. Laryngoscope 97:261266

Weber SF, Washburn RG (1990) InvasiveAspergillusinfec-tions complicating coronary artery bypass grafting.South Med J 83:584588

Weiland D, Ferguson RM, Peterson PK, Snover DC, Sim-mons RL, Najarian JS (1983) Aspergillosis in 25 renaltransplant patients. Ann Surg 198:622629

White CJ, Kwon-Chung KJ, Gallin JI (1988) Chronic gran-ulomatous disease of childhood; an unusual case ofinfection with Aspergillus nidulans var. echinulatus.Am J Clin Pathol 90:312316

Wilson BJ, Wilson CH (1961) Oxalate formation in moldyfeedstuffs as a possible factor in livestock toxic dis-ease. Am J Vet Res 22:961969

Winn RE, Ramsey PD, McDonald JC, Dunlop KJ (1983) Max-illary sinusitis from Pseudallescheria boydii: efficacyof surgical therapy. Arch Otolaryngol 109:123125

Winston DJ, Jordan MC, Rhodes J (1977)Allescheria boydiiin the immunosuppressed host. Am J Med 63:830835

Woods GL, Goldsmith JC (1990) Aspergillus infection ofthe central nervous system in patients with acquiredimmunodeficiency syndrome. Arch Neurol 47:181184

Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita VT(1970) Aspergillosis: The spectrum of the disease in98 patients. Medicine 49:147173

Young RC, Jennings A, Bennett JE (1972) Species identifica-tion of invasive aspergillosis in man. Am J Clin Pathol58:554557

Yu VL, Muder RR, Poorsattar A (1986) Significance of isola-tion ofAspergillusfrom the respiratory tract in diag-nosis of invasive pulmonary aspergillosis. Am J Med81:249254

Zapater RC, Arrechea A (1975) Mycotic keratitis by Fusar-ium: a review and report of two cases. Ophthalmolo-gia 170:112

Zeilender S, Drenning D, Glauser FL, Bechard D (1990)Fatal Cunninghamella bertholletiae infection in an

immunocompetent patient. Chest 97:14821483Zellner SR, Selby JB, Loughrin JJ (1969) Aspergillosis: anunusual presentation. Am Rev Respir Dis 100:217220

Ziskind J, Pizzolato P, Buff EE (1958) Aspergillosis of thebrain. Am J Clin Pathol 29:554559

Documents

Opportunistic Mold Infections