Infectious Disease Board Review--Sample

Educational Review Manualin Infectious DiseaseFourth Edition – 2009

Editor-in-Chief:

Burke A. Cunha, M.D.Chief, Infectious Disease Division, Winthrop-University Hospital, Mineola, New York andProfessor of Medicine, SUNY School of Medicine, Stony Brook, New York

CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

CHAPTER 10: SYSTEMIC MYCOSES FOR THE ID BOARDS 367

Chapter10:SystemicMycosesfor the ID Boards

Donna C. Sullivan, PhDStanley W. Chapman, MD

Contents

1. Classification

2. Candidiasis

3. Blastomycosis

4. Histoplasmosis

5. Cryptococcosis

6. Coccidioidomycosis

7. Sporotrichosis

8. Paracoccidioidomycosis

9. Emerging Fungal Infections

10. Further Reading

368 EDUCATIONAL REVIEW MANUAL IN INFECTIOUS DISEASE

1. Classification

Clinical Classification

• Based on the site of infection.

• Includes superficial, cutaneous, subcutaneous andsystemic mycoses.

Mycologic Classification

The mycologic classification listed below is usefulfor treatment decisions. The yeasts and dimorphicfungi are susceptible to both amphotericin B (AmB)and the azoles. In contrast, the molds are generallyresistant to the azoles, in particular, ketoconazoleand fluconazole, and AmB deoxycholate, or any ofthe lipid preparations, is the drug of choice whenmold forms are seen in tissue. The newer azoles,including itraconazole and voriconazole, haveproven successful in the treatment of aspergillosis,and posaconazole appears promising for the treat-ment of mucormycosis.

Yeasts• Unicellular organisms that reproduce by budding.

• Clinical examples are Candida albicans andCryptococcus neoformans.

Molds• Filamentous, tubular structures called hyphae.

• Grow by branching and longitudinal extension.

• Clinical examples are Aspergillus species andthose organisms causing mucormycosis (ie, Rhi-zopus, Absidia, Cunninghamella).

Dimorphic• Pathogens that grow in the mycelial phase in

nature and in culture at 25º C.

• Converts to yeast form after infection and in cul-ture at 37º C.

Opportunistic vs. NonopportunisticClassification

• Opportunistic fungi are typically associated with alow virulent potential for normal hosts, but cancause invasive disease in immunocompromised

hosts (eg, invasive mold disease in transplantpatients or disseminated candidiasis in neu-tropenic patients) and are associated with highmorbidity and mortality.

• Nonopportunistic fungi possess innate virulencethat allows them to infect and invade host tissuesin immunocompetent patients. Clinical examplesinclude the organisms causing the endemicmycoses, B dermatitidis and H capsulatum.

* Increased severity of disease, however, isnoted to occur when these organisms infectimmunocompromised patients, particularlyAIDS patients. Disseminated disease is morefrequent, as is CNS disease, including menin-gitis and brain abscess.

Immune Response

• Humoral response is not felt to be important inhost defense or establishing immunity. It is thebasis of diagnostic testing; in general, complementfixation antibody testing is more sensitive but lessspecific than precipitin antibodies.

• Cellular response is of major importance in hostdefense and in immunity against reinfection.

• A positive skin test indicates prior exposure to theorganism and is generally not helpful as a diagnos-tic tool.

Microbiology

• A majority of the endemic mycoses are dimorphicfungi; they occur in nature and in culture at roomtemperature (eg, 25º C) as filamentous molds, butthey grow as unicellular yeast forms in tissue or inculture at 37º C.

• A definitive diagnosis requires culture of theorganism from clinically relevant tissue.

• A presumptive diagnosis is made by visualizationof the characteristic yeast or hyphae form in spu-tum, secretions or tissue.


• Assays identifying fungal antigens in serum andurine are commercially available and may havesome utility in the diagnosis, monitoring responseto therapy and early identification of relapse.

• Several nucleic acid detection assays have beendeveloped for the systemic mycosis.

Candida Species• Yeast forms, hyphae, and pseudohyphae are easily

seen in clinical specimens.

• Cells are 4-6 micrometers in diameter and are thin-walled.

Blastomyces dermatitidis• Broad-based budding yeast approximately 8-15

micrometers in diameter with multiple nuclei.

• Double refractile cell wall typically with singlebud.

Histoplasma capsulatum• Oval to round budding cells approximately 1-3

micrometers in diameter; often found clustered inhistocytes.

• Difficult to detect in small numbers; in dissemi-nated disease, can be seen intracellularly in neu-trophils when buffy coat preparations from periph-eral blood are examined with Giemsa stain.

Cryptococcus neoformans• Encapsulated yeast approximately 2-15 microme-

ters in diameter.

• Buds are single and “pinched off.” Capsule is usu-ally easily seen and is useful for diagnosis. In somecases, however, only minimal capsule is present.Pseudohyphae are rarely seen.

Coccidioides immitis• Spherules vary in size from 10-200 micrometers in

diameter; some contain endospores.

• Endospores can be released and form newspherules.

Sporothrix schenckii• Cells are variable in size ranging from 4-6

micrometers in diameter.

• Classically described as cigar-shaped, butcan be round to oval-shaped as well.

Paracoccidioides brasiliensis• Cells are variable in size ranging from 5-60

micrometers in diameter.

• Larger cells are surrounded by smaller budsand fat globules thus creating the “pilot’swheel” appearance.

Therapy• AmB is generally used as initial therapy in

disseminated or life-threatening disease,with switch to an azole when patient is stabi-lized.

• Lipid formulations of AmB are commonlyused instead of AmB deoxycholate, owingto poor tolerance or disease progression.

• Initial therapy with an azole is generallyacceptable in patients with endemicmycoses who have a normal immune func-tion and non-CNS limited disease.

• The echinocandins (caspofungin, anidula-fungin and mycafungin) have activityagainst Candida species, including flucona-zole resistant strains.

• The echinocandins have proven utility asprimary or salvage therapy for aspergillosis,alone or in combination with itraconazole orvoriconazole.

• Posaconazole appears to be promising in theprevention and treatment of mucormycosisin immunocompromised hosts.

• 5-flucytosine is only used in combinationtherapy for patients with cryptococcalmeningitis, and for patients with candidalendocarditis and meningitis. It should neverbe used as a single agent due to the rapiddevelopment of resistance.


2. Candidiasis

Microbiology

• Causative organisms are Candida albicans, Cparapsilosis, C tropicalis, C lusitaniae, Cglabrata, C guilliermondii, C kefyr (formerlypseudotropicalis), C krusei and C dubliniensis.

Epidemiology

• Candida species are normal commensals in themouth, GI tract, vagina, and less commonly, on theskin. Opportunistic infection occurs when there isa shift in the balance of normal flora, disruption ofnormal biologic barriers and when immune statusis compromised.

• Candidiasis is the most common fungal infectionand is characterized by diversity in clinical mani-festations, ranging from benign mucocutaneousdisease to invasive dissemination, deep-tissueinvolvement and candidemia.

• Candida species are the fourth most commoncause of nosocomial bloodstream infections in theUnited States.

• The majority of disseminated infections appear tobe from an endogenous source, usually the gut,and not from exogenous sources, although nosoco-mial infections have been reported.

• Fungemia with C parapsilosis has been stronglyassociated with catheter-related infections.

• Patients at high risk for development of can-didemia include those with hematologic malignan-cies, solid or bone marrow transplantation, neu-tropenia, corticosteroid use, treatment with broad-spectrum antibiotics, renal failure, complicationsof GI surgery, critical care instrumentation andhyperalimentation.

• Although C albicans is the most common singlespecies to cause infection, non-albicans speciesare increasing, especially in invasive and vaginalcandidiasis, and are associated with azole resis-tance.

Key Clinical Features

Cutaneous• Skin lesions are pruritic, erythematous, confluent

papules that may progress to pustules or ulcerscharacteristically associated with satellite lesions.Tend to develop in areas where the skin is moist,such as the perineal area; infection is more exten-sive and persistent in immunocompromised hosts.

MucousMembraneOral candidiasis• Raised, creamy white lesions on tongue and buccal

mucosa; other forms are atrophic and appear asglossitis and angular cheilitis; risk factors arerecent antibiotic or steroid use, cancer and AIDS.

Vulvovaginitis• Common infection; 75% of women will have at

least 1 episode.

• Edema and pruritus of vulva with curd-like dis-charge.

• Associated with increased estrogen states, diabetesmellitus, antibiotic use, HIV infection, corticos-teroid use, IUDs and diaphragm use.

Esophageal candidiasis• Odynophagia, dysphagia and substernal chest

pain.

• May occur in absence of oral candidiasis.

• Primarily seen in setting of AIDS orchemotherapy.

ChronicMucocutaneousCandidiasis• Represents a heterogenous group of persistent or

recalcitrant Candida infections of skin, mucousmembranes, hair and nails despite antifungal ther-apy; typically does not progress to dissemination.

• Typically presents in first 2 years of life.

• Alopecia and disfiguring lesions of the face, scalpand hands.

• Associated with cell-mediated defect against Can-dida antigens; endocrinopathies in 50%.


Genitourinary• Presence in urine may represent colonization,

lower tract disease, upper tract disease or dissemi-nated disease that involves the renal pelvis.

• Ascending infection is the most common route forUTIs; it is unusual for candiduria to result in can-didemia

• Lower tract infection is usually asymptomatic andis seen in patients with indwelling catheters.

• Fever, dysuria, hematuria, frequency, suprapubicpain, with or without costovertebral angle tender-ness, are seen most commonly with upper tractinfection; not distinctive from other urinarypathogens.

• Fungus balls occasionally form and obstruct theGU tract, requiring emergent drainage.

Candidemia andAcuteDisseminatedCandidiasis• Most commonly seen in patients with cancer (par-

ticularly hematologic malignancies and neutrope-nia), complicated postoperative courses and burns;multiple organs are usually involved, includingkidneys, brain (including meninges), lungs, heart,eye, GI tract, skin, lungs and endocrine glands.

ChronicDisseminatedCandidiasis(HepatosplenicCandidiasis)• Reported almost exclusively in patients with

hematologic malignancies; patients exhibit rightupper quadrant pain, nausea, vomiting, anorexiaand high spiking fevers; classically occurs afterrecovery from neutropenia.

Respiratory• Rare manifestation; occurs usually as a local or

diffuse bronchopneumonia or from hematogenousspread; can also involve the larynx and epiglottis.

Gastrointestinal• Can occur in setting of peritoneal dialysis, compli-

cated GI surgery, or dissemination and contiguousextension from another localized infection; dis-semination occurs in only 25% of focal infectionsand very rarely when associated with peritonealdialysis.

Bone and joint• Occurs in disseminated disease or from direct

extension from injection drug use, trauma or sur-gical inoculation; typically requires open drainagefor optimal outcome.

Endocarditis• Usually seen in patients with prosthetic valves,

injection drug users or in line-associated can-didemia that has been prolonged; typically associ-ated with large vegetations; antifungal and surgi-cal therapy is needed for cure.

Key Laboratory and Radiologic Features

ChronicMucocutaneousCandidiasisLabs• T-cell abnormalities; 50% exhibit anergy.

• Immunoglobulins and B cells are normal.

GenitourinaryLabs• Pyuria; yeast cells and hyphae.

Radiology• CT may reveal abscess or masses if renal involve-

ment is via hematogenous spread.

Candidemia andAcuteDisseminatedCandidiasisLabs• Blood cultures positive in 50%.

• Biopsy of skin lesions typically reveals organ-isms; culture of material usually yields growth oforganism.

• Pyuria and positive urine cultures typically occur.

• The sensitivity and specificity of antigen basedtests are still being investigated.

Radiology• CT may or may not reveal abscesses or masses.

ChronicDisseminatedCandidiasis (Hep-atosplenicCandidiasis)Labs• Elevated transaminases.


• Blood cultures are frequently negative (approxi-mately 85%).

• The sensitivity and specificity of antigen basedtests are still being investigated.

Radiology• CT reveals characteristic multiple lucency in liver,

spleen, and occasionally kidneys and lung.

RespiratoryLabs• Yeast is typically present in sputum in many hospi-

talized patients and causes difficulty in discerningcolonization from infection; histopathology maybe necessary to diagnose invasion.

Radiology• CXR reveals bilateral finely nodular diffuse infil-

trates.

GastrointestinalLabs• Blood cultures are usually negative.

• Peritoneal or abscess/mass cultures are usuallypositive.

Radiology• CT of abdomen may reveal localized abscesses.

Bone and Joint• Blood cultures are usually negative.

• Material from open drainage or aspirate typicallyreveals yeast on smear with positive culture.

Radiology• Similar to other fungal or mycobacterial bone

infections.

Endocarditis• Blood cultures are typically positive with estab-

lished fungemia.

Radiology• Echocardiogram reveals large vegetations, which

are friable and easily embolize.

Therapeutic Options

Oropharyngeal, Skin andParonychia• Topical therapy is first line of therapy, followed by

systemic therapy for refractory or recurrent dis-ease; drainage is most important in paronychialinfections.

• Topical therapy most frequency involves theazoles such as miconazole, ketoconazole and itra-conazole. Polyenes such as amphotericin B canalso be used topically.

• Systemic therapy includes oral azoles such asfluconazole, itraconazole or voriconazole. Intra-venous AmB and caspofungin are reserved forazole-refractory infections.

• Duration of therapy depends on clinical response,comorbid diseases and underlying immune status.

• AIDS patients are more likely to have more severedisease and usually require prolonged therapybecause of the high relapse rates

EsophagealCandidiasis• Topical therapy is ineffective, so oral azoles

(fluconazole, itraconazole solution or voricona-zole) are used for initial therapy.

• Intravenous lipid AmB formulation or echinocan-dins (caspofungin, anidulafungin or mycafungin)are used for azole refractory or recurrent infections.

• Duration is for at least 2 weeks; recurrent or refrac-tory infections may require prolonged therapy.

• Suppressive therapy may be used for patients withdisabling recurrent infections; itraconazole solu-tion, voriconazole or caspofungin may be used forfluconazole-refractory esophageal candidiasis.

CandidalOnychomycosis• Topical therapy is ineffective; treat with itracona-

zole 200 PO BID.

• Treat for 7 days; repeat monthly for 3-4 months.


Table 1

Differential Diagnosis of Candidiasis

Type Infectious Noninfectious

Mucocutaneous Erythrasma Seborrheic dermatitisLangerhans cell histiocytosis

Chronic mucocutaneous Other chronic fungal infections Squamous cell carcinomacandidiasis Dermatophyte infection

Genitourinary Bacterial UTITuberculosis (disseminated or miliary) Bladder malignancyAcute or chronic urethral syndromes Renal calculiincluding STDs

Candidemia and acute Bacterial sepsis Drug feverdisseminated candidiasis Viral hepatitis Graft versus host disease

Other disseminated fungal infections Drug-induced hepatitisTuberculosis

Chronic disseminated candidiasis Tuberculosis Drug fever(hepatosplenic candidiasis) Other fungal infections Graft versus host disease

Viral hepatitis Drug-induced hepatitisShock liver

Respiratory Pneumocystis pneumonia Congestive heart failureTuberculosis Noninfectious ARDSOther fungal pneumonias Graft versus host diseaseBacterial pneumonia Drug-induced lung injury

Gastrointestinal Tuberculosis MalignancyBacterial peritonitisCholecystitis

Bone and joint Tuberculosis MalignancyOther fungal bone infections

Endocarditis Bacterial endocarditis SLE endocarditisMarantic endocarditis


Table 2

Complications of Candidiasis

Type Clinical outcome Prognostic factors

Mucocutaneous Generally good; may be recurrent Immune status

Chronic mucocutaneous Recurrent candidiasis; bacterial Presence of secondarycandidiasis superinfection may occur; bacterial infections

disseminated candidiasis is rare

Genitourinary Response to therapy is generally good Presence of urinary catheterif involvement is at bladder or below Immune status

Candidemia and acute High attributable mortality Resolution of risk factors,disseminated candidiasis particularly neutropenia

Chronic disseminated candidiasis Response to therapy may be delayed; Resolution of risk factors(hepatosplenic candidiasis) high relapse rate Appropriate antifungal therapy

Respiratory Similar to disseminated candidemia Prompt diagnosisAppropriate antifungal therapy

Gastrointestinal Peritoneal dialysis infection responds Resolution of risk factorswell to catheter removal and Adequate drainage andantifungal therapy debridementDependent on underlying cause of Appropriate antifungal therapybreach in GI mucosa

Bone and joint Tends to be chronic and associated Prompt diagnosiswith poor functional outcome Adequate drainage or

debridementAppropriate antifungal therapy

Meningitis High mortality; associated with high Prompt diagnosisrelapse rate Removal of CNS devices if

related to neurosurgicalprocedure

EndocarditisSuppurative phlebitis Good response with resection of vein Involvement of peripheral vein;

appropriate antifungal therapyPericarditis Generally poor prognosis Ability to resection pericardium;

appropriate antifungal therapyEndocarditis Generally poor prognosis; Ability to perform valve

propensity relapse resection; appropriateantifungal therapy


ChronicMucocutaneousCandidiasis• For oropharyngeal, topical azoles, oral azoles or

polyenes (nystatin, AmB solution).

• For refractory or recurrent infections, fluconazole100-200 mg/day PO or itraconazole 200 mg/d PO,lipid AmB >0.3 mg/kg/d IV if azole-refractoryinfection.

• For esophageal candidiasis, PO or IV fluconazole100-200 mg/day or itraconazole 200 mg/d.

• Chronic suppressive therapy with an azole is therule.

UrinaryCandidiasis• Important to remove any GU catheter or prosthesis

if possible to reduce relapse rates.

• Oral fluconazole 200 mg/day for 7-14 days, lipidAmB (0.7-1.0 mg/kg/d), or flucytosine (in patientswith infection due to non-albicans species of Can-dida).

• Bladder irrigation with AmB (50-200 μg/ml) maytransiently clear funguria but is rarely indicated.

• Treat for at least 2 weeks; if candiduria is persis-tent despite therapy, evaluate for disseminated dis-ease.

Candidemia andAcuteHematogenouslyDissemi-natedCandidiasis• If feasible, remove all existing central venous

catheters.

• Lipid AmB (0.7-1.0 mg/kg/d), fluconazole IV (400mg/d), or combination of the two.

• Caspofungin 70 mg IV PB first dose, then 50 mg/d.

• For uncomplicated line-associated infection, ther-apy can be continued for 2 weeks following thefirst negative blood cultures; otherwise, therapyshould continue for at least 4-6 weeks.

• Neutropenic patients should receive recombinantcytokine (GC-, SF- or MC-stimulating factor).

Candidal Endophthalmitis

• AmB (0.7-1.0 mg/kg/d) ± flucytosine.

• Oral or IV fluconazole, 6-12 mg/kg/d.

• Vitrectomy plus antifungal therapy (both intra-venous and intravitreal) may improve visual out-come.

• All patients with candidemia should have at least 1dilated retinal exam by an ophthalmologist.

• Continue antifungal therapy until complete resolu-tion of disease (6-12 weeks).

EndovascularCandidiasis• AmB (0.7-1.0 mg/kg/d) or lipid AmB (3-6

mg/kg/d) ± flucytosine.

• Oral or IV fluconazole 6-12 mg/kg/d.

• Caspofungin 70 mg IV PB first dose, then 50 mg/d.

• Surgical therapy is essential for successful out-come.

• Suppurative phlebitis of peripheral vein: 2 weeksof antifungal therapy after surgical resection ofvein.

• Endocarditis: early removal of infected valves(native and prosthetic) followed by at least 6 weeksof antifungal therapy; if valve replacement not pos-sible, continue lifelong suppressive therapy withfluconazole.

• Pericarditis: resection or debridement of infectedpericardial tissue followed by a minimum of 6weeks of antifungal therapy.

ChronicDisseminatedCandidiasis (HepatosplenicCandidiasis)• Mild or stable disease: fluconazole 6 mg/kg/d.

• Severely ill or refractory disease: lipid AmB (3-5mg/kg/d) or AmB (0.6-0.7 mg/kg/d).


• If patient has clinical response and stabilizes withinitial course of AmB, may switch to fluconazolefor remainder of course; therapy should continueuntil there is calcification or resolution of lesions.

RespiratoryCandidiasis• Pneumonia: lipid AmB (3-5 mg/kg/d) or AmB

(0.7-1.0 mg/kg/d) or fluconazole; caspofungin 70mg IV PB first dose, then 50 mg/d.

• Laryngeal: lipid AmB (3-5 mg/kg/d) or AmB (0.7-1.0 mg/kg/d) as initial therapy; may change to oralor IV fluconazole when improvement and/or sta-bility have occurred.

• Pneumonia and laryngitis usually secondary tohematogenously disseminated infection and ther-apy should be directed to primary focus

• Therapy should continue until clearance of localand systemic sites of infection.

Bone and JointCandidiasis• Combined surgical debridement and antifungal

therapy: lipid AmB (3-5 mg/kg/d) or AmB (0.5-1.0 mg/kg/d) for 6-10 weeks.

• AmB IV for 2-3 weeks followed by oral flucona-zole for a total 6-12 months of therapy.

GICandidiasis• Biliary tree should be treated by mechanical

restoration of functional drainage combined withantifungal therapy: Lipid AmB (3-5 mg/kg/d) orAmB (0.7-1.0 mg/kg/d) or fluconazole (400-800mg/d IV or PO).

• Treatment for 2-3 weeks generally required;catheter removal is necessary in peritoneal dialysisinfection

CandidalMeningitis• AmB (0.7-1.0 mg/kg/d) + flucytosine (25 mg/kg

QID) adjusted to produce serum levels of 40-60μg/ml.

• Fluconazole has been used as follow-up therapyand long-term suppressive therapy.

• Therapy should continue for a minimum of 4weeks after resolution of all CSF and radiographicabnormalities and patient is neurologically stable.

Empirical Therapy inFebrileNon-neutropenicPatients• Lipid AmB (3-5 mg/kg/d) or AmB (0.7-1.0

mg/kg/d) or fluconazole (400-800 mg/d).

• With empirical use, less toxic agents are preferred;selected patients that demonstrate Candida colo-nization at multiple sites, other risk factors for can-didiasis or candidemia, and lack of alternative eti-ologies of fever.

Empirical Therapy inFebrileNeutropenicPatients• Lipid formulation AmB (3-6 mg/kg/d), AmB

deoxycholate (0.7-1.0 mg/kg/d) or caspofungin 70mg loading dose followed by 50 mg IV.

• Oral or IV fluconazole if patient is low risk forinvasive aspergillosis.

• Treat for duration of febrile neutropenia.

ID Board Pearls

• Host factors that predispose patients to candidiasisinclude:

* Physiological (pregnancy, extremes of age)

* Trauma (maceration, infection, burn wound)

* Hematological (neutropenia, cellular immun-odeficiency)

* Endocrinological (diabetes mellitus,hypoparathyroidism, Addison's disease)

* Iatrogenic (chemotherapeutics, corticos-teroids, oral contraceptives, antibiotics,catheters, surgery)

* Other (intravenous drug addiction, malnutri-tion, malabsorption, thymoma)

• Candida pneumonia occurs only as part of dissem-inated candidiasis


3. Blastomycosis

Synonyms

• Gilchrist’s disease, Chicago disease, North Ameri-can blastomycosis.

Microbiology

• The causative organism is Blastomyces dermati-tidis.

Epidemiology

• Endemic areas include the south-central andsoutheastern states bordering on the Mississippiand Ohio River basins, and states bordering theGreat Lakes and the St. Lawrence River.

• In sporadic cases, most patients are male (1.7:1),30-70 years of age, and are associated with occu-pational or recreational exposure to soil.

• Epidemics have been reported and noted to exhibitno seasonal pattern or predilection to a particularage, sex or race.

• Infections in immunocompromised hosts are asso-ciated with increased severity, more frequent dis-semination (especially to the CNS) and highermortality.

Diagnosis

• Definitive diagnosis is by culture of the organismfrom clinical specimens. However, slow growth ofthe organism makes culture impractical for rapiddiagnosis.

Table 3

Differential Diagnosis of Blastomycosis


Acute pulmonary infection Bacterial pneumonia Hypersensitivity pneumonitisViral pneumonia

Chronic pulmonary infection Tuberculosis SarcoidosisOther fungal pneumonias Neoplasm

Skin Bacterial infection CarcinomaHistoplasmosisSporotrichosis(Mycobacterium other than TB)

Bone Tuberculosis Metastatic bone diseaseOther fungal pathogens

Genitourinary Bacterial pathogens BPHTuberculosis NeoplasmCryptococcosis

CNS Tuberculous meningitis NeoplasmBacterial abscessesOther fungal meningitisCNS toxoplasmosis


• Direct visualization of characteristic broad-basedbudding yeast forms in histologic or cytologicspecimens allows prompt, presumptive diagnosisof blastomycosis and may serve as the basis forinitiation of therapy.

• Antigen testing of urine or other body fluids mayalso be diagnostic of blastomycosis, and is usefulwhen the organism is suspected but not rapidlydemonstrated by other methods.

• Serologic testing lacks sensitivity and specificityand must be interpreted with caution.

• Complement fixation (CF) tests are positive infewer than 50% of patients; cross reactions withHistoplasma capsulatum and Coccidioides immitisfrequently occur.

• Immunodiffusion tests are highly specific but lacksensitivity, particularly in acute disease.

Table 4

Therapeutic Options for Blastomycosis

Type Preferred Alternative

Pulmonary

Mild-to-moderate Itraconazole 200-400 mg/d for at least Fluconazole6 months 6 months 400-800 mg/d for

at least TKDisseminated

CNS AmB deoxycholate at least 2 g total dose Fluconazole 800 mg/d canbe considered if patient is

Lipid AmB 3-5 mg/kg/d intolerant of AmBNon-CNSMild-to-moderate Itraconazole 200-400 mg/d for at least Ketoconazole or fluconazole

6 months; if bone involvement is present, 400-800 mg/d for at leasttreatment should be for 12 months 6 months

Life-threatening AmB deoxycholate 1.5-2.5 g total dose Initial therapy with AmBwithLipid AmB 3-5 mg/kg/d switch to itraconazole

200-400 mg/d after clinicalstabilization

Immunocompromised host AmB deoxycholate 1.5-2.5 g total dose Initial therapy with AmBwithLipid AmB 3-5 mg/kg/d switch to itraconazole

200-400 mg/d afterclinical stabilization

Pregnancy AmB 1.5-2.5 g total dose Azoles contraindicatedin pregnancy


• Radioimmunoassay of WI-I (cell wall antigen)antibody has been shown to have a sensitivity andspecificity of 85% and 95%, respectively. This testis under investigation for future clinical use.

• Nucleic acid detection techniques are currentlyavailable for the diagnosis of blastomycosis. Acommercially available chemiluminescent DNAprobe (Gen Probe, San Diego, CA) has beenshown to have a sensitivity of 87.4% and 100%specificity when 74 target and 219 nontarget fungiwere tested.

Therapy

• Some immunocompetent hosts with limited pul-monary disease may spontaneously resolve theinfection without therapy. Patients who are nottreated should be followed carefully for progres-sion of disease.

• Treatment is required for all patients with extra-pulmonary disease or progressive pulmonary dis-ease. Immunocompromised hosts should betreated, most frequently with amphotericin B(AmB).

• Lipid AmB (3-5 mg/kg/d) or AmB deoxycholate(0.7-1.0 mg/kg per day) for 1-2 weeks is the pre-ferred initial treatment for life-threatening blasto-mycosis and patients with CNS disease.

• Itraconazole is the drug of choice for treatment ofpatients with mild-to-moderate pulmonary or non-CNS disseminated disease. Two oral preparationsare available. Important differences in bioavail-ability of the two preparations have clinical signifi-cance. Oral capsules require acid for absorptionand should be taken with Coca-Cola or food.Treatment failures have been well documented inpatients on H2-blockers or proton pump inhibitors.The liquid preparation does not require acid and istaken on an empty stomach.

• Owing to the bioavailability of itraconazole, bloodlevels should be performed on all patients failingtreatment with this drug. Some physicians rou-tinely obtain blood levels on patients treated withthe capsules irrespective of clinical response. Aserum level >1.0 μg/ml is recommended.


AcutePulmonary Infection• 50% of cases may be asymptomatic; after incuba-

tion period of 4-6 weeks, a flu-like illness occurswith fever, chills, myalgias, arthralgia, cough andpleuritic chest pain, often with spontaneous recov-ery; severity of illness is variable and can be mildto fulminant disease.

Chronic Pulmonary Infection (MostCommon)• Weight loss, low-grade fever, fatigue, productive

cough, pleuritic chest pain.

DisseminatedNon-CNSSkin• Most common extrapulmonary site of disseminate

infection can occur in isolation, but is most oftenseen in multiorgan involvement. Lesions are ver-rucous or ulcerative in appearance; skin involve-ment can also occur via direct inoculation (eg, dogbite) and is associated with regional lym-phadenopathy; subcutaneous nodules or “coldabscesses” that contain numerous organisms occurin the setting of pulmonary or extrapulmonary dis-ease.

Bone and joint• Second most common site of dissemination; most

common sites include the ribs, vertebrae and longbones; usually not associated with pain, but can bepainful in setting of contiguous soft tissueabscesses and draining sinuses; arthritis is purulentand occurs via contiguous spread.

Genitourinary• Prostatitis and epididymo-orchitis are most com-

monly reported sites; GU disease is involved inless than 10% of cases.

CNS• Intracranial abscesses or meningitis usually occursin less than 5% of disseminated disease in normalhosts. CNS disease occurs in 40% of AIDS patients.


AcutePulmonary InfectionLabs• Nonspecific.


Radiology• Patchy alveolar infiltrates in single or multiple

lobes; hilar enlargement, pleural effusions andcavitation are uncommon; in severe fulminant dis-ease, CXR may have diffuse military pattern.

Chronic Pulmonary InfectionLabs• Nonspecific.

Radiology• Alveolar infiltrates and mass lesions are most com-

mon finding; pleural effusions, hilar adenopathyand cavitation occur as well.

DisseminatedDiseaseNon-CNSLabsSkin• Nonspecific.

Bone• Nonspecific.

Radiology• Typically well-circumscribed osteolytic bone

lesions are seen.

GenitourinaryLabs• Pyuria is common.

• KOH/wet prep of urine may be positive.

• Urine cultures are frequently positive after pro-static massage.

• Examination of urine sediment after centrifugationenhances visual and cultural identification.

CNSLabs• CSF formula reveals lymphocytic pleocytosis withelevated protein and normal glucose.

• CSF culture is low yield.

Radiology• Ring-enhancing mass lesions on CT or MRI.

Prognosis

AcutePulmonary Infection• Some immunocompetent hosts may resolve spon-taneously without therapy; treated patients typicallydo well.

• Prognosis depends on immune status.

Chronic Pulmonary Infection• Generally responds well to therapy.

Prognosis depends on timeliness of diagnosis,underlying pulmonary disease and immune status.

DisseminatedPulmonary Infection• Generally responds well to therapy; CNS has

poorer prognosis, especially in immunocompro-mised patients.

• Prognosis depends on timeliness of diagnosis andimmune status.

ID Board Pearls

• Fungus usually occurs with broad based bud, usu-ally single refractile yeast in clinical specimens.

• Blastomycosis may coexist or mimic bron-chogenic carcinoma and tuberculosis.

• Skin and mucous membrane lesions may mimicsquamous cell carcinoma.


4. Histoplasmosis

Synonyms

• Darling’s disease, reticuloendothelial cytomyco-sis, cave disease, spelunker’s disease.

Microbiology

• The causative organism is Histoplasma capsula-tum, which is typically found in tissue as intracel-lular yeast in histiocytes.

• Mycelial phase occurs in environment and cultureat 37°C.

Epidemiology

• Endemic in the United States throughout the Ohioand Mississippi river valleys; also found in Centraland South America.

• Found in the soil; particularly soil contaminatedwith bird and bat guano.

• Outbreaks have been reported in persons withheavy exposure to chicken houses, blackbirdroosts and caves.

• Primary infection is via inhalation of spores withdissemination to the reticuloendothelial system;90% of cases in normal hosts are subclinical.

• Severe disseminated disease is associated withinfants and immunocompromised hosts, particu-larly HIV-infected patients.

Therapy

• Mild acute pulmonary disease in normal host maynot need antifungal therapy.

• All patients with chronic pulmonary histoplasmo-sis and disseminated disease require therapy.

• Lipid AmB 3 mg/kg per day or AmB deoxycholate0.7-1.0 mg/kg per day for 1-2 weeks followed byitraconazole 200 mg BID is standard therapy formoderately severe or severe disease.

Table 5

Differential Diagnosis of Histoplasmosis


Acute pulmonary Blastomycosis NeoplasmsHistoplasmosis SLECoccidioidomycosis SarcoidosisParacoccidioidomycosisTuberculosisPneumocystis pneumoniaViral pneumoniaBacterial pneumonia

Chronic pulmonary Histoplasmosis NeoplasmsBlastomycosis SLE

Sarcoidosis

Disseminated Bacterial sepsis Lymphoproliferative disorderInflammatory bowel diseaseSarcoidosisNeoplasms


• Itraconazole is the azole of choice. The differentformulations of itraconazole, including bioavail-ability of the two different oral preparations arediscussed in the therapy section for blastomycosis.

• Alternative azole therapies include fluconazoleand voriconazole.

• AIDS patients require suppressive therapy follow-ing the initial treatment course, preferably withitraconazole 200 mg/d indefinitely.


AcutePulmonary• May be asymptomatic in normal hosts with mild

exposure. Flu-like illness within 10-18 days char-acterized by fever, chills, malaise, headache, non-productive cough and chest pain. Disease has ashorter incubation period and is typically milder ina previously exposed person. Immune-mediatedgranulomatous inflammatory pericarditis, ery-thema nodosum or erythema multiforme occur inless than 10% of cases.

Chronic Pulmonary• Occurs in approximately 8% of cases. Seen in

older males with underlying chronic, obstructivepulmonary disease. Symptoms are typically pro-gressive and include low-grade fever, productivecough, dyspnea and weight loss.

ProgressiveDisseminated• Rare. Seen primarily in immunocompromised

host. Clinical course may be acute, subacute orchronic over months to years. Symptoms includefever, malaise and weight loss. Patients typicallyhave hepatosplenomegaly. Mucosal ulcerationsthroughout the GI tract are seen in 40% of patients.Other sites that may be involved: skin, bone, heartand meninges. AIDS patients with overwhelmingdisease may present with a sepsis syndrome andARDS.

Disseminated in Infants• Uncommon. Onset is acute with fever, lethargy,

cough, weight loss and diarrhea. Most patientshave hepatosplenomegaly. Less than half ofpatients are seen with palpable lymphadenopathyand oropharyngeal ulcers.

Table 6

Complications of Histoplasmosis


Acute pulmonary Spontaneous recovery without Immune statustherapy occurs in some normal hosts;response to therapy is generally good

Chronic pulmonary Response to therapy is generally good Immune statusBlastomycosis Underlying lung disease

Disseminated Response to therapy generally good Immune statusSite of involvement

Granulomatous mediastinitis May result in significant airway Time to diagnosisobstruction Extent of inflammatory reaction

Response to steroid therapy

Fibrosing mediastinitis Generally poor despite antifungal Time to diagnosisor steroid therapy Extent of fibrosis


GranulomatousMediastinitis• Represents a hyperimmune response with bulky

enlargement of mediastinal lymph nodes due togranulomatous inflammation from active disease.Chest pain, hemoptysis and dyspnea may occursecondarily to nodal compression of the airways,superior vena cava or pulmonary vessels. Symp-toms are typically mild and resolve within a fewmonths.

FibrosingMediastinitis• Rare hyperimmune response characterized by a

slowly progressive and extensive fibrosis in reac-tion to prior episode of histoplasmosis. Mostpatients are between 20 and 40 years of age andexhibit night sweats, cough, dyspnea, chest painand hemoptysis. Usually progresses to involvestructures adjacent to the mediastinal lymphnodes, including the heart and great vessels, upperairways and esophagus.


AcutePulmonaryLabs• WBC is variable.

• Elevated serum alkaline phosphatase.

Radiology• Hilar adenopathy.

• Patchy infiltrates that evolve to calcification.

• Radiographic findings in histoplasmosis may besimilar to sarcoidosis. Histoplasmosis must beexcluded before treating patients with immuno-suppressive agents.

Chronic PulmonaryLabs• Anemia in 50%.

• Elevated alkaline phosphatase in 30%.

• Elevated WBC in 30%.

Radiology• Cavitary lesions with thin or thick walls are seen in

the upper lobes.

• Minimal or no hilar or mediastinal adenopathy.

Disseminated inAIDSLabs• Anemia.

• Pancytopenia.

• Elevated alkaline phosphatase.

• Marked LDH elevation.

Radiology• Reticulonodular infiltrates.

• Mediastinal adenopathy.

• CXR may be normal in 30%.

Disseminated in InfantsLabs• Severe anemia.

• Pancytopenia.

• Elevated bilirubin.

• Elevated alkaline phosphatase.

Radiology• Diffuse patchy pneumonitis.

• Hilar and mediastinal adenopathy.

Therapeutic Options

AcutePulmonaryMild to moderate• Treatment is usually unnecessary in immunocom-

petent hosts.

• Itraconazole loading dose of 200 mg every 8 hoursfor 3 days followed by 200-400 mg/d for 6-12weeks.

Severe• Lipid AmB 3 mg/kg/d or AmB deoxycholate 0.7

mg/kg/d ± prednisone 60 mg/d for 2 weeks fol-lowed by itraconazole 200-400 mg/d for 12 weeks.


Chronic PulmonaryMild to moderate• Itraconazole loading dose of 200 mg every 8 hours

for 3 days followed by 200-400 mg/d 1-2 years;75%-85% response rate.

Severe disease or itraconazole failure• Lipid AmB 3 mg/kg per day or AmB 0.7 deoxy-

cholate mg/kg/d, then itraconazole 200 mg/d for 1-2 years; >95% effective.

DisseminatedCNS meningitis• Lipid AmB 3 mg/kg /d or AmB deoxycholate 0.7-

1.0 mg/kg/d for 3 months followed by fluconazole200-400 mg/d for 1 year.

Non-CNSMild to moderate• Non-AIDS: Itraconazole 200 mg/d for 6-18

months; >95% effective.

• AIDS: Itraconazole 200 mg/d indefinitely.

Severe• Non-AIDS: AmB deoxycholate 0.7-1.0 mg/kg/d or

lipid AmB 3-5 mg/kg/d initially, followed by itra-conazole 200-400 mg/d for 6-18 months.

• AIDS: AmB induction prior to itraconazole 200mg/d indefinitely.

GranulomatousMediastinitis• Treatment is usually unnecessary in immunocom-

petent hosts.

• Itraconazole loading dose of 200 mg every 8 hoursfor three days followed by 200-400 mg/d for 6-12weeks for symptomatic cases.

• Surgical resection of bulky nodes should be con-sidered in patients with persistent obstructivesymptoms following antifungal therapy.

FibrosingMediastinitis• Antifungal therapy is generally felt to be of little

benefit in late fibrotic stage; if ESR and CF titersare elevated, antifungal therapy (itraconazole 200-400 mg/d for 12 weeks) may be beneficial; corti-costeroid therapy is not recommended; surgicaland surgical stents to relieve obstruction may beconsidered in special cases.

ID Board Pearls

• AIDS-defining illness in HIV positive patients.

• Associated with bilateral hilar adenopathy andcavitary lesions (like coccidiomycosis).

• Associated with peripheral eosinophilia (like coc-cidiomycosis), which distinguishes histoplasmosisfrom tuberculosis.

• Mouth ulcers frequently present and scrapingsusually reveal organisms.

• Mucous membrane and gastrointestinal lesionsmay present with bleeding in disseminated diseasein immunocompromised hosts.


5. Cryptococcosis

Microbiology

• The causative organism, Cryptococcus neofor-mans, is monomorphic yeast in tissue and culture.The mucopolysaccharide capsule plays a key rolein pathogenesis in addition to providing a distinc-tive appearance in clinical specimens.

Epidemiology

• Worldwide distribution; most associated withpigeon debris and feces without causing avian dis-ease.

• Infection follows inhalation of fungi; approxi-mately 60% of patients have an initial subclinicalcourse.

• High predilection to invade the central nervoussystem.

• Disease is typically more frequent in immunocom-promised hosts, but also occurs in patients with nodemonstrable underlying immune defects.

Treatment

• Asymptomatic immunocompetent hosts with cul-ture positive pulmonary infection without evi-dence of CNS involvement can be monitored care-fully without antifungal therapy.

• Patients with progressive pulmonary infiltrates canbe treated with fluconazole for 3-6 months whendisease is mild and there is no evidence of dissemi-nated disease, including any spread to the CNS.

• If flucytosine (5FC) is administered for more than2 weeks, renal function should be monitored care-fully and doses adjusted by nomogram or, prefer-ably, by a serum level obtained 2 hours afteradministration of a dose. Optimal levels are 30-80mcg/mL.

• Management of increased intracranial pressure(ICP) is important in reducing morbidity and mor-tality in HIV-infected patients with cryptococcalmeningitis.

• Maintain ICP ≤20 cm H2O with daily CSFdrainage. Persistent elevated pressure may requirea lumbar drain or ventriculoperitoneal shunt.

• Corticosteroids are not recommended in HIV-infected patients with increased ICP due to crypto-coccal meningitis.


Pulmonary• May be asymptomatic. Typical symptoms include

low-grade fever, weight loss, and dull chest painwith scant productive cough and dyspnea. Severedisease with respiratory failure is more common inimmunocompromised patients.

CNS• May occur in isolation without evidence of prior

pulmonary involvement or in a setting of dissemi-nated disease. Clinical presentation may be acuteor chronic. Nonspecific symptoms includeheadache and nausea. Patient may be afebrile withminimal meningeal signs. Papilledema is seen inapproximately 30% and cranial nerve palsies areseen in 20% of patients. Altered mental status canrange from mild behavioral changes to obtunda-tion.

Disseminated• Painless, morphologically variable skin lesions are

seen in about 10% of cases. Osteolytic bony focican be seen in about 10% of cases. Unusualreported sites include eye, heart, GI (includingliver), GU (including epididymitis, prostatitis andorchitis) and arthritis.


PulmonaryLabs• Routine laboratory studies are nonspecific.

• Sputum culture sensitivity is 10%-30% in activedisease. May require lung biopsy to demonstratetissue invasion.

• Serum cryptococcal antigen may be positive inisolated pulmonary disease.


• If the serum cryptococcal antigen is positive, alumbar puncture with CSF evaluation should beperformed to rule out CNS disease.

Radiology• Variety of findings, including nonspecific intersti-

tial pattern, solitary nodules or focal infiltrates.

• Pleural effusions and cavitary formation areuncommon.

CNSLabs• Routine laboratory studies are nonspecific.

• CSF formula reveals lymphocytic pleocytosis withlow glucose and high protein.

• India ink usually demonstrates the encapsulatedyeast.

• CSF and serum cryptococcal antigen are usuallypositive. Serum cryptococcal antigen may be moresensitive than CSF.

• AIDS patients may present with a noninflamma-tory cellular response. A poor clinical outcome canbe predicted by a CSF cell count of less than 20WBC, greater than 1:2024 antigen titer and analtered mental status.

Radiology• Hydrocephalus may be seen on head CT.

DisseminatedLabs• Blood culture and serum cryptococcal antigen may

be positive.

• Nonspecific.

• Serum cryptococcal antigen is usually positive.

Radiology• Depends on organ involvement; can appear as

tumors on imaging.

Differential Diagnosis

• InfectiousPulmonary* Blastomycosis

* Histoplasmosis

* Coccidioidomycosis

* Paracoccidioidomycosis

* Tuberculosis

* Pneumocystis jiroveci (carinii) pneumonia

•NoninfectiousPulmonary* Neoplasms

* SLE

* Sarcoidosis

• InfectiousCNS* Tuberculous meningitis

* Viral meningitis

* Viral meningoencephalitis

* Histoplasmosis

* Blastomycosis

•NoninfectiousCNS* Mollaret’s meningitis

* Drug-induced meningitis

* Vasculitides

• InfectiousDisseminated* Blastomycosis

* Histoplasmosis


* Tuberculosis


•NoninfectiousDisseminated* Neoplasms

Therapeutic Options in HIV-NegativePatients

PulmonaryMild to moderate symptoms• Fluconazole 200-400 mg/d for 6-12 months.

• Itraconazole 200-400 mg/d for 6-12 months.

• Lipid preparation 3-5 mg/kg/d or AmB deoxy-cholate 0.7 mg/kg/d (total dose 1-2 g) for 6-10weeks.

Severe symptoms and immunocompromised hosts• Lipid preparation 3-5 mg/kg/d or AmB deoxy-

cholate 0.7 mg/kg/d plus flucytosine 100 mg/kg/dfor 2 weeks, then fluconazole 400 mg/d for at least10 weeks.

• Lipid preparation 3-5 mg/kg/d or AmB deoxy-cholate 0.7 mg/kg/d + flucytosine 100/kg/d for 6-10 weeks.

• Lipid preparation 3-5 mg/kg/d or AmB deoxy-cholate 0.7 mg/kg/d for 6-10 weeks.

Therapeutic Options in HIV-infectedPatients

PulmonaryMild to moderate• Fluconazole 200-400 mg/d indefinitely.

• Itraconazole 200-400 mg/d indefinitely.

• Fluconazole 400 mg/d plus flucytosine 100-150mg/kg/d for 10 weeks.

CNS• Lipid preparation 3-5 mg/kg/d or AmB deoxy-

cholate 0.7-1.0 mg/kg/d plus flucytosine 100mg/kg/d for 2 weeks, then fluconazole 400 mg/dfor at least 10 weeks.

• Lipid preparation 3-5 mg/kg/d or AmB deoxy-cholate 0.7-1.0 mg/kg/d plus flucytosine 100mg/kg/d 6-10 weeks.

• Lipid preparation 3-5 mg/kg/d or AmB deoxy-cholate 0.7 mg/kg/d for 6-10 weeks.

• Fluconazole 400-800 mg/d for 10-12 weeks.

• Fluconazole 400-800 mg/d plus flucytosine 100-150 mg/kg/d for 6 weeks.

Maintenance therapy• Fluconazole, 200-400 mg PO QD, until CD4+

count ≥300.

• Itraconazole, 200 mg PO BID, until CD4+ count≥300.

• Lipid AmB 5 mg/kg or AmB deoxycholate 1mg/kg IV 1-3 times weekly, until CD4+ count≥300.

ID Board Pearls

• Skin lesions of disseminated disease mimic mol-luscum contagiosum.

• Cryptococcal pneumonia does not produce cavi-tary lesions.

• Risk factors for cryptococcal meningitis includeHIV/AIDS, organ transplant, cancer, sarcoidosis,corticosteroid therapy, diabetes mellitus, COPD,cirrhosis, rheumatoid arthritis, SLE, pregnancyand splenectomy.

• Intracranial hypertension needs to be monitoredand aggressively managed with daily lumbarpuncture or shunt, if necessary.

6. Coccidioidomycosis

Synonyms

•Valley fever.

Microbiology

• The causative organism is the dimorphic fungusCoccidioides immitis; it exists as a saprophyticmycelium in the environment. Arthroconidia formfrom the mycelia and break away, either to returnto the soil or to become airborne and potentiallyinhaled. In the tissues, the arthroconidia developinto spherules that contain endospores; eachendospore has the potential to form a newspherule.

• Growth occurs rapidly (3-4 days) in the laboratorywithout special requirements. Laboratory person-nel should be informed that coccidioidomycosis issuspected so proper caution can be used when han-dling cultures of the highly infectious mycelialforms.

Epidemiology

• Endemic in soil of southwestern United Statesincluding California, western Texas, New Mexicoand Arizona. It is also found in some areas of Mex-ico and Central and South America.

• Primary infection is via inhalation ofarthroconidia.

• Approximately 100,000 cases are reported peryear in the United States. Outbreaks have beenassociated with conditions that disturb the soil andperiods when there is rain/drought cycling.

• At-risk populations for disseminated diseaseinclude immunocompromised hosts (infants,patients receiving any immunosuppressive ther-apy, pregnant patients, AIDS patients) and those ofAfrican or Filipino ancestry.

Diagnosis

• IgM antibodies can be measured by various meth-ods, are usually positive within 3 weeks of primaryinfection and disappear within 4 months.

• IgG antibodies are complement-fixing and tend tooccur later in illness, correlate more closely withdisease activity and persist for 6-8 months.

• IgG titers can be used to determine responsivenessto therapy and to predict relapses.

Therapy

• Although the majority of normal hosts sponta-neously resolve early infection without therapy,some patients may benefit from antifungal treat-ment. The decision to treat may be based on sev-eral clinical factors:

* Greater than 10% body weight loss

* Night sweats for greater than 3 weeks

* Infiltrates in more than 50% of one lung orportions of both lungs

* Persistent or prominent hilar adenopathy

* Complement-fixation antibody titer greaterthan 1:16

* Anergic to coccidioidal antigens

* Inability to work

* Persistent symptoms for more than 2 months

• All immunocompromised hosts or patients at riskfor dissemination should be treated.

• Relapse following a course of therapy occurs inapproximately one-third of all patients and mostoften at site of initial infection. The decision totreat patients with prolonged or indefinite therapyis based on the precarious location of the initialinfection and immune status.

• Coccidioidal meningitis is the most lethal compli-cation of disseminated infection and requires earlydiagnosis and aggressive treatment. Without ther-apy, the mortality is greater than 95% within 2years.



Table 7

Differential Diagnosis for Coccidioidomycosis


Acute pulmonary Viral upper respiratory infection AsthmaViral or bacterial sinusitis Drug-induced hypersensitivityViral or bacterial tracheobronchitis pneumonitisRickettsial diseasesP jiroveci (carinii) pneumonia

Solitary pulmonary nodule Early lung abscess NeoplasmBlastomycosisHistoplasmosisTuberculosis

Cavitary lung disease Early lung abscess SarcoidosisTuberculosis Neoplasm

Chronic fibrocavitary disease Blastomycosis SarcoidosisHistoplasmosis NeoplasmCoccidioidomycosisParacoccidioidomycosisTuberculosis

DisseminatedCNS Tuberculousmeningitis Mollaret’smeningitis

Viral meningitis Drug-inducedmeningitisViral meningoencephalitis SLEOther fungal pathogens Granulomatous angiitis

Non-CNSSkin Syphilis Neoplasm

Actinomycosis SarcoidosisTuberculosis

Osteoarticular Fungal pathogens TraumaMycobacterial pathogens GoutBacterial pathogen Osteoarthritis


Table 8

Key Diagnostic Tests for Coccidioidomycosis

Type Microbiology Serology

Acute pulmonary disease Sputum40%-70%positive IgM90%positivewithin 3weeksIgG 50%positivewithin 3months

Solitary pulmonary nodule Sputumculture is typically negative IgG and IgMmay both benegative if primary infectionis remote

Cavitary lung disease Sputumculturemay be positive IgG and IgMmay both benegative if primary infectionis remote

Chronic fibrocavitary disease SputumKOHand culture usually positive IgMmay be positiveIgG usually positive

Disseminated disease Elevated IgG titer is hallmark ofdisseminated disease

Meningitis CSF culture 15%positive CSF IgG 75%positive

Table 9

Complications of Coccidioidomycosis


Acute pulmonary Majority of patients resolve primary Immune statusinfection inweeks tomonths Initial spore burden

Solitary pulmonary nodule Excellent Immune status

Cavitary lung disease Generally good Immune status

Chronic fibrocavitary disease Progressive pulmonary decline Early diagnosis and treatmentSeverity of underlying lung diseaseImmune status

DisseminatedCNS Significant neurologic sequelae Immune status

usually occur; associatedwith high Early and aggressive therapymorbidity andmortality Underlying comorbid diseases

Non-CNSSkin Generally good Immune status

Early diagnosis and treatment

Osteoarticular Joint infection typically respondswell Immune statusto antifungal therapy;may require Early diagnosis and treatmentsurgical debridement of synovialtissue. Vertebral osteomyelitismayrequire surgical debridement tostabilize neurologic function


Table 10

Therapeutic Options for Coccidioidomycosis

Type Preferred Alternative

Acute pulmonary Infection usually resolves Azole therapy for 3-6monthswithout therapy Itraconazole 200mgBID

Fluconazole 400-800mg/dKetoconazole 400mg/d

Solitary pulmonary nodule Surgical resection Adjuvant azole therapy for 3-6months if resection of noduleis incomplete or reactivationof disease occurs

Cavitary lung disease Azole therapy for 3-6months Surgical resection of cavityin symptomatic patients may be necessary if patient

remains symptomatic followingmultiple courses of azoletherapy

Chronic fibrocavitary disease Azole therapy for 12months AmBdeoxycholate 0.7-1.0Switch to alternative azole or increase mg/kg/d for 1-2 grams total ordosage in refractory cases lipid formulation 3-5mg/kg/day

for azole-refractory cases

DisseminatedCNS Azole therapy indefinitely Adjuvant intrathecal AmB

Fluconazole 400mg/dItraconazole 400-600mg/d

Non-CNS Azole therapy for 12months;treatment should continueindefinitely in HIV-infected patientsItraconazole 200mgBID (may bemore effective in skeletal infection)Fluconazole 400mg/dKetoconazole 400mg/d

For patients whose diseaseprogresses on azoles, or whoare intolerant to azoles, can betreated with AmB



AcutePulmonary• Subclinical disease occurs in 60%; remainder

develop flu-like illness with fever, malaise, nightsweats, cough, dyspnea and pleuritic chest pain 1-3 weeks following exposure (“Valley fever”).Other manifestations include a maculopapularrash and arthralgias (“desert rheumatism”), ery-thema nodosum or erythema multiforme. The lat-ter usually resolves without therapy in normalhosts.

SolitaryPulmonaryNodule• May result with 5% of infections; typically is

asymptomatic, but may present with chest pain,cough and hemoptysis.

CavitaryLungDisease• Occurs in up to 8% of infections; arises in setting

of infarcted tissue during primary infection; typi-cally thin-walled, solitary, and peripheral; patientsusually asymptomatic, but may present with chestpain, cough and hemoptysis. Cavities can alsoform after a nodule liquifies and drains into abronchus.

Chronic FibrocavitaryDisease• Failure to resolve initial infection; characterized

by progressive pulmonary disease, weight loss,fatigue, night sweats, shortness of breath, chestpain, productive cough and hemoptysis. Fre-quently seen in diabetes.

DisseminatedCNS• Persistent severe headache and intention tremors.

Cerebral infarction can occur late in the diseasesecondary to arteritis.

Non-CNSSkin• Lesions have variable appearance but are typically

wart-like and have a predilection for the nasolabialfold.

Osteoarticular• Bone or joint involvement is seen in approxi-

mately 30% of disseminated disease.

• Bone disease is unifocal in 60% of cases, with theskull, metacarpals, metatarsals, spine and tibiabeing the most frequently involved sites. In con-trast, vertebral involvement is typically multifocalwith predilection for the ileum and sacrum. Mostcritical complication results from spread to themeninges.

• Over 90% of joint infections are monarticular. Theknee and ankle are the most frequently involvedsites. Arthritis is characterized by marked synovi-tis.

Key Laboratory and Radiographic Features

AcutePulmonaryLabs• Nonspecific.

• ESR elevation.

• Eosinophilia >5% in 25% of patients.

Radiology• Normal in 50% of patients.

• Unilateral infiltrate with ipsilateral adenopathy.

SolitaryPulmonaryNoduleLabs• Nonspecific.

Radiology• Nodules are usually peripheral and 2-3 cm in

diameter.

CavitaryLungDiseaseLabs• Nonspecific.

Radiology• Cavities are very thin-walled with no associated

infiltrate; usually 2-3 cm in diameter and arelocated on the lung periphery.

Chronic FibrocavitaryDiseaseLabs• Nonspecific.


Radiology• Bilateral nodular densities, cavitation and hilar

adenopathy.

DisseminatedCNSLabs• Lymphocytic pleocytosis.

• Elevated CSF protein.

• Decreased CSF glucose.

Radiology• MRI head may show evidence of arteritis or

infarct.

Non-CNSLabsSkin

• Nonspecific.

RadiologyOsteoarticular• Bone lesions most commonly osteolytic; bone

scans more sensitive than plain films in detectinglesions.

ID Board Pearls

• Coccidioidomycosis may present as erythemanodosa during the early phase of disease.

• Associated with bilateral hilar adenopathy andcavitary lesions (like histoplasmosis).

• Associated with peripheral eosinophilia (likehistoplasmosis) which distinguishes coccidiomy-cosis from tuberculosis.

• CNS disease is difficult to treat and may requirelong term azole therapy.

7. Sporotrichosis

Microbiology

• The causative organism is Sporothrix schenckii.

• Characteristic cigar-shaped yeast form is difficultto identify in clinical specimens.

• The presence of Splendore-Hoeppli bodies,although not diagnostic, is notably associated withsporotrichosis and can provide an important pre-sumptive clue.

• Diagnosis based on recovery of organism from tis-sue and fluids from infected sites.

Epidemiology

• Worldwide distribution; majority of cases arereported from tropical and subtropical areas.

• Found in the soil, decaying vegetation, plants, andplant products such as commercial sphagnummoss, straw, wood and mulch.

• High-risk activities associated with environmentalexposure to fungus include gardening, farming,hay baling and carpentry.

• Cutaneous inoculation has occurred from animals,including cats, armadillos, dogs, birds and insectbites.

• Classically presents as a cutaneous or lymphocuta-neous syndrome in immunocompetent hosts withoccupational or recreational exposure to fungus.

• Extra cutaneous disease is associated withunderly-ing immunodeficiency; most often seen in patientswith AIDS, alcoholism, chronic obstructive pul-monary disease and diabetes.


FixedCutaneousDirect inoculation• Limited to skin, often on face or trunk; appears asplaque-like or verrucous lesion at site of inocula-tion; onset after inoculation is days to a few weeks.


Table 11

Complications of Sporotrichosis


Cutaneous and Spontaneous resolution has been Immune statuslymphocutaneous reported; however, it is recommended Prompt diagnosis and therapy

that all patients receive therapy.Most commonly occurs inimmunocompetent hostswithexcellent outcome. Disseminationis rare. Potential superinfection ofnodular or ulcerative lesions

Osteoarticular Typically associatedwith a poor Early diagnosis with prompt therapyfunctional outcomedue to delays in Immune statusdiagnosis, but is not life-threatening.Characterized by progressivedeterioration of joint functiondespite therapy. Increased risk fordisease extension to contiguousstructures and beyond inimmunocompromised hosts

Pulmonary Indolent and progressive pulmonary Early diagnosis and prompt therapydecline in untreated patients. Extent of diseaseResponse to therapy varieswith Underlying lung diseaseprognostic factors Underlying comorbid diseases

Immune status

Disseminated Raremanifestation; associatedwith Early diagnosis and prompt therapysignificantmorbidity andmortality Immune status

Extent of disease

Meningeal Raremanifestation; associatedwith Early diagnosis andprompt therapysignificantmorbidity andmortality Immune status


LymphocutaneousDirect inoculation• Initial lesion is papular and develops days to

weeks after exposure; evolves to erythematousnodules that may ulcerate; lesions are not typicallysuppurative or tender; similar lesions progressalong regional lymphatics proximal to site of inoc-ulation; systemic symptoms are not typically seen.

PulmonaryInhalation• Associated with alcoholism; unusual manifesta-

tion; presents as subacute to chronic pneumoniawith nonspecific symptoms and signs such asfever, night sweats, weight loss, dyspnea, coughwith purulent sputum and hemoptysis. Mimicspulmonary TB and other chronic fungal infections.

OsteoarticularHematogenous or direct inoculation• Arthritis (single or multiple) is the predominant

presentation, with or without cutaneous lesions;when osteomyelitis is seen, it usually affects bonecontiguous to an infected joint. Commonlyaffected joints are the knee, elbow, wrist, ankle andhand joints; tenosynovitis and bursitis have beenreported.

DisseminatedDirect inoculation or inhalation• Uncommon, seen primarily in patients with AIDS;

fever, night sweats and weight loss; diffuse lym-phocutaneous ulcerative lesions; visceral involve-ment can occur as well.

MeningeaHematogenous• Presents as chronic meningitis with fever, altered

mental status; usually seen in disseminated dis-ease, but can occur as isolated involvement; seenin severely immunocompromised patients.


Microbiology• Fungal stains and culture from infected sites fre-

quently are positive. However, CSF KOH and cul-ture are often negative in meningeal disease.

• Large volumes (20-30 mL) of CSF obtained onthree different occasions maximize the yield oforganism in culture.

Laboratory• Routine tests are nonspecific.

• CSF reveals lymphocytic pleocytosis with ele-vated protein in meningeal disease.

Serology• Serologic testing is not accessible for routine use.

Radiology• Chest radiograph findings in pulmonary disease

include unilateral or bilateral upper lobe cavitarylesions with degrees of fibrosis and nodular densi-ties.


Cutaneous/Lymphocutaneous• Infectious

* Nocardiosis

* Mycobacterium marinum

* Leishmaniasis

* Tularemia

* Blastomycosis

* Phaeohyphomycosis

* Paracoccidioidomycosis

• Noninfectious

* Sarcoidosis

* Neoplasm

Pulmonary• Infectious

* Tuberculosis

* Blastomycosis


* Histoplasmosis


• Noninfectious* Sarcoidosis

Osteoarticular• Infectious

* Tuberculosis

* Blastomycosis

* Histoplasmosis

* Candidiasis

• Noninfectious* Degenerative joint disease

Disseminated• Infectious

* Tuberculosis

* Blastomycosis

* Nocardiosis

• Noninfectious* Neoplasm

Meningeal• Infectious

* Tuberculosis

* Other fungal pathogens

• Noninfectious* Vasculitides including SLE, GA (granuloma-

tous angiitis)

* Drug-induced meningitis

Therapeutic Options

Cutaneous andLymphocutaneousPreferred• Itraconazole 100-200 mg/d for 2-4 weeks after all

lesions have resolved, usually for 3-6 months total;efficacy is >90%; associated with potential druginteractions.

• Terbinafine, 500 mg BID for patients who do notrespond to itraconazole.

Alternative• 1-SSKI increasing from 5-50 drops/d TID as toler-

ated for 3-6 months or until 1 month after lesionshave resolved.

• Low cost and generally effective.

• Inconvenient dosing frequency and metallic taste;associated with allergic reactions, salivary glandenlargement and GI intolerance.

• Fluconazole 400 mg/d for 6 months; can be used ifintolerant of other therapy; less efficacious thanitraconazole or SSKI; duration of therapy islonger.

• Local hyperthermia (42-43ºC) daily (at least 40minutes per treatment) for 2-3 months. Low costwith no risk of drug exposure, can be used asadjunctive therapy with itraconazole; dedicatedadherence is difficult due to length of timerequired for treatment response; can be consideredwhen azole therapy is not possible, such as in preg-nancy.

• AmB is effective but risk:benefit not justified in alocalized non-life-threatening infection.

PulmonaryPreferred• Lipid AmB 3-5 mg/kg/d or AmB deoxycholate

0.7-1.0 mg/kg/d for 1-2 g total dose; outcome isgenerally poor due to underlying lung disease anddelay in diagnosis.

• Itraconazole 200 mg orally BID for 12 monthsafter patent has favorable response to AmB.


• In severe life-threatening disease, AmB plus surgi-cal resection appears to be the most effective ther-apy, if tolerated based on underlying lung disease.

Alternative• Itraconazole 200 BID if AmB not tolerated or if

less severe disease is present; outcome generallypoor due to underlying lung disease and delays indiagnosis.

OsteoarticularPreferred• Itraconazole 200 BID for 12 months; efficacy is

60%-80%.

Alternative• Lipid AmB 3-5 mg/kg/d or AmB deoxycholate

0.7-1.0 mg/kg/d for 1-2 g total dose is recom-mended in extensive disease; efficacy is 60%-80%but is only used if itraconazole fails because ofhigher intolerance.

Disseminated• Lipid AmB 3-5 mg/kg/d preferred.

• Itraconazole 200 BID recommended as step-downtherapy after patient responds to AmB for 12months of therapy.

• In AIDS, itraconazole 200 BID for lifelong sup-pression.

Meningeal• Lipid AmB 3-5 mg/kg/d preferred but AmB

deoxycholate 0.7-1.0 mg/kg/d; in AIDS, itracona-zole 200 BID for lifelong suppression.

ID Board Pearls

• Sporotrichosis is generally an indolent infectionthat requires prolonged therapy.

• Due to the temperature sensitivity of the fungus,local application of hyperthermia can be used inpregnant women for the treatment of cutaneouslesions.

• Pulmonary sporotrichosis may present with thin-walled cavitary lesions (like coccidiomycosis).

8. Paracoccidioidomycosis

Synonyms

• South American blastomycosis, Lutz’s mycosis.

Microbiology

• Causative organism is Paracoccidioidesbrasiliensis.

• Yeast forms vary in size and exhibit multiple bud-ding in clinical specimens.

• “Pilot’s wheel” appearance is due to the arrange-ment of the smaller budding cells attached to thelarger mother cell with interspersed lipid globules.

Epidemiology

• Endemic to some, but not all areas in Central andSouth America. Majority of cases (80%) arereported from Brazil, followed by Colombia andVenezuela. All reported cases from outside anendemic area had once lived or visited an endemicarea; latency in some cases was as long as 15years.

• Habitat is elusive, but is presumed to be in thehighly humid soil. Inhalation of spores is the pri-mary route of infection.

• No evidence for person-to-person spread; out-breaks have not been reported.

• Most cases occur in men (15:1) between 30-60years of age. When seen in younger patients (13%of cases), the gender difference diminishes. Estro-gens are thought to block conidia from yeast trans-formation in the infected host.

• Risk factors associated with infection include hav-ing a history of agricultural occupation, smoking,alcoholism and malnutrition.

• Infection can result from a primary focus without alatency period or from endogenous reactivation ofquiescent foci.



Primary Infection• Lung.

• Most infections are subclinical.

Acute Juvenile Form• Extensive infection of liver, spleen, lymph nodes

and bone marrow; lung involvement is minimal.

• Clinical course develops in subacute pattern ofweeks to months; patients are severely ill withfever, malaise, weight loss and lymphadenopathy.Abdominal pain related to colonic obstructionfrom enlarged mesenteric nodes can be seen.

ChronicAdult Form• Lungs involved in 90% of cases; concomitant

extrapulmonary involvement is common, includ-ing mucous membranes, skin, reticuloendothelialsystem and adrenals.

• Markedly chronic course of months to years withnonspecific complaints of cough, weight loss,fever; skin and mucous membrane lesions of theface, oral and nasal mucosa may be large, verru-cous or ulcerative.


Microbiology• KOH smear has 93% sensitivity. Characteristic

“Pilot’s wheel” morphology of yeast cells fromlipid globules.

Laboratory• Routine tests are nonspecific.

Serology• Immunodiffusion serology is 95% sensitive and

specific, but remains positive for years.

• Complement fixation test is most useful followingresponse to therapy.

Radiology• CXR reveals bilateral and symmetric disease with

patchy infiltrates and nodular densities; cavitiescan develop, but hilar adenopathy is uncommon.


Acute Juvenile Form• Infectious

* Tuberculosis

* Blastomycosis

* Leishmaniasis

• Noninfectious* Lymphoproliferative disease

Chronic adult form• Infectious

* Tuberculosis

* Blastomycosis

* Histoplasmosis

* MOTT, including Mycobacterium leprae

* Leishmaniasis

* Syphilis

• Noninfectious* Neoplasm

* Sarcoidosis

* Crohn’s disease

Therapeutic Options

Acute Juvenile FormPreferred• Itraconazole 100 mg/d for 6 months.

Alternative• Ketoconazole 200-400 mg/d for 12 months.

• Fluconazole 200-400 mg/d for 12 months.

• Lipid AmB 3-5 mg/kg/d or AmB deoxycholate 0.7mg/kg/d for 3-4 months ± follow-up therapy withsulfadiazine to decrease relapse rate.

• Sulfadiazine 6 g/d for 3-5 years.

• Organism may be seen in clinical specimens withmultiple small buds.


ChronicAdult FormPreferred• Itraconazole 200 mg/d for 6 months.

Alternative• Ketoconazole 200-400 mg/d for 12 months.

• Fluconazole 200-400 mg/d for 12 months.

• Lipid AmB 3-5 mg/kg/d or AmB deoxycholate 0.7mg/kg/d for 3-4 months ± follow-up therapy withsulfadiazine to decrease relapse rate.

• Sulfadiazine 6 g/d for 3-5 years.

Complications

Acute Juvenile Form• Behaves as a lymphoproliferative disorder; associ-

ated with significant short-term mortality.

• Prognostic factors include early diagnosis, nutri-tional status and immune status.

ChronicAdult Form• Chronic course from months to years.

• Relapse rate up to 30% despite therapy.

• Sequelae from fibrotic healing include cor pul-monale, cardiac constriction, and stenosis of glot-tis and trachea.

• Prognostic factors include early diagnosis, nutri-tional status, underlying comorbid disease,immune status and development of critical fibroticsequelae.

ID Board Pearls

• Prognosis of paracoccidioidomycosis is goodwhen treated, however treatment regimens arevery long and relapse is frequent.

• Granulomatous inflammation with many giantcells containing organism.

• Focal area of central caseation mixed with pyo-genic abscesses are usually present.

9. Emerging Infections

• Penicilliosis

* Microbiology: Thermally dimorphic organ-ism Penicillium marneffei

* Epidemiology: Disease of immunocompro-mised individuals living in or traveling toSoutheast Asia.

* Diagnosis: Culture.

* Therapy: AmB for severely ill patients for 2months, less severe disease or those whohave responded to AmB may be treated withitraconazole; HIV/AIDS patients, suppres-sive therapy with itraconazole.

* Clinical manifestations:

• Similar to disseminated histoplasmosis.

• Primary portal of entry is the lungs withhematologic dissemination.

• Diffuse papular lesions similar to mollus-cum contagiosum are common inHIV/AIDS patients.

• Small yeast cells may be seen onhistopathologic examination.

• Fusariosis

* Microbiology: Invasive mold infectionassociated with Fusarium species, mostcommonly F solani.

* Diagnosis: Blood cultures are positive in upto 50% of cases; presence of a mold in bloodcultures obtained from neutropenic patientsshould be suggestive for fusariosis

* Therapy:

• Fusarium species are often highly resis-tant to many antifungal agents.

• AmB in high doses is most commonlyused therapy and has met with limitedsuccess.

• Most clinicians prefer therapy withvoriconazole, IV loading dose: 6 mg/kgevery 12 hours for 2 doses; followed bymaintenance dose of 4 mg/kg every 12hours successful in a small number ofpatients.

• Therapy is continued until the neutrope-nia has resolved and a clinical response isdocumented. Prognosis for disseminatedinfection is related to reversal of the neu-tropenia.


• Skin and respiratory tract are the primaryportals of entry for Fusarium.

• Localized skin infections may occur atsites of trauma in immunocompetenthosts.

• Disseminated disease from the skin orgastrointestinal tract occurs in immuno-compromised patients.

• Clinical presentation is generally nonspe-cific with fever and skin lesions whicheventually necrose and appear similar toecthyma gangrenosum.

• Radiography and pathology: similar toinvasive aspergillosis or zygomycosis.

• Pseudallescheriasis (Scedosporosis)

* Microbiology: Pseudoallescheria boydii,Scedosporium apiospermum (the asexualform of P boydii) and S prolificans recognizedas emerging pathogens.

* Diagnosis: Hyphal elements seen in the tis-sues of patients with Pseudoallescheria andScedosporium infection resembleAspergillus, including intravascular invasion.



• Rare causes of sinopulmonary infectionsin immunocompetent hosts and may pre-sent as fungus balls in the lungs orparanasal sinuses.

• Severe pneumonia, invasive sinusitis andhematogenous dissemination, includingbrain abscesses, occur in immunosup-pressed hosts, especially bone marrowtransplant patients.

* Therapy:

• Treatment outcome is poor and mostpatients with disseminated disease die.

• Amphotericin B is not effective in thetreatment of pseudallescheriasis or sce-dosporosis.

• Voriconazole IV loading dose: 6 mg/kgevery 12 hours for 2 doses; followed bymaintenance dose of 4 mg/kg every 12hours may be effective.

• Surgical debridement and drainage ofabscesses may also be necessary.

10. Further Reading

Books and Book Chapters

Anaissie EJ, McGinnis MR, Pfaller MA. ClinicalMycology. New York, NY: Churchill Livingstone;2003.

Chapman SW. Sullivan, DC. Blastomyces dermati-tidis. In: Mandell GL, Gordon DR, Bennett JE,Dolin R, eds. Principles and Practice of InfectiousDiseases. 7th ed. New York, NY: Churchill Living-stone; in Press.

Chapman SW, Sullivan DC. Diagnosis and treat-ment of blastomycosis. In: Hospenthal DR, RinaldiMG, eds. Diagnosis and Treatment of HumanMycoses. Totowa, NJ: Humana Press Inc; 2008:277-293.

Chapman SW, Sullivan DC. Blastomycosis. In:Kasper A, Fauci D, Longo E, et al, eds. Harrison’sPrinciples of Internal Medicine. 17th ed. New York,NY: McGraw Hill; 2008: 1249-1251.

Chapman SW, Sullivan DC. Miscellaneousmycoses and algal infections. In: Kasper A, FauciD, Longo E, et al, eds. Harrison’s Principles ofInternal Medicine. 17th ed., New York, NY:McGraw Hill; 2008: 1263-1267.

Deepe GS. Histoplasma capsulatum. In: MandellGL, Gordon DR, Bennett JE, Dolin R, eds. Princi-ples and Practice of Infectious Diseases. 6th ed.Philadelphia, PA: Churchill Livingstone; 2005:3012-3026.

Dismukes WE, Pappas PG, Sobel JD. ClinicalMycology. Oxford, England: Oxford UniversityPress; 2003.

Edwards JE. Candida species. In: Mandell GL, Gor-don DR, Bennett JE, Dolin R, eds. Principles andPractice of Infectious Diseases. 6th ed. Philadel-phia, PA: Churchill Livingstone; 2005: 2938-2958.

Emmons CW, Binford CH, Utz JP, Kwon-ChungKJ. Medical Mycology. 3rd ed. Philadelphia, PA:Lea & Febiger; 1977.


Fleming RV, Anaissie EJ. Emerging fungal infec-tions. In: Wingard JR, Anaissie EJ, eds. FungalInfections in the Immunocompromised Patient.Boca Raton, FL: Taylor & Francis; 2005:311-340.

Frey D, Oldfield RJ, Bridger RC. Color Atlas ofPathogenic Fungi. Chicago, IL: Year Book MedicalPublishers, Inc; 1979.

Galgiani J. Coccidioides species. In: Mandell GL,Gordon DR, Bennett JE, Dolin R, eds. Principlesand Practice of Infectious Diseases. 6th ed.Philadelphia, PA: Churchill Livingstone; 2005:3040-3051.

Larone DH. Medically Important Fungi. 4th ed.Washington, DC: ASM Press; 2002.

Perfect JR. Cryptococcus neoformans. In: MandellGL, Gordon DR, Bennett JE, Dolin R, eds. Princi-ples and Practice of Infectious Diseases. 6th ed.Philadelphia, PA: Churchill Livingstone; 2005:2997-3012.

Restrepo A. Paracoccidioides brasiliensis. In: Man-dell GL, Bennett JE, Gordon DR, Dolin R, eds.Principles and Practice of Infectious Diseases. 6thed. Philadelphia, PA: Churchill Livingstone; 2005:3062-3068.

Rex JH, Okhuysen PC. Sporothrix schenckii. In:Mandell GL, Gordon DR, Bennett JE, Dolin R, eds.Principles and Practice of Infectious Diseases. 6thed. Philadelphia, PA: Churchill Livingstone; 2005:2984-2988.

Sarosi GA, Davies SF. Fungal Diseases of the Lung.Orlando, FL: Grune & Stratton, Inc; 1986.

Sobel, JD. Candidiasis. In Hospenthal DR, RinaldiMG, eds. Diagnosis and Treatment of HumanMycoses. Totowa, NJ: Humana Press Inc.; 2008:137-162.

Journal Articles

Benard G, Duarte AJ. Paracoccidioidomycosis: amodel for evaluation of the effects of humanimmunodeficiency virus infection on the naturalhistory of endemic tropical diseases. Clin Infect Dis.2000;31:1032-1039.

Blumberg HM, Jarvis WR, Soucie JM, et al. Riskfactors for candidial bloodstream infections in sur-gical intensive care unit patients: the NEMISprospective multicenter study. Clin Infect Dis.2001;33:177-186.

Bradsher RW. Clinical features of blastomycosis.Semin Respir Infect. 1997;12:229-234.

Brummer E, Castaneda E, Restrepo A. Paracoccid-ioidomycosis: an update. Clin Microbiol Rev.1993;6:89-136.

Chapman SW, Dismukes WE, Proia LA, et al. Clini-cal practice guidelines for the management of blas-tomycosis. Clin Infect Dis. 2008;46:1801-1812.

Chapman SW, Lin AC, Hendricks KA, et al.Endemic blastomycosis in Mississippi: epidemio-logical and clinical studies. Semin Respir Infect.1997;12:219-228.

Chapman SW, Pappas P, Kauffman C, et al. Com-parative evaluation of the efficacy and safety of twodoses of terbinafine (500 and 1000 mg day(-1)) inthe treatment of cutaneous or lymphocutaneoussporotrichosis. Mycoses. 2004;47:62-68.

Galgiani JN, Ampel NM, Blair JE, Catanzaro A,Stevens DA, Williams PL. Coccidioidomycosis.Clin Infect Dis. 2005;41:1217-1223.

Graybill JR, Sobel J, Saag M, et al. Diagnosis andmanagement of increased intracranial pressure inpatients with AIDS and cryptococcal meningitis.Clin Infect Dis. 2000;30:47.

Kauffman CA, Bustamante B, Chapman SW, Pap-pas PG. Clinical practice guidelines for the manage-ment of sporotrichosis. Clin Infect Dis.2007;45:1255-1265.


Kauffman CA. Sporotrichosis. Clin Infect Dis.1999;29:231-236.

Kaufmann CA, Vazquez JA, Sobel JD, et al and theNational Institute for Allergy and Infectious Dis-eases (NIAID) Mycoses Study Group. Clin InfectDis. 2000;30:14-18.

Lundstrom T, Sobel J. Nosocomial candiduria: areview. Clin Infect Dis. 2001;32:1602-1607.

Ostrosky-Zeichner L. Prophylaxis and treatment ofinvasive candidiasis in the intensive are setting. EurJ Clin Microbiol Infect Dis. 2004;23:739-744.

Pfaller MA, Jones RN, Doern GV, et al. Blood-stream infections due to Candida species: SENTRYantimicrobial surveillance program in North Amer-ica and Latin America. Antimicrob AgentsChemother. 2000;44:747-751.

Pappas PG. Blastomycosis in the immunocompro-mised patient. Semin Respir Infect. 1997;12:243-251.

Pappas PG, Kaufmann CA, Andes D, et al. ClinicalPractice Guidelines for the Management of Can-didiasis: 2009 Update by the Infectious DiseasesSociety of America. Clin Infect Dis. 2009;48:503–535.

Powderly WG. Cryptococcal meningitis and AIDS.Clin Infect Dis. 1993;5:837-842.

Queiroz-Telles F, McGinnis MR, Salkin I, GraybillJR. Subcutaneous mycoses. Inf Dis Clin NorthAmerica. 2003;17:59-85.

Saag MS, Graybill RJ, Larsen RA, et al. Practiceguidelines for the treatment of cryptococcosis. ClinInfect Dis. 2000;30:710-718.

Sathapatayavongs B, Batteiger BE, Wheat LJ, et al.Clinical and laboratory features of disseminatedhistoplasmosis during two large urban outbreaks.Medicine. 1983;62:263-270.

Sobel JD for the Mycoses Study Group. Practiceguidelines for the treatment of fungal infections.Infectious Diseases Society of America. Clin InfectDis. 2000;30:652.

Stevens D. Coccidioidomycosis. N Engl J Med.1995;332:1077-1082.

Walsh TJ, Anaissie EJ, Denning DW, etal.Treatment of Aspergillosis: Clinical PracticeGuidelines of the Infectious Diseases Society ofAmerica. Clin Infect Dis. 2008; 46:327-360.

Walsh TJ, Rex JH. All catheter-related candidemiais not the same: assessment of the balance betweenthe risks and benefits of removal of vascularcatheters. Clin Infect Dis. 2002;34:600-602.

Walsh TJ, Pappas P, Winston DJ, et al. Voriconazolecompared with liposomal amphotericin B for empir-ical antifungal therapy in patients with neutropeniaand persistent fever. N Engl J Med. 2002;346:225-234.

Wheat LJ, Connolly-Stringfield PA, Baker RL, et al.Disseminated histoplasmosis in the acquiredimmune deficiency syndrome: clinical findings,diagnosis and treatment, and review of the litera-ture. Medicine. 1990;69:361-374.

Wheat LJ, Freifeld AG, Kleiman MB, et al . Clinicalpractice guidelines for the management of patientswith histoplasmosis: 2007 update by the InfectiousDiseases Society of America. Clin Infect Dis.2007;45:807-825.



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Infectious Disease Board Review--Sample