1

A case of adiaspiromycosis causing1

respiratory failure and a review of human2

infections due to the fungi Emmonsia and3

Chrysosporium4

5

Gregory M. Anstead,*1,2 Deanna A. Sutton,3 and John R.6

Graybill17

81Department of Medicine, Division of Infectious Diseases; and93Department of Pathology, Fungus Testing Laboratory10

University of Texas Health Science Center at San Antonio11

San Antonio, TX 7822912

132Department of Medicine, Division of Infectious Diseases14

South Texas Veterans Healthcare System15

San Antonio, TX 7822916

17

Submitted to: Journal of Clinical Microbiology18

19

*Address correspondence to:20

Gregory M. Anstead, MD, PhD21

Department of Medicine; Division of Infectious Diseases22

University of Texas Health Science Center at San Antonio23

7703 Floyd Curl Drive MC788124

San Antonio, TX 7822925

Phone: 210-567-466626

Fax: 210-567-467027

Email: anstead@uthscsa.edu28

29

Running title: Adiaspiromycosis causing respiratory failure30

31

32

2

We report a case of a 27 year-old male who presented with respiratory distress that33

required mechanical ventilation. Transbronchial biopsy revealed adiaspores of the34

fungus Emmonsia crescens within granulomata, a condition known as35

adiaspiromycosis. The patient received amphotericin products and corticosteroids,36

followed by itraconazole, and made a full recovery. Emmonsia crescens is a saprobe37

with a wide distribution that is primarily a rodent pathogen. The clinical38

characteristics of the 21 cases of human pulmonary adiaspiromycosis reported since39

the last comprehensive review in 1993 are described, as well as other infections40

recently reported for the genus Emmonsia. Pulmonary adiaspiromycosis has been41

reported primarily in persons without underlying host factors, and has a mild to42

severe course. It remains uncertain if the optimal management of patients with43

severe pulmonary adiaspiromycosis is supportive, antifungal treatment,44

corticosteroids, or a combination of the latter two. The classification of fungi45

currently in the genus Emmonsia have undergone considerable revision since their46

original description, including being grouped with the Chrysosporium at one time.47

Molecular genetics has clearly differentiated the Emmonsia from the Chrysosporium.48

Nevertheless, there has been a persistent confusion in the literature regarding the49

clinical presentation of infection with fungi of these two genera; to clarify this50

matter, the reported cases of invasive chrysosporiosis were also reviewed. Invasive51

Chrysosporium infections typically occur in impaired hosts, and can have a fatal52

course; based on in vitro susceptibilities, amphotericin B, itraconazole, and53

voriconazole are the most active drugs.54

55

3

INTRODUCTION56

Adiaspiromycosis is primarily a pulmonary infection of rodents, fossorial57

mammals, and their predators, caused by the soil fungi Emmonsia crescens and E. parva58

(5,53). It is a rare human infection. In this infection, inhaled Emmonsia conidia enlarge59

to form non-replicating adiaspores. As in other mammals, the infection in humans60

usually involves lungs, with only a few other well-documented cases of infection at other61

body sites (35,53). Numerous case reports have been published about human62

adiaspiromycosis, but much of the medical literature on this infection has been widely63

dispersed in many less accessible non-English journals. Furthermore, the inconsistent64

nomenclature and taxonomy of the Emmonsia and their confusion with fungi of the genus65

Chrysosporium has resulted in an overall lack of consistent information on66

adiaspiromycosis and chrysosporiosis. Herein, we report a case of adiaspiromycosis that67

resulted in respiratory failure. We also review the true cases of adiaspiromycosis that68

have reported since the last comprehensive assessment of cases by England and69

Hochholzer in 1993 (20). Furthermore, we differentiate the cases of adiaspiromycosis70

from the true and probable cases of invasive chrysosporiosis.71

CASE REPORT72

A 27 year-old Hispanic male presented with a 5-day history of nonproductive73

cough, dyspnea, pleuritic chest pain, and weight loss. Initial vital signs were temperature74

99.2 °F, bp 112/67, pulse 104 per minute, and respiration rate 22 breaths per minute. On75

exam, there were crackles throughout both lung fields. A chest X-ray showed marked76

bilateral interstitial infiltrates (Fig. 1). The white blood cell count was 15,800/mm3 (85%77

pmns, 6% lymphocytes, 4% monocytes, 5% eosinophils). The hematocrit, platelet count,78

and routine serum chemistry values were within normal limits, except for aspartate and79

4

alanine transaminase levels of 45 and 104 U/L, respectively. An arterial blood gas80

measurement on room air showed pH 7.49, PCO2 31 mm Hg, and PO2 50 mm Hg. The81

impression was military tuberculosis or pneumocytosis and the patient received isoniazid,82

rifampin, pyrazinamide, ethambutol, and trimethoprim/sulfamethoxazole. The patient83

emigrated from Mexico two years ago and worked at a construction site. He denied84

substance abuse and recent travel.85

Bronchoscopy with lavage and trans-bronchial biopsy was performed on hospital86

day-3. Both specimens were negative for acid-fast bacillus stain and culture. The87

Gomori’s methenamine-silver (GMS)-stained biopsy specimen showed thick, capsulated88

structures (either empty or with a few internal globules) centrally in non-necrotizing89

granulomas (Fig. 2). The impression was coccidioidomycosis. The patient received one90

dose of fluconazole and then amphotericin B 40 mg IV each day. The anti-mycobacterial91

drugs and trimethoprim/sulfamethoxazole were discontinued.92

However, serologic studies for coccidioidomycosis were repeatedly negative.93

Other negative studies included: viral and routine cultures; urine Histoplasma and94

Legionella antigens; serum cryptococcal antigen; and serologic tests for the human95

immunodeficiency virus, Mycoplasma, Toxocara, and Chlamydia.96

Despite treatment with amphotericin B, the patient’s respiratory status97

deteriorated. On day-13, methylprednisolone 100 mg IV four-times daily was started.98

Later that day, the patient went into respiratory failure and required mechanical99

ventilation. On day-16, amphotericin B was changed to amphotericin B lipid complex at100

5 mg/kg/d because the patient developed renal tubular acidosis. Because of the patient’s101

5

lack of improvement, an open lung biopsy of was performed on day-18, which showed102

only GMS-positive material suggestive of residual fungal elements.103

At this point, the histopathology specimen from the original trans-bronchial104

biopsy was reviewed again, and a diagnosis of adiaspiromycosis due to Emmonsia105

crescens was made. The patient’s pulmonary status was gradually improving. He was106

weaned from mechanical ventilation after 6 days. Amphotericin B lipid complex was107

discontinued on day-25 and itraconazole 200 mg orally each day was started. A CT scan108

performed on day-26 showed diffuse bilateral interstitial thickening (Fig. 3). Three days109

before hospital discharge, pulmonary function tests showed a moderate restrictive defect.110

The patient was discharged on tapering prednisone and itraconazole 200 mg orally daily111

for 12 days. At follow-up three months after discharge, the patient was asymptomatic,112

and he had returned to his previous weight.113

With the diagnosis of this unusual mycosis, the patient was interviewed again114

about exposures. He reported that two weeks prior to the onset of his illness he disposed115

of a partially decomposed cat carcass at his construction worksite in Bexar Co., TX (near116

San Antonio), and some debris showered down upon his face at that time.117

Methods118

To find previously published cases of emmonsiosis and chrysosporiosis119

MEDLINE was searched from 1965 to December 2010 using the search terms120

“adiaspiromycosis,” “Emmonsia,” and “Chrysosporium.” Additional cases were found121

by bibliographic branching. Papers in non-English languages were translated into122

English by using the online translation tool Yahoo! Babel Fish.123

6

(http://babelfish.yahoo.com). Other information was obtained from Google searches124

using the same search terms.125

RESULTS AND DISCUSSION126

Review of Adiaspiromycosis127

History of the Description of the Organisms and their Nomenclature and Taxonomy.128

The nomenclature and taxonomy of these fungi has been a source of ongoing129

confusion, so it is instructive to clarify this issue and justify the nomenclature that we130

have adopted for this paper. Furthermore, the nomenclatural confusion has caused many131

authors to lump cases due to Chrysosporium together with those caused by E. crescens132

and E. parva and so the clinical presentation of disease caused by the two genera has also133

been quite muddled in the literature (40,41,63,67,68).134

In 1939, Kirschenblatt described cystic structures in the lungs of rodents from the135

former Soviet Union and proposed that these were due to a fungus that he named136

Rhinosporidium pulmonale (27). In 1942, Emmons and Ashburn observed spherical non-137

budding cells up to 14 µm in diameter in the lungs of rodents in Arizona; they thought138

this fungus was a zygomycete, so they placed it in the genus Haplosporangium, and used139

the species epithet parvum because of the small size of its sporangium (18). In 1947,140

Dowding observed fungal cells, up to 300 µm in diameter, in the lungs of rodents from141

Alberta (15). Although this fungus resembled H. parvum in its culture characteristics and142

microscopic appearance, it formed both larger cells in vivo and larger chlamydospores143

when grown at 37oC. In the 1950s, it was determined that H. parvum was not a144

zygomycete and was closely allied to Blastomyces on the basis of conidial characteristics.145

Ciferri and Montemartini created the new monotypic genus Emmonsia for H. parvum in146

7

1959 (9) and in 1960 Emmons and Jellison (19) added E. crescens (the fungus from the147

Canadian rodents). The two species were differentiated by the size of their adiaspores148

and maximum growth temperatures (53).149

The confusion commenced in 1962 when Carmichael broadened the genus150

Chrysosporium to include all fungi that produce aleurioconidia, solitary single-cell151

conidia that are released by disintegration of the supporting structure (7). Furthermore,152

Carmichael treated E. parvum and E. crescens as varieties of the same species. Thus, E.153

parvum and E. crescens were renamed C. parvum var. parvum and C. parvum var.154

crescens, respectively (7). Some mycologists embraced the reclassification (33), but155

others advocated retaining the genus name Emmonsia, but also designating the two156

species as varieties, i.e., E. parvum var. parvum and E. parvum var. crescens (65).157

Meanwhile, other species assigned to Emmonsia in the 1960s, E. brasilensis and E .158

ciferrina, were reclassified as C. pruinosum (43).159

Currently, fungi of the genera Emmonsia and Chrysosporium are classified as160

follows: Kingdom Eumycota, Division Ascomycota, Class Euascomycetes, Order161

Onygenales, Family Onygenaceae. Other genera in this family include Blastomyces,162

Coccidioides, Histoplasma, and Paracoccidioides (11). Genetically, Emmonsia is more163

closely related to Blastomyces, Histoplasma , and Paracoccidioides than to164

Chrysosporium or Coccidioides (11). (For a comparison of Emmonsia with these genera,165

see Sigler (53)).166

In 1996, Sigler described the teleomorph (meiotic stage) of E. crescens,167

Ajellomyces crescens, which is the same genus as the teleomorphs of Blastomyces168

dermatitidis and Histoplasma capsulatum. Genetic sequencing of these fungi confirmed169

8

the relatedness of Emmonsia to Blastomyces (34,46); in fact, E. parva is more closely170

related to Blastomyces than to E. crescens. It would be justified, based on genetic171

analyses, to place the Emmonsia in the same genus as Blastomyces. However, because of172

the chaos that would ensue from a genus-level name change of these medically173

significant fungi, Blastomyces and Histoplasma have retained their current names. Also,174

it is appropriate that the Emmonsia not be classified as Chrysosporium and that E. parva175

and E. crescens be considered distinct species.176

In 1998, a cutaneous mycosis was reported in an AIDS patient; histopathologic177

analysis of the skin revealed small yeast-like budding cells, (2-4 µm in diameter), larger178

thick-walled cells (8-10 µm in diameter), and pseudohyphae. In culture, the fungus was179

morphologically compatible with Emmonsia, but was genetically distinct from E. parva180

and E. crescens, and was described as a new species, E. pasteuriana (22).181

Another nosological obfuscation has been the cavalier use of the term182

adiaspiromycosis. The term derives from the Greek ‘diaspeirios’, meaning ‘to spread’183

and ‘a’, denoting a negative, so named because the adiaspore is not known to divide in184

tissue or to disseminate (19). Thus, the term adiaspiromycosis is correctly applied to185

describe the infection only when the Emmonsia adiaspores are observed in tissue. For186

example, E. pasteuriana produces yeast-like forms in tissue (22), so the infection could187

be called emmonsiosis, but not adiaspiromycosis. In a case of pulmonary infection188

observed in a rheumatoid arthritis patient, fungi were observed within the macrophages189

obtained in the bronchoalveolar lavage, and were identified as an Emmonsia species190

based on genetic sequencing, but adiaspores were not observed in the biopsy specimen.191

The authors appropriately did not use the term adiaspiromycosis to describe the infection192

9

(72). Furthermore, the term adiaspiromycosis should not be used for infections due to193

Chrysosporium (57).194

Mycology of Emmonsia and Chrysosporium195

Members of both genera produce solitary, single-celled conidia called196

aleurioconidia because of their lytic method of conidial dehiscence. The tissue forms of197

E. crescens and E. parva have large, thick-walled chlamydospore-like non-reproducing198

spores called adiaspores (53), whereas Chrysosporium produces hyphae in tissue (49,68).199

For Chrysosporium in culture, the colonies are yellowish-white to buff, and slow200

to moderately fast growing. The conidia are single-celled and the smooth to roughened201

aleurioconidia are sessile (formed directly on the sides of the hyphae) or formed at the202

ends or on the sides of unswollen stalks. Alternate arthroconidia are also sometimes203

present (55).204

For Emmonsia, the colonies are yellowish-white to buff. The aleurioconidia are205

single-celled, smooth to roughened, formed sessile or on the sides of swollen stalks. The206

formation of two to three conidia from the same cell is also a common feature.207

Emmonsia forms adiaspores at maximum growth temperatures. Members of Emmonsia208

differ from the Chrysosporium by their swollen stalk and the telomorph of E. crescens in209

the genus Ajellomyces (55).210

Clinical Presentation of Human Infection211

The first human case, presenting as a solitary pulmonary nodule, was reported in212

1964 (13). Disseminated human pulmonary disease was first observed in 1971 (28).213

Approximately 67 probable cases of human pulmonary adiaspiromycosis due to E.214

crescens have been described in the literature. England and Hochholzer, in their 1993215

10

case series and review (20), identified 46 cases; there have been 21 other cases reported216

since that time or omitted from their review (Table 1). Adiaspiromycosis may be217

discovered incidentally after histopatholgic exam of the lung in other conditions.218

Alternatively, the disease may have an indolent course with fever, weight loss, fatigue,219

cough, hemoptysis, and dyspnea. In such cases, the chest radiograph usually shows220

bilateral reticulonodular infiltrates suggestive of military tuberculosis. Disseminated221

pulmonary infection can have a severe or even fatal course (6,20,31,36,38,52). The222

patient reported herein suffered moderate restrictive lung disease after the infection;223

likewise, in two prior cases, restrictive disease was observed (50).224

In the 21 patients with pulmonary adiaspiromycosis due to E. crescens (Table 1),225

in four cases, the disease was discovered incidentally. In the 16 other cases in which a226

clinical course were described, one case was fatal, and five other patients had severe227

disease, two of these requiring mechanical ventilation. Host factors were not important228

in the severity of the infection.229

There have been two reports of adiaspiromycosis of the appendix that developed230

after oral ingestion of the fungus (16,29); in one of these cases, peritonitis was observed231

after appendiceal rupture (16). However, the reported cases of cutaneous232

adiaspiromycosis (25,57) and adiaspiromycosis of the cornea (67) are probably due to233

other fungi (53).234

An unusual outbreak of ocular adiaspiromycosis was reported from northern235

Brazil in 2006. Local ophthalmologists reported 18 children with conjunctival nodules to236

health authorities. Subsequently, 5084 children were screened for external ocular237

changes and decreased visual acuity. Active ocular disease (conjunctivitis with238

11

episcleritis and anterior uveitis) was diagnosed in 64 children; 104 had ocular sequelae.239

Of children with ocular nodules, 14 received biopsies, which revealed microulceration240

and inflammatory infiltrates. In two specimens, subconjunctival inflammation and241

adiaspores of E. crescens were observed. In 32 patients that were treated with topical or242

oral prednisone, the disease resolved in 78%. The investigators hypothesized that243

exposure to freshwater sponge spicules caused an initial conjunctival irritation;244

subsequent exposure to airborne conidia of E m m o n s i a caused the ocular245

adiaspiromycosis (35).246

Two cases of adiaspiromycosis reportedly due to E. parva have been described in247

AIDS patients (Table 2). In the case from Echavarria et al. (17), infection was248

disseminated to the bone marrow, multiple bony sites, and the lungs. Adiaspores were249

observed in the pus obtained during debridement of the bony lesions; hyphae were250

observed in culture at 20oC and adiaspores at 40oC. The second case due to E. parva251

involved a patient with AIDS who presented with cough, dyspnea, and a pulmonary mass252

(64). Biopsy of the mass showed “fungal elements”, not otherwise described. A253

specimen obtained by bronchoalveolar lavage grew a dimorphic fungus, with a mould254

observed at 25oC and adiaspores (12-15 µm) at 37oC.255

Pathogenesis and Histopathology256

In adiaspiromycosis due to E. crescens, the inhaled aleurioconidia, 2-4 µm in257

diameter, reach the alveoli and enlarge to a diameter of 220-700 µm, a volume increase258

of about one million-fold. The fungus does not propagate in vivo and probably does not259

disseminate from the lungs (69). This lack of replication in human tissues is unique to260

pathogenic fungi (8).261

12

With the hematoxylin-eosin stain, the thick (20-70 µm) walls of the adiaspores262

appear to be composed of two layers: a narrow eosinophilic outer layer and a chitinous263

thicker inner hyaline layer. With GMS, the wall stains uniformly. The adiaspores are264

usually empty, but may contain small globules (71). The host response to the adiaspores265

is the formation of large granulomata (0.5-3 mm) composed of epitheloid and giant cells.266

The granulomata are in a similar stage of evolution, indicating a response to a single267

exposure (71). Grossly, there may be firm white nodules a few millimeters in diameter in268

the lung parenchyma (20,45). Necrosis and caseation are typically not observed, but have269

been reported (8,45).270

The extent of pulmonary involvement depends of the quantity of inhaled271

aleurioconidia. If a single conidium is inhaled, a solitary pulmonary nodule results. If272

numerous conidia are inhaled, disseminated pulmonary disease occurs. Respiratory273

compromise is due to compression of small airways and displacement of pulmonary274

tissue by granulomata (69). Dissemination outside the lung has not been reported for E.275

crescens and the case described for E. parva (17Echavarria) is questionable (55).276

However, extension to the local pulmonary lymph nodes has been reported in humans277

and animals (2,36).278

Diagnosis of adiaspiromycosis279

The diagnosis of adiaspiromycosis is usually made by observing its unique280

histopathologic appearance. Organisms that might be confused for Emmonsia in281

histologic specimens are Coccidioides sp. and Rhinosporidium seeberi (71).282

Coccidioides spherules will usually have distinct endosporulation. However, after283

necrosis, pulmonary nodules due to Coccidioides may contain empty spherules (44).284

13

Nevertheless, these are much smaller than the adiaconidia of Emmonsia, with thinner285

walls. Rhinosporidium also has endosporulation, and is smaller than either Emmonsia286

species (71). Helminths that infect the lungs, such as Strongyloides or Dirofilaria, may287

also resemble adiaspiromycosis (20). The staining characteristics of E. crescens are288

described by Sun et al. (60).289

Overall, Emmonsia crescens is difficult to culture from clinical specimens (20).290

At 37°C, on brain heart infusion blood agar, the aleurioconidia of E. crescens enlarge to291

become adiaconidia 25-400 µm in diameter; E. parva requires 40°C to produce292

adiaconidia, which are 10-25 µm in diameter (53).293

Epidemiology of Human Adiaspiromycosis294

Cases of human adiaspiromycosis have been reported from Brazil, France, the295

former Czechoslovakia, the former Soviet Union, Romania, Honduras, Guatemala,296

Venezuela, Finland, United Kingdom, Argentina, Spain, Germany, and the United States297

(NC, OK, AZ, NY, GA)(12,20,40,71). However, since E. crescens is geographically298

widespread, it would be expected that cases may be observed in many different locales.299

Table 1 shows the demographic data of the 21 patients with pulmonary300

adiapiromycosis due to E. crescens described since the review of England and301

Hochholzer or omitted from that review (20). From Table 1, the average age of the302

patients was 40 years, with a range of 2-74 years old; 90% are male, probably because of303

greater occupational exposure to dusts. New areas in which the disease has been reported304

include the United Kingdom and Finland (12,40); however, 62% of the 21 new cases of305

pulmonary adiaspiromycosis were reported from Brazil, which is also the location of the306

newly recognized ocular adiaspiromycosis (35). It is unclear if the E. crescens is actually307

14

more common in Brazil, or this is simply reporting bias. Certainly, the fungus has a wide308

distribution in nature elsewhere (5,53).309

This patient probably encountered the organism in his occupation as a carpenter at310

a construction site. In most previous cases of adiaspiromycosis, the persons had311

occupations with soil or dust exposure (20). However, the handling of a decomposing cat312

two weeks prior to the onset of symptoms may have also been the source of his infection.313

A time frame of several weeks is typical for the granulomatous reaction to occur in the314

lungs in response to the presence of the fungus or for adiaspiromycosis to develop in315

experimentally-induced disease (2,53). In the life cycle of the fungus, the decomposition316

of dead mammals containing adiaspores is the means by which the organism returns to317

the soil. Carnivores may have adiaspores in both the lungs and the gastrointestinal tract318

(30). Another report suggested that proximity to dead mammals may be important in the319

transmission of the disease (4). Thus, in this case, the soil near the dead cat may have320

contained the aleurioconidia of the fungus, resulting from germination of adiaspores from321

the decomposing carcass.322

Treatment of adiaspiromycosis323

The most appropriate treatment for adiaspiromycosis is unknown. Many human324

cases are self-limited or asymptomatic, but several cases that have resulted in respiratory325

failure and death have been reported (4,6,20,31,38,45,52,56). In the cases of326

adiaspiromycosis reported in Table 1, 57% of the patients were treated with an antifungal327

agent. However, because the organism does not replicate in tissue, it is not entirely clear328

if antifungal therapy is necessary (70).329

Recently, the susceptibility of an isolate of E. crescens to various antifungal330

15

agents was determined. The MICs (µg/mL) of amphotericin B, itraconazole,331

voriconazole, caspofungin, fluconazole, and flucytosine were 0.06, 0.12-0.25, 0.06, 0.5,332

64, and 8, respectively, with no significant difference in susceptibilities between the333

aleuriospores and adiaspores. Only amphotericin B was fungicidal (5). The334

susceptibility to azoles is similar to that of Histoplasma and Blastomyces (42Otcenasek335

and Ditrich 1983).336

Anecdotally, clinical improvement in patients with adiaspiromycosis has been337

reported using a number of drugs, including ketoconazole (Table 1), pimafucin (28),338

levamisole (4), thiabendazole (4), flucytosine (47), inhaled pimaricin (4), and339

amphotericin B (Table 1). However, it is uncertain if antifungal treatment accelerated340

recovery, or if this was merely the natural history of the infection. Patients appeared to341

benefit from corticosteroids in three previous cases (10,28,56) and in this case as well;342

this intervention seems reasonable in the immunocompetent patient because the major343

pathogenic effect of the fungus is due to the host granulomatous response. In severe344

pulmonary adiaspiromycosis in the immunocompetent host, it is reasonable to give both345

antifungal treatment to destroy the organism that provokes the inflammation and346

corticosteroid treatment to modulate that response. The disease is so rare that controlled347

clinical trial data will never be available; however, an animal model may be able to348

suggest if antifungal treatment, corticosteroids, both, or none may be beneficial.349

Review of Chrysosporium Infection350

Chrysosporium is a large genus of saprobic soil fungi that includes over sixty351

species (66). Many of the species are keratinolytic, breaking down shed keratinized352

residues, such as hair and feathers (1). Common members of the genus include C.353

16

keratophilum, C. tropicum, C. merdarium, C. inops, C. pannicola, C. queenslandicum,354

and C. zonatum (3). Chrysosporium species may be encountered in the mycology355

laboratory as contaminants of cutaneous and respiratory samples, but are occasionally356

isolated as true agents of dermatomycoses from samples of human skin and nails357

(11,58,61). They are rarely associated with invasive human disease, but in the358

immunocompromised patient, they can be aggressive opportunistic pathogens.359

The Chrysosporium are similar to Geomyces species and the mould phase of360

Blastomyces dermatiditis and share the teleomorph genus Arthroderma with many361

species of dermatophytic fungi (61). They are resistant to cycloheximide and can be362

recovered from selective media for dermatophytes (61), and potato dextrose agar (1).363

The common species of Chrysosporium can usually be differentiated by the morphology,364

location, and size of the conidia (3,26); however, many species share similar features and365

definitive identification may require genetic sequencing (66). The mycology atlas of de366

Hoog and coworkers (11) has excellent diagrams to differentiate common species of367

Chrysosporium from those of Emmonsia . Unlike E. crescens and E. parva,368

histopathologic specimens from Chrysosporium infections reveal hyphae within the369

tissue (49,59,68). Unfortunately, in several of the cases of reported Chrysosporium370

infection, the fungus was not identified to the species level and the specimen was not371

banked to allow a definitive identification (48).372

Table 3 shows the reported cases of probable non-dermatomycotic373

Chrysosporium infection. Since the 1990s, several species of Chrysosporium have been374

reported as agents of invasive human disease: C. zonatum (49), C. tropicum (23), the C.375

anamorph of Nannizziopsis vriesii (58), and several unidentified or unclassified species376

17

(Table 3). Unlike adiaspiromycosis, invasive Chrysosporium infection usually occurs in377

the immunocompromised host and is usually widely disseminated at the time of378

diagnosis.379

The pathogenicity of C. zonatum was compared to that of C. indicum in a murine380

model, using a peritoneal route of infection. In the C. zonatum group, the infection was381

uniformly fatal by 27-days, with fungus detected in the lungs in 100% of mice and in the382

kidneys and liver of 29%. The affected organs showed granuloma formation and383

necrosis. By contrast, in the C. indicum group, the fungus was completely cleared.384

Chrysosporium zonatum may be more pathogenic than other members of the genus385

because of its tolerance of host temperature (1).386

Eleven non-dermatomycotic cases of chrysosporiosis have been described in the387

medical literature. Two of these cases were patients with pulmonary fungal balls and two388

had localized disease, leaving seven cases of invasive disease. In six of the invasive389

cases, there was a specific host factor that promoted the mycosis, with five of the six390

patients being immunosuppressed, and the last having a prosthetic heart valve. Five of391

the seven patients (71%) with invasive disease survived, including three of four patients392

that were highly immunocompromised. In vitro susceptibility data for the activity of393

antifungal agents against the Chrysosporium is limited; MIC data is available for C.394

zonatum: amphotericin B (! 0.06 to 0.25 µg/mL); itraconazole (0.25 to 2 µg/mL);395

flucytosine (>128 µg/mL); and fluconazole (32 to 128 µg/mL) (49). Thus, amphotericin396

B is the recommended agent, with itraconazole susceptibility being strain-dependent;397

fluconazole and flucytosine are not active. In a study comparing amphotericin B,398

voriconazole, and fluconazole against C. keratophilum and Chrysosporium spp.,399

18

amphotericin B had MIC90 values ranging from 0.34 to 1.56 µg/mL; voriconazole was400

more active, with 0.08-0.20 µg/mL, whereas fluconazole showed low activity (73). Thus,401

even though fluconazole or 5-flucytosine was used in four of the cases in Table 3, they402

probably provided little benefit.403

CONCLUSIONS404

Since the time of the last comprehensive review in 1993 (20), 21 cases of human405

pulmonary adiaspiromycosis have been reported. Brazil has emerged as the country with406

the most reported cases. New manifestations of the disease have been described,407

including E. parva infection in HIV patients and ocular adiaspiromycosis. Two408

additional pathogenic species of Emmonsia have been described, but not as causes of409

adiaspiromycosis. Molecular genetics has delineated the relationship of the Emmonsia to410

each other and to Blastomyces, Histoplasma, Coccidioides, and Paracoccidioides. The411

same techniques have also allowed differentiation of Emmonsia and the Chrysosporium,412

but confusion of the two genera persists in the literature. Herein, we have endeavored to413

clarify the morphologic and clinical characteristics of these two genera. Pulmonary414

adiaspiromycosis has been reported primarily in persons without underlying host factors,415

and has a mild to severe course. It remains uncertain if the optimal management of416

patients with severe pulmonary adiaspiromycosis is supportive care, antifungal treatment,417

corticosteroids, or a combination of the latter two modalities. Invasive Chrysosporium418

infection typically occurs in impaired hosts, and can have a severe or fatal course; based419

on in vitro susceptibilities, amphotericin B, itraconazole, and voriconazole are the most420

active drugs.421

19

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28

FIGURE LEGENDS

Figure 1. Chest radiograph on admission of the patient, showing marked bilateral,

predominately interstitial, infiltrates and prominent right paratracheal soft tissue,

suggesting lymphadenopathy.

Figure 2. Histopathologic section (hematoxylin-eosin) of lung in this patient with

adiaspiromycosis, showing adiaspores and granuloma formation (400-X).

Figure 3. Computerized tomography of the chest of the patient on hospital day-26

showing diffuse bilateral interstitial thickening.

Table 1. Case reports of pulmonary infections due to Emmonsia crescens described since

the review of England and Hochholzer (20) or omitted from that review.

Patient Location Host Factor Species (Author’s

Nomenclature)

Presentation Severity Treatmenta

Outcome

27 y/o

M

USA

(TX)

None Emmonsia crescens Cough, dyspnea,

pain, wt loss

Resp

failure

Ampho,

methylpred

Recovered this

pt

25 y/o

M

Argentina Prior

TB

Emmonsia

parvab

Cough, dyspnea Resp

failure

Ampho Recovered 6

45 y/o

M

Brazil None Emmonsia parva

var. crescens

Incidental N/Ac

None N/A 8

74 y/o

F

USA

(NY)

Cancer,

pulmonary

radiation

Emmonsia

crescens

Nonproductive

cough, anorexia Mild

Not

reported

Not

reported

60

2 y/o

F

Finland Asthma Emmonsia parva

var. crescens

Fever, dry

cough

Mild Ampho Recovered 40

54 y/o

M

Brazil Smoker Not

specifiedd

Fever, headache,

myalgia, nausea,

wt loss

Diffuse

pulmonar

y

Keto Recovered 50

29 y/o

M

Brazil Smoker Emmonsia

parva var.

crescens

Fever, cough,

pain, dyspnea,

wt loss

Diffuse

pulmonar

y

None Recovered 50

60 y/o

M

Brazil Lung

cancer

Emmonsia

crescens

Incidental Hilar

lymph

nodes/

incidental

None N/A 36

26 y/o

M

Brazil None Emmonsia

parva

var. crescens

Fever, night

sweats, cough,

thorax pain

Diffuse

pulmonar

y

Keto Recovered 51

51 y/o

M

France Meso-

thelioma

C. parvum var.

crescens

Incidental N/A None N/A 62

57 y/o

M

France Lung

cancer

C. parvum var.

crescens

Incidental N/A None N/A 62

18 y/o

M

Brazil None Emmonsia

crescens

Thoracic pain,

cough

Severe Keto Recovered 31

35 y/o

M

Brazil None Emmonsia

parvum var

crescens

Fever, cough,

weight loss over

2 mos

Diffuse

pulmonar

y

Keto Recovered 32

52 y/o

M

Brazil Prior pulm

histoplas-

mosis

Emmonsia

parva var.

crescens

Fever,

productive

cough, wt loss

Diffuse

pulmonar

y

None Recovered 10

47 y/o

M

Brazil None Emmonsia

parva var.

crescens

Fever,

nonproductive

cough, dyspnea,

weight loss

Diffuse

pulmonar

y

None Recovered 10

43 y/o

M

Brazil None Emmonsia

parva var.

crescens

Fever, cough,

weight loss,

dyspnea, thorax

pain

Diffuse

pulmonar

y

Itra, then

prednisone

Recovered 10

30 y/o

M

France None Emmonsia

crescens

Cough, thoracic

pain, dyspnea,

weakness, wt

loss over 2

weeks

Diffuse

pulmonar

y

Itra Recovered 14

56 y/o

M

United

Kingdom

Lung

cancer

Emmonsia

crescens

Sudden

collapse

Localized

Pulmonar

y/mild

Vori Recovered 12

37 y/o

M

Brazil None Chrysosporium

parvumb

Fever, cough,

dyspnea,

anorexia, weight

loss

Diffuse

pulmonar

y/severe

Keto Recovered 52

40 y/o

M

Brazil None Emmonsia parva

var. crescens

Fever, cough,

thorax pain,

dyspnea

Diffuse

pulmonar

y/severe

Prednisone Recovered 56

31 y/o

M

Brazil None Emmonsia parvum

var. crescens

Fever, cough,

myalgias,

dyspnea

Diffuse

pulmonar

y/severe

Ampho Died 38

a Ampho = amphotericin B, Itra = itraconazole; Keto = ketoconazole; Vori =

voriconazole; Methylpred = methylprednisolone.

b Mis-identified. Should be E. crescens.

c Not applicable.

d Not specified, but appears to be E. crescens.

Table 2. Case reports of infections due to non-E. crescens Emmonsia species

Patient Location Host Factor Species (Author’s

Nomenclature)

Presentation Organs

affected/

severity

Treatmenta

Outcome Ref

64 y/o

M

Germany RAb

Emmonsia

sp.c

Dyspnea,

fever, fatigue

Diffuse

Pulmonary/

moderate

Itra Chronic,

relapsing

72

40 y/o

M

Israel AIDS,

smoker

Emmonsia

parva var.

parvad

Cough,

dyspnea

Diffuse

Pulmonary/

severe

Ampho,

Flu

Recovered 64

40 y/o

F

France AIDS Emmonsia

pasteuriana

Extensive

skin ulcers

Skin/

widespread

Ampho Died,

unrelated

cause

22

32 y/o

M

Colombia HIV

infection

Chrysosporium

parvum var.

parvumd

Wrist pain,

swelling

Lungs,

Bones/

widespread

Ampho Recovered 17

a Ampho = amphotericin B, Flu = fluconazole; Itra = itraconazole.

b RA = rheumatoid arthritis, on corticosteroids.

c Emmonsia based on species based on sequence data, but not E. crescens or E. parva

based on histopathology.

d Emmonsia parva using the nomenclature adopted herein.

Table 3. Non-dermatomycotic infections due to Chrysosporium species.

Patient Place Host Factor Species Organs

Affected

Disease

Severity

Treatmenta Outcome Ref

74 y/o

M

Spain Diabetes C. tropicum Sinus,

Brain

Severe Surgery,

L-AB, Flu

Recovered 23

50 y/o

F

Malaysia Neutro-

penia

Chrysosporium

sp.

Lungs,

Skin,

Brain,

Sinus, Blood

Disseminated Ampho,

Itra

Recovered 21

18 y/o

F

USA

(MN)

BMT Chrysosporium

sp.

Sinuses,

Brain, Lungs

Disseminated Ampho,

5FC

Died 68

38 y/o M Nigeria AIDS Chrysosporium

anamorph

Brain,

Sinus,

Lungs

Disseminated Vori,

ARV

Recovered 58

15 y/o

M

Greece CGD C. zonatum Lungs,

Pericardium,

Bones

Disseminated Ampho, then

Itra,

then L-AB

Relapsed,

recovered

49

35 y/o

M

USA

(NY)

Heart

transplant

Chrysosporium

sp.

Skin Localized Topical

Ciclopirox,

oral Flu

Recovered 57

24 y/o

M

USA

(NY)

None Chrysosporium

sp.

Bone Localized

osteomyelitis

Ampho Recovered 59

N/a Japan Prior TB C. zonatum Allergic

Pneumonitis/

fungus ball

Colonization Pred, Itra;

Intracav

ampho

Recovered 24

N/a Japan Prior TB C. zonatum Allergic

Pneumonitis/

fungal ball

Colonization Itra, then

Ampho

Died 54

61 y/o

M

USA

(IL)

Prosthetic

aortic valve

Chrysosporium

sp.

Heart valve Endocarditis None Died 63

43 y/o

M

Saudi

Arabia

None Chrysosporium

parvab

Cornea Localized Surgery X3

Top Mico,

Top Ampho,

Oral Flu

Relapsing,

recovered

67

a 5FC = 5-flucytosine; Ampho = amphotericin B, ARV = antiretroviral therapy; Flu =

fluconazole; Intracav = intracavitary; Itra = itraconazole; Mico = miconazole; Keto =

ketoconazole; L-AB = liposomal amphotericin B; Pred = prednisolone; Top = topical.

b Based on discussion herein, this is an incorrect species epithet.