OVERVIEW: What every practitioner needs to know

Are you sure your patient has a disseminated fungal infection? What should you expect to find?

Key symptoms of the disease
  • Blastomycosis: (Figure 1) Cutaneous findings should raise suspicion for disseminated disease.

    Growing lesion(s), may complain of oozing from the lesion(s)

    Pulmonary symptoms (primary site of infection): greater than 50% are asymptomatic

    Ranging from mild “cold” symptoms to cough, dyspnea, night sweats, weight loss, and hemoptysis

    Symptoms related to other sites of dissemination

    Bone, central nervous system (CNS), genitourinary system

  • Coccidioidomycosis Cutaneous findings, with the exception of erythema nodosum, should raise suspicion for disseminated disease.

    Skin lesions are commonly asymptomatic

    Symptoms related to other sites of dissemination

    Supraclavicular/cervical lymphadenopathy, bone and joints, CNS

  • Cryptococcosis: (Figure 2, Figure 3) Cutaneous findings should raise suspicion for disseminated disease.

    Skin lesions commonly asymptomatic

    Symptoms related to other sites of infection

    Lungs, CNS (meningeal symptoms), bone, prostate, kidneys, eyes, and peritoneum

  • Histoplasmosis Cutaneous findings should raise suspicion for disseminated disease.

    Acute progressive disseminated histoplasmosis (PDH): abrupt onset

    Fever, malaise, weight loss

    Rash, typically asymptomatic

    Symptoms related to organs involved

    Reticuloendothelial system, pulmonary

    Subacute progressive disseminated histoplasmosis

    Fever, weight loss, painful mucosal ulcers, fatigue

    Symptoms related to organs involved

    Gastrointestinal (GI) tract, liver, heart, adrenal glands, CNS

    Chronic progressive disseminated histoplasmosis: primarily immunocompetent individuals

    Mild symptoms

    Malaise, fatigue, fever less common

    Painful oropharyngeal ulcers

    Symptoms related to organs involved

    CNS, heart, bone, adrenal glands, liver

  • Paracoccidioidomycosis: (Figure 4) Mucocutaneous findings are nearly always an indication of disseminated disease.

    Lesions near mucocutaneous borders, painful ulcers, growing warty lesions

    Dysphagia, odynophagia, painful mucosal ulcers/lesions, dysphonia

    Dry cough, dyspnea, may have sputum production or hemoptysis

    Weakness, fatigue, weight loss

    In juveniles

    Swollen lymph nodes with or without overlying ulceration associated with pain

  • Sporotrichosis: (Figure 5, Figure 6) Cutaneous disease does not indicate disseminated disease in most cases.

    Chronic ulcers, tender nodules on face, scalp, and around painful joints

    Arthralgias

    Low-grade fever

    Weight loss

    Symptoms related to organs involved

    Lungs, CNS, liver, spleen

  • Penicilliosis: Cutaneous findings should raise suspicion for disseminated disease.

    Skin lesions on face, extremities, and upper trunk

    Low-grade fever, weight loss, malaise

    Symptoms related to organs involved

    Liver, spleen, GI tract, lungs, pericardium

Figure 1.

Verrucous, crusted plaque with red-brown border

Figure 2.

Umbilicated skin-colored papules, central crust

Figure 3.

Ulcerated papulonodule

Figure 4.

Ulcerated, crusted indurated plaque

Figure 5.

Large painful ulceration overlying painful ankle joint

Figure 6.

Crusted indurated pink-erythematous plaques

Key cutaneous findings of the disease
  • Blastomycosis

    Chronic, slowly enlarging plaque

    Draining, verrucous surface with crusting (thick, gray-brown in color)

    Granulation tissue with seropurulent exudate beneath crust

    Central ulceration resolves with cribriform scarring

    May have pustules, warty vegetations, or draining sinuses at the advancing edge

    Papulopustules, violaceous nodules, ulcers

    Commonly on exposed skin

    Occasional mucous membrane involvement occurs

  • Coccidioidomycosis (Figure 7)

    Several lesion morphologies

    Verrucous nodules

    Pink papules

    Umbilicated papules

    Subcutaneous abscesses

    May develop more chronic plaques resembling blastomycosis

    Favors the face especially the melolabial (nasolabial) folds

  • Cryptococcosis: The cutaneous findings reported are many and nonspecific.

    Head and neck involved most commonly

    Papules

    Molluscum-like with a central hemorrhagic crust: seen in approximately 50% of those with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and cutaneous lesions

    Acne-like pustules

    Basal cell carcinoma-like

    Abscesses

    Draining sinuses from abscesses or underlying osteomyelitis

    Cellulitis-like plaques

    Granuloma-like papules/plaques

    Ulcers

  • Histoplasmosis: The cutaneous findings reported are many and nonspecific.

    Acute progressive disseminated histoplasmosis

    Skin: papular eruption with crusting, petechiae, ecchymoses

    Mucosae: lesions uncommon but may present as ulcers

    Subacute progressive disseminated histoplasmosis

    Mucosae: oropharyngeal solid indurated plaques progress to ulcers (Figure 8)

    Skin: ulcers, nodules, plaques, umbilicated papules, abscesses, furuncles, folliculitis

    Oropharyngeal ulceration with firm, induraed periphery: tongue, buccal mucosae, larynx, gingivae

    Ulcers may occur on genitals

  • Paracoccidioidomycosis

    Oral mucosa: often first site of involvement in disseminated disease

    Small papules, ulcerations on gingivae, tongue, lips

    Extend overtime to destroy surrounding structures: nose or lips (Figure 9)

    Skin:

    Ulcerated or verrucous indurated papules/plaques near mucocutaneous borders, trunk, or limbs

    Characteristic “mulberry” appearance

    Ulceration overlying enlarged cervical or supraclavicular lymph node(s)

  • Sporotrichosis

    Red, tender nodules

    Cold abscesses

    Chronic ulcers, draining fistulae

    Tend to occur on face, scalp, and around arthritic joints but may be anywhere on the skin

    Swollen, tender joints of the extremities

  • Penicilliosis (Figure 10)

    Umbilicated and/or crusted papules

    Pustules

    Nodules

    Ulcers

    Abscesses

    Face, upper trunk, and extremities most commonly involved

    May have generalized lymphadenopathy

    Palatal and pharyngeal lesions are commonly seen in HIV-infected patients

Figure 7.

Red crusted plaques and papules

Figure 8.

Indurated sublinguial ulceration

Figure 9.

Crusted ulceration in histoplasmosis

Figure 10.

Penicilliosis – facial and upper extremity papules/pustules

How did the patient develop a disseminated fungal infection? What was the primary source from which the infection spread?

  • Blastomycosis

    Blastomyces dermatitidis: dimorphic fungus

    The male to female ratio is 6:1

    Risk of infection is higher with outdoor activity after heavy rains.

    North America, Central America, Africa, Middle East, India

    States bordering Mississippi and Ohio Rivers, Southeast United States, and Great Lakes region

    Acquired by inhalation of conidia from the soil

    25% of infections in those with AIDS are believed to be caused by reactivation

    The skin is the most common site of dissemination, approximately 80%.

  • Coccidioidomycosis

    Coccidioides immitis: dimorphic fungus

    Found in the soil and in vegetation; rodent burrows

    Epidemics occur when soil is disrupted

    Western Hemisphere

    Southwest United States

    Mexico

    Central America: Guatemala, Nicaragua, Honduras

    South America: Paraguay, Argentina, Brazil, Colombia

    Acquired by inhalation of spores from the soil

    The skin is involved in 15 to 20% of disseminated cases.

  • Cryptococcosis

    Cryptococcus neoformans var. neoformans and C. neoformans var. gattii: dimorphic fungi

    Found worldwide in the soil, especially that soiled with bird droppings

    C. gattii appears associated with Eucalyptus trees

    Acquired by inhalation of spores from soil

    The skin is involved in approximately 10 to 15% of patients with disseminated disease and is the third most common organ involved

    This occurs less commonly in those with HIV/AIDS, in whom the CNS is the most common site of dissemination

    Cutaneous involvement can be seen up to 8 months prior to other symptoms of overt systemic disease.

  • Histoplasmosis

    Histoplasma capsulatum: dimorphic fungus

    Found worldwide in the soil, especially that soiled with bat and bird droppings and in river basins

    Most common in North America: Mississippi and Ohio River basins most common; Potomac, Delaware, Hudson, and St Lawrence Rivers

    Acquired by inhalation of spores from soil or excreta of birds/bats

    The skin is involved in approximately 6% of patients with disseminated disease and may be more common in those with AIDS and organ transplantation

  • Paracoccidioidomycosis

    Paracoccidioides brasiliensis: dimorphic fungus

    Endemic to Central and South America especially Brazil, Argentina, Venezuela, Colombia, and Ecuador

    Cases reported in the United States, Mexico, Europe, and Asia

    Appears to require high humidity throughout the year along with mild temperatures restricting it to certain locations

    Most patients are men and predominantly in laborers

    Acquired by inhalation of conidia

    Initial infection is commonly subclinical to mildly symptomatic

    Disseminated disease has two main clinical presentations (overlap does occur)

    Chronic adult form: pulmonary and extrapulmonary (mucocutaneous often) involvement

    Acute to subacute juvenile form: reticuloendothelial system involvement (liver, spleen, lymph nodes); pulmonary complaints are minimal

  • Sporotrichosis

    Sporothrix schenckii: dimorphic fungus

    Worldwide distribution

    Found in soil, plants, and plant products

    Cases tend to be the result of occupational or recreational exposure.

    Most cases are limited to the regional lymphatic type of sporotrichosis.

    In those with decreased immunity, multifocal cutaneous and extracutaneous disease may occur.

    Exposure through gardening, farming, minting, horticulture, etc. should be sought.

  • Penicilliosis

    Penicillium marneffei: dimorphic fungus

    Southeast Asia and southern China

    Found in healthy bamboo rats and soil near their burrows; their role in human infection is unclear

    Cases are seen most commonly in young adults with HIV

    Infection risk may increase during the rainy season.

    60 to 70% of those with disseminated disease will have skin manifestations.

Which individuals are of greater risk of developing a disseminated fungal infection?

  • Blastomycosis:

    HIV-positive patients, especially if CD4 is less than 200cells/mL, are more likely to demonstrate:

    Symptomatic pulmonary infection

    Disseminated disease

    CNS involvement (up to 40% of those with blastomycosis)

    Solid organ transplant

    Hematologic malignancy

    Tumor necrosis factor (TNF)-α inhibitor therapy (US Food and Drug Administration data)

  • Coccidioidomycosis

    HIV/AIDS

    Ethnic groups

    Hispanics

    Native Americans

    Filipinos

    Vietnamese

    African Americans

    Elderly

    Infants

    Pregnant women, especially in the third trimester

    Blood types AB or B

    Other immunosuppressed patients (i.e., Hodgkin lymphoma, solid organ transplant, high-dose corticosteroids, TNF-α inhibitors)

  • Cryptococcosis

    HIV/AIDS

    Malignancy

    Solid organ

    Hematologic

    Iatrogenic immunosuppression

    High-dose corticosteroids

    Organ transplant recipients

    TNF-α inhibitors

    Hyper-immunoglobulin (Ig)M & Hyper IgE syndromes

    Diabetes mellitus

    Cirrhosis

    Sarcoidosis

  • Histoplasmosis

    HIV/AIDS

    Solid organ transplant recipients, especially renal

    Hematologic malignancy: leukemia, lymphoma

    Latrogenic immunosuppression: corticosteroids, anti-TNF-α therapy

    Systemic lupus erythematosus

  • Paracoccidioidomycosis

    Men, especially laborers in agricultural occupations, in endemic regions

    In prepubertal age groups, gender difference does not exist

    Chronic alcoholism and malnutrition may be involved

    HIV/AIDS—clinical course may be more acute and severe

    Involves predominantly reticuloendothelial system and skin

    CD4 less than 50cells/mL

  • Sporotrichosis

    Latrogenic immunosuppression: corticosteroids, anti-TNF-α therapy

    Organ transplant recipients

    HIV/AIDS CD4 less than 100cells/mL

    Hematologic malignancy

    Chronic alcoholism

    Diabetes mellitus

  • Penicilliosis

    HIV/AIDS

    Immunosuppression for other reasons

    Contact with South-East Asia

Beware: there are other diseases that can mimic a disseminated fungal infection:

  • Blastomycosis

    Halogenoderma

    Caused by excessive ingestion of bromides or iodides

    Pemphigus vegetans

    Common locations include the scalp and body folds.

    Often begin with flaccid bullae

    Tongue may have cerebriform changes.

    Syphilis

    Associated with other signs of tertiary syphilis

    Vegetative lesions tend to prefer the areas near mucocutaneous junctions and the scalp.

    Verruca: more common when blastomycosis occurs on the hands and feet

    Warts are not crusted and do not ooze purulent material.

    Folliculitis: when papules and pustules predominate

    Cutaneous leishmaniasis

    Nocardiosis

    Dissemination seen in same risk groups

    Forms draining abscesses and vesiculopustular plaques

    Cutaneous tuberculosis

    Numerous morphologic types are possible.

    Other dimorphic fungal infections

    Identification of causative organism required

  • Coccidioidomycosis

    Other disseminated fungal infections

    Identification of causative organism required

    Molluscum contagiosum

    Umbilicated papules

    Do not ulcerate or develop necrotic centers with crusting

    No systemic symptoms

    Basal cell carcinoma(s): pink papule form of coccidioidomycosis

    Basal cell carcinomas tend to be solitary.

    Cutaneous leishmaniasis

  • Cryptococcosis

    Other disseminated fungal infections

    Molluscum contagiosum

    Umbilicated papules

    Do not ulcerate or develop necrotic centers with crusting

    No systemic symptoms

    Acne

    Involves typical acne regions: face, chest, back, shoulders

    Comedones present

    Folliculitis

    Bacterial cellulitis, abscesses, or osteomyelitis

  • Histoplasmosis

    Other disseminated fungal infections

    Identification of causative organism required

    Bacterial abscesses

    Furunculosis

    Folliculitis

    Lepromatous leprosy

    Cutaneous tuberculosis or atypical mycobacterial infection

    Leishmaniasis

  • Paracoccidioidomycosis

    Mucocutaneous leishmaniasis

    Tuberculosis

    Syphilis

    Lymphoma

    Natural killer cell type

    Other disseminated fungal infections

    Identification of causative organism required

    Wegener granulomatosis

    May have hemoptysis and renal involvement

  • Sporotrichosis

    Other disseminated fungal infections

    Identification of causative organism required

    Leishmaniasis

    Syphilis

    Tertiary syphilis

    Cutaneous tuberculosis

    Atypical mycobacterial infection

    Sarcoidosis

    Ulcerations are rare in sarcoidosis

    Leprosy with Lucio’s phenomenon

    Seen in Mexico

    Ulcerations typically only on legs

    Rheumatoid arthritis (RA)

    Ulcerations uncommon in RA

  • Penicilliosis

    Other disseminated fungal infections, especially histoplasmosis

    Identification of causative organism required

    Molluscum contagiosum

    Umbilicated papules

    Do not ulcerate or develop necrotic centers with crusting

    No systemic symptoms

    Leishmaniasis

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • All disseminated fungal infections

    Complete blood count (CBC) with differential

    Basic metabolic panel

    Serum transaminases

    Blood cultures for bacteria and fungus

    HIV serology

  • Blastomycosis

    Urine antigen assay: 93% sensitivity, 79 to 89% specificity

    Role in diagnosis unclear

    Most helpful for those with disseminated or severe pulmonary disease

    Cross reacts with Histoplasma, Paracoccidioides, and Penicillium

    Direct observation of thick-walled, broad-based budding yeasts (5-7µm) from/in tissue

    KOH (potassium hydroxide): skin scrapings, sputum, biopsy specimen, purulent exudate

    Histopathology of skin specimen: Hematoxylin/eosin and fungal stains: pseudoepitheliomatous hyperplasia with neutrophilic abscesses; sense dermal mixed infiltrate with histiocytes, giant cells, and neutrophils; organisms are few in number

  • Coccidioidomycosis

    Direct observation of thick-walled unencapsulated spherules (5-200 µm) with endosporulation from/in tissue

    KOH/Calcofluor: sputum, cerebrospinal fluid (CSF), biopsy specimen, purulent exudate

    Histopathology of skin specimen: hematoxylin and eosin (H&E) and fungal stains: pseudoepitheliomatous hyperplasia with neutrophilic abscesses; dense dermal mixed infiltrate with histiocytes, giant cells, and neutrophils; organisms may be free in the tissue or within giant cells and tend to be present in large numbers

    Enzyme-linked immunoassays for IgM (acute disease) or IgG (disseminated disease, exposure)

    Should be confirmed with immunodiffusion tube precipitin and immunodiffusion compliment-fixation testing, respectively

    Higher titers reflect more extensive coccidioidal infection

    Increasing complement-fixing concentrations are associated with worsening disease

    Decreasing titers are useful in monitoring response to treatment

    Urine antigen assay

    Detects antigenuria in 70% of patients with disease; negative in 99% of those without fungal infection

    Cross-reacts in 10% of those with other systemic fungal infections

  • Cryptococcosis

    Direct observation of encapsulated yeast (4-12µm gelatinous reaction; 2-4µm granulomatous reaction) from/in tissue

    10% KOH and/or India ink: CSF, biopsy specimen, urine, exudate: increased difficultly with sputum and exudates

    Histopathology of skin specimen: H&E and fungal stains

    There are two reaction patterns, each may be seen in the same specimen

    Gelatinous: Numerous organisms in aggregates; little tissue reaction

    Granulomatous: pronounced mixed inflammation (histiocytes, lymphoid cells, giant cells, fibroblasts); areas of necrosis; much fewer organisms; within giant cells or histiocytes

    Capsule stains with Alcian blue, mucicarmine, methylene blue

    Yeast stains with special stains such as Periodic acid Schiff (PAS) or Grocott methenamine silver (GMS), PAS, Fontana-Masson

    Cryptococcal antigen testing of serum and/or CSF

    Accurate in the diagnosis of invasive infection

    Used to screen high-risk AIDS patients with CNS symptoms in high incidence areas

    Can be useful when immune reconstitution inflammatory syndrome (IRIS) is considered; Titer is stable or decreasing in IRIS

  • Histoplasmosis

    Direct observation of yeast (2-5µm) from/in tissue

    Wright-Giemsa, PAS, GMS: blood, bronchial washings, sputum, lymph node touch smears, CSF, ulcer exudate

    Histopathology of skin specimen: H&E and fungal stains

    Mixed granulomatous reaction

    Spores are seen within macrophages and giant cells.

    Suppurative inflammation may exist with ulceration.

    Elevated lactate dehydrogenase (LDH) greater than 600IU/mL in a patient with HIV, pulmonary infiltrates, and fever greater than 38°C

    CBC

    Anemia, leukopenia, thrombocytopenia in acute and subacute progressive disease

    Skin test

    Only 30 to 55% of patients with disseminated disease will have positive result

  • Paracoccidioidomycosis

    Direct observation of yeast (10-60µm) from/in tissue:

    Wet mount of exudate, purulent material, or sputum

    Histopathology of skin specimen: H&E and fungal stains

    Pseudoepitheliomatous hyperplasia or ulceration

    Granulomatous infiltrate with lymphocytes, histiocytes, and Langhan giant cells; polymorphonuclear neutrophils (PMNs) may also be present

    Characteristic yeast cells (Mariner wheel) are seen within giant cells.

    Suppurative inflammation may exist with ulceration.

    Antibody tests

    Complement fixation: positive in 97% of severe cases

    Titer improves with successful therapy

    Cross-reacts with Histoplasma capsulatum

    Immunodiffusion: highly specific, no titer to follow therapeutic response

    IgG, IgM, and IgE can be detected

    Responses vary during the disease course.

    Antigen testing: early diagnosis; helpful when evaluation of antibodies is equivocal

  • Sporotrichosis

    Direct observation of yeast (4-6µm) from/in tissue:

    Histopathology of skin specimen: H&E and fungal stains

    Granulomatous and suppurative infiltrate

    Characteristic cigar-shaped yeast cells are difficult to identify (may be more numerous in immunosuppressed patients).

    Asteroid bodies may be seen: PAS positive stellate shaped eosinophilic material surrounding fungi

  • Penicilliosis

    Direct observation of yeast (2-6µm) from/in tissue

    Smears of skin lesions, lymph nodes, or bone marrow

    Histopathology of skin specimen: H&E and fungal stains

    There may be granulomatous, suppurative, or necrotizing inflammatory reaction; the latter is most common in immunosuppressed patients.

    The organism may be seen within macrophages or extracellularly.

    Extracellular organisms are larger with a transverse septum.

Results that confirm the diagnosis

  • Blastomycosis

    Culture on Sabouraud’s agar at 25°C (white mold) and blood agar at 37°C (brown, wrinkled colony)

    Sputum, tissue (e.g., skin) biopsy, CSF, or urine

    Initial growth is more dependable at 30°C and is recommended.

  • Coccidioidomycosis

    Culture on Sabouraud agar

    Sputum, tissue (e.g., skin) biopsy, CSF

    Grows well at room temperatures

    Highly infectious at early stage of growth, 5-7 days

    Morphology not sufficient to definitely identify

    Detection of a specific coccidioidal antigen in an extract of the fungus

    Detection of a specific ribosomal ribonucleic acid (RNA) sequence using a deoxyribonucleic acid (DNA) probe

  • Cryptococcosis

    Culture: can grow on most bacterial and fungal media

    Sputum, tissue (e.g., skin) biopsy, CSF, urine, exudate, blood

    Growth can be seen as early as 3 days.

  • Histoplasmosis

    Histoplasma antigen assay by enzyme-linked immunosorbent assay (ELISA)

    Serum and/or urine

    Found in up to 90% of patients with acute progressive disseminated disease

    Urine samples cross-react with B. dermatitidis, C. immitis, Penicillium marneffei, and Paracoccidioides brasiliensis.

    Culture on Sabouraud agar at room and body temperature

    Use of polymerase chain reaction (PCR) probes for early identification of growth

    Blood, CSF, bone marrow, tissue biopsy, bronchoalveolar lavage, sputum

  • Paracoccidioidomycosis

    Culture: mycosel or Sabouraud agar with antibiotics and cycloheximide at 20-25°C

    Only positive in 85% of cases

    20-30 days incubation often required

    Often requires multiple samples on multiple media

  • Sporotrichosis

    Culture on Sabouraud agar may grow yeast as early as 3 days

    Definitive diagnostic method

  • Penicilliosis

    Culture at 30°C with conversion to yeast at 37°C

    Dimorphism is not seen in other genus of Penicillium

What imaging studies will be helpful in making or excluding the diagnosis of a disseminated fungal infection?

  • Blastomycosis

    Chest radiograph is reasonable in all patients who present with cutaneous lesions to evaluate for active pulmonary disease.

    Evaluation of other organs should be based on symptoms, signs, and clinical suspicion of involvement and comorbidities.

    computed tomography (CT) or magnetic resonance imaging (MRI) of head prior to lumbar puncture

  • Coccidioidomycosis

    Chest radiograph in disseminated disease is often negative.

    Evaluation of other organs should be based on symptoms, signs, and clinical suspicion of involvement and comorbidities.

    CT or MRI of head prior to lumbar puncture

  • Cryptococcosis

    Chest radiograph when symptoms are present

    CT or MRI of brain should be strongly considered in HIV-positive patients with skin manifestations, especially if CNS symptoms exist.

  • Histoplasmosis

    Chest radiography for acute and subacute progressive dissemination

    To evaluated for extent of dissemination

    Consider CT of chest, abdomen, and pelvis

    Abdominal ultrasound

    CT/MRI brain

  • Paracoccidioidomycosis

    Chest imaging with radiograph or CT scan to evaluate extent of pulmonary disease

    Evaluation of reticuloendothelial system is best made using gallium 67 nuclear medicine scan.

    Evaluation of other organs should be based on symptoms, signs, and clinical suspicion of involvement.

  • Sporotrichosis

    Technetium bone scan should be considered to evaluate for bone and joint involvement.

    Evaluation of other organs should be based on symptoms, signs, and clinical suspicion of involvement.

  • Penicilliosis

    Chest imaging with radiograph or CT scan to evaluate extent of pulmonary disease

    Evaluation of other organs should be based on symptoms, signs, and clinical suspicion of involvement.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has a disseminated fungal infection, what therapies should you initiate immediately?

  • Dermatology can be very useful in evaluating, diagnosing, and treating cutaneous manifestations of disseminated fungal infections.

  • Infectious disease consultation is recommended when disseminated fungal infection is suspected.

  • Orthopedic or General Surgery may be needed for debridement of osteomyelitis.

Key principles of therapy
  • When an immunosuppressed patient has skin involvement consistent with or suspicious for disseminated fungal infection, treating providers should assume the infection is disseminated and treat appropriately while working diligently to identify the causative organism.

  • Identification of the specific organism is imperative to proper treatment of the patient. Every effort should be made to correctly identify the causative organism.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

  • If the patient has severe systemic illness and is immunosuppressed, amphotericin, deoxycholate 0.7 to 1mg/kg/day, or lipid preparation 3 to 5mg/kg intravenously (IV) are good initial anti-infective choices once the appropriate samples have been obtained.

  • For patients who are mild to moderately ill without evidence of CNS disease, itraconazole 200mg three times a day for 3 days, then 200mg twice a day, would be reasonable.

  • In patients suspected of having CNS disease, a lipid formulation of amphotericin 5mg/kg IV daily would be the best choice.

See Table I. Treatment of specific pathogens

Table I.n

Treatment

Other key therapeutic modalities

  • Surgical debridement of osteomyelitis may be required to clear the infection.

  • Incision and drainage of cutaneous abscesses may be necessary

  • Attempts to improve patient immunity should be considered: HAART, reduction of prednisone to 20mg/day or less, etc.

  • Monitor for IRIS

    Cryptococcosis

    Worsening signs and symptoms in spite of negative cultures and/or falling antigen titers

    Management of increased intracranial pressure is imperative

    2-4 weeks’ course of prednisone at 0.5mg/kg/day may be beneficial

  • When to stop secondary prophylaxis therapy in most disseminated fungal infections in those with immunosuppression is not agreed on.

  • Coccidioidomycosis

    Echinocandins, specifically caspofungin, have been used successfully in experimental coccidioidal infections.

  • Cryptococcosis

    Recombinant interferon (IFN)-γ has been used successfully as adjunctive therapy for meningitis in patients with AIDS. Patients received 100 or 200μg three times per week, along with usually antifungal therapy.

  • Paracoccidioidomycosis

    Posaconazole appears effective.

What complications could arise as a consequence of a disseminated fungal infection?

What should you tell the family about the patient's prognosis?

  • Blastomycosis

    Adult respiratory distress syndrome (ARDS), empyema, diffuse pneumonitis

    Osteomyelitis, septic arthritis

    Recurrent disease, especially in those with HIV/AIDS

  • Coccidioidomycosis

    Diffuse pneumonitis with shock (seen in one third of HIV-infected individuals, cluster of differentiation (CD)4 often <100), pulmonary cavitation

    Osteomyelitis, septic arthritis

    Meningitis, CNS vasculitis, and abscesses requiring surgical therapy

    Hepatic involvement

  • Cryptococcosis

    Dementia, chronic meningitis

    Pneumothorax, pulmonary cavities, ARDS

    Keratitis, chorioretinitis, endophthalmitis

    Osteolytic bone lesions, arthritis

    Mycotic aneurysm, endocarditis

    Adrenal insufficiency

  • Histoplasmosis

    ARDS

    Anemia, leukopenia, thrombocytopenia

    Disseminated intravascular coagulation

    Reactive hemophagocytic syndrome

    Colonic mass, GI tract ulceration, and perforation

    Chorioretinitis

    Encephalopathy, histoplasmoma

    Adrenal insufficiency

  • Paracoccidioidomycosis

    Fibrotic lung disease, bullae, emphysema

    Cor pulmonale

    Adrenal insufficiency

  • Sporotrichosis

    Pulmonary cavities, lung abscesses

    Meningitis and parenchymal brain lesions

    Endophthalmitis

    Hepatosplenic involvement

    Fungemia

  • Penicilliosis

    Pulmonary cavities, hemoptysis

    Pericarditis

    Anemia, leukocytosis

  • Blastomycosis

    Mortality is as high as 30-40% in immunosuppressed patients.

    The patient will require long-term antifungal therapy.

  • Coccidioidomycosis

    Diffuse pulmonary pneumonia with shock in an immunodeficient patient has a high mortality rate.

    In HIV-positive patients with a CD4 count greater than 250cells/mL, the risk of serious complications and disseminated disease are similar to those without HIV.

    Untreated meningitis is nearly always fatal within 2 years of diagnosis.

    In those with nonmeningeal disseminated disease, recurrence rates from 25 to 35% have been reported, even in those without HIV,

    When the meninges are involved, 80% recur when therapy is discontinued,

  • Cryptococcosis

    There is a 10-25%, 6-12 month mortality with meningitis.

    Ability to control underlying condition (AIDS, malignancy) is the most important prognostic factor.

    Poor prognostic findings include:

    High burden of yeast at diagnosis: strong positive CSF India ink, cryptococcal antigen (CRAg) 1:1 to 024 or higher, poor inflammatory response in CSF

    Level of sensorium at diagnosis: lucid versus stuperous/coma

    Relapses may occur.

    IRIS:

    This may occur in HIV-positive patients, as well as those who are immunosuppressed for solid organ transplant.

    Increasing symptoms of cryptococcal meningitis: headache, altered mental status, fever, increased intracranial pressure

    Several weeks to 1 year after initiating highly active antiretroviral therapy (HAART) or decreasing immunosuppression in those with posttransplantation; mean 6 weeks after initiation of antifungal therapy

    This is not the result of failed antifungal therapy.

    May improve with corticosteroids if seriously ill

    Can occur with other infections as well

  • Histoplasmosis

    There is a 100% mortality in untreated acute PDH in immunosuppressed patients; treatment improves this to under 20%.

    Reactive hemophagocytic syndrome is nearly uniformly fatal despite aggressive treatment.

    In those with HIV, dyspnea, thrombocytopenia (<100,000), and elevated LDH are associated with death in the first 30 days of treatment.

    Without therapy, subacute and chronic PDH will progress to death.

  • Paracoccidioidomycosis

    There is a 17-25% mortality rate with the use of sulfonamides and/or amphotericin.

    There is a 20-25% relapse rate with sulfonamide use.

    Itraconazole has a 90% response rate.

    Attention is needed to an often present malnourished state.

  • Sporotrichosis

    Treatment will continue for several months; relapses are common.

    Although exact numbers are not known, mortality from disseminated disease in patients with HIV/AIDS remains significant.

  • Penicilliosis

    Treatment failure rates range from 22 to 63%.

    Long-term therapy is required to prevent relapse.

How do you contract a disseminated fungal infection and how frequent is this disease?

  • Blastomycosis is caused by Blastomyces dermatitidis, a dimorphic fungus. The exact incidence of disease is not entirely known. The fungus is endemic in the southeast United States and in the states along the Mississippi and Ohio Rivers and the Great Lakes region of both the United States and Canada. The infection is initiated by inhalation of conidia, most commonly associated with recreation or work outdoors. In the appropriate host (immunosuppressed patients with HIV/AIDS, solid organ transplant, etc.), the fungus can disseminate to other organs, the most common being the skin.

    The majority of cases of disseminated blastomycosis in those with AIDS are thought to be primary infections, although as many as 25% caused by reactivation of latent disease.

    It is felt that humidity may play a role in the growth of the organism in the soil given the predilection for waterways and association with infection following heavy rains and that decaying vegetation or wood may also be required.

    Some evidence suggests that beaver lodges may be a reservoir of the fungus.

    Transmission has been reported from men with prostatic involvement to their sexual partners (causing vaginal disease), as well as from a the bite of a dog suffering from pulmonary blastomycosis resulting in primary cutaneous blastomycosis

  • Coccidioidomycosis is caused by Coccidioides immitis and C. posadasii, dimorphic fungi. They are endemic to the Southwest United States and parts of Mexico and Central and South America, although the organisms are not spread uniformly in these regions. The initial infection is caused by inhalation of the arthroconidia into the lungs. Most people do not develop symptoms, whereas others have only mild flu-like illness. In others, the initial infection can be accompanied by high fevers, malaise, and head ache. The incubation period ranges from 1 to several weeks.

    Most new infections occur in the summer months with a second peak in Arizona during the month of October before the winter rains.

    Estimated incidence in the United States is approximately 3% per year in endemic regions.

    In immunocompetent hosts, dissemination occurs in less than 1% of infections.

  • Cryptococcosis is caused by Cryptococcus neoformans var. neoformans and C. neoformans var. gattii, dimorphic fungi found worldwide. The initial infection is caused by inhalation of yeast into the lungs. Most do not develop symptoms of initial infection and may clear the yeast effectively, whereas, in others, the yeast may lay dormant until loss of immunity occurs. In immunosuppressed hosts, pulmonary involvement can progress rapidly to death over days.

    Use of HAART has reduced the incidence of cryptococcosis in developed countries.

    Incidence remains very high in developing countries.

    Animals can develop cryptococcosis, but animal-to-human transmission has not been precisely established.

    Human-to-human transmission may occur with organ transplantation.

  • Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus found worldwide. The initial infection is caused by inhalation of microconidia into the lungs. The initial infection is characterized by mild symptoms, including cough, fever, night sweats, and hilar adenopathy. Some will develop severe pulmonary disease or nonspecific cutaneous findings, including erythema nodosum.

    Risk of infection increases when the soil is disrupted, especially by those involved recreationally or through employment.

    Disease is more common in men, but skin test positivity rates are similar among genders.

    Human-to-human transmission is not seen.

    Starling, chicken, and bat excreta have demonstrated spores.

    Approximately 25% of AIDS patients in endemic regions envelop disseminated disease (pre-HAART era data).

  • Paracoccidioidomycosis is caused by Paracoccidioides brasiliensis, a dimorphic fungus endemic to Central and South America, especially Brazil. The initial infection is caused by inhalation of conidia into the lungs, and it may be asymptomatic or only mildly so. A progressive disease occurs following the pulmonary infection that tends to be chronic, systemic, and progressive.

    The incidence in Brazil ranges from 10 to 30 cases per million population.

    Mortality rate is 1.4 cases per million per year.

    Up to 70% of farm workers in endemic areas test positive with skin testing.

    The male predominance in adulthood (15:1) is felt to be related to inhibition of transition to yeast by estrogen.

    It is isolated sporadically from nonhuman sources.

    Armadillos harbor the fungus.

    Human-to-human transmission does not appear to occur.

  • Sporotrichosis is caused by Sporothrix schenckii a dimorphic fungus found worldwide in soil, plants, and plant products. Most infections are caused by traumatic inoculation during work or recreational activities. Inhalation of spores has been documented rarely. In immunosuppressed patients, the risk of dissemination is higher involving the skin, lungs, bones, and joints, as well as viscera at times.

    Most cases come from tropical and subtropical regions.

    Common environmental exposures include straw, thorny plants, wood, and sphagnum moss.

    Transmission from several animals has been reported from armadillos, squirrels, horses, dogs, cats, pigs, mules, birds, and insects.

  • Penicilliosis is caused by Penicillium marneffei a dimorphic fungus found in soil and Bamboo rats from Southeast Asia and southern China. It is believed that inhalation of conidia into the lungs is the initial site of infection. Disseminated disease is seen most commonly in those infected with HIV who live in or have visited the endemic region.

    Bamboo rats may be involved with transmission of the yeast to humans, but their role has yet to be firmly established.

    Exposure through occupation or recreational activities to soil seems to be associated with subsequent disease.

What pathogens are responsible for this disease?

  • Blastomycosis is caused by Blastomyces dermatitidis a dimorphic fungus endemic in the southeast United States and in the states along the Mississippi and Ohio Rivers and the Great Lakes region of both the United States and Canada.

  • Coccidioidomycosis is caused by Coccidioides immitis (found mostly in California) and C. posadasii (found in other states in the United States and in other countries).

  • Cryptococcosis is caused by Cryptococcus neoformans var. neoformans and C. neoformans var. gattii, dimorphic fungi found worldwide.

  • Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus found worldwide.

  • Paracoccidioidomycosis is caused by Paracoccidioides brasiliensis, a dimorphic fungus endemic to Central and South America, especially Brazil.

  • Sporotrichosis is caused by Sporothrix schenckii, a dimorphic fungus found worldwide in soil, plants, and plant products.

  • Penicilliosis is caused by Penicillium marneffei, a dimorphic fungus found in soil and bamboo rats from Southeast Asia and southern China.

How do these pathogens cause a disseminated fungal infection?

  • Blastomycosis

    Blastomyces dermatitidis cause disease primarily through environmental exposure to conidia. Inhalation of conidia is the primary route of infection. The conidia convert to yeast forms in the lung.

    Once conidia convert to yeast, the organism is much more difficult to kill, a common finding in other dimorphic fungi.

    The thick wall of the yeasts may be anti-phagocytic.

    The adhesion glycoprotein, BAD-1, likely acts as the predominant virulence factor of the yeast form.

    BAD-1 inhibits compliment activation required for PMN phagocytosis and killing.

    BAD-1 inhibits TNF-α induction.

    BAD-1 promotes a type 2 T helper (Th2) response with decreased interleukin (IL)-12 and IFN-γ and an increase in IL-10.

  • Coccidioidomycosis

    Coccidioides immitis and C. posadasii cause disease primarily through environmental exposure to arthroconidia. There appears to be no difference in the clinical diseases caused by the two species, and susceptibilities to antifungal agents are similar. Inhalation of the arthroconidia is the primary route of infection, and a single arthroconidium can naturally acquire pulmonary infection. As the arthroconidia, which become lodged in the distal bronchioles, become spherules, and inflammation results. To disseminate, the spherules may enter the pulmonary vascular system or the lymphatic system after being phagocytosed by macrophages.

    In patients with disseminated disease, there is decreased IFN-γ from their peripheral mononuclear cells when exposed to coccidioidal antigens.

    There does not seem to be an accompanying increase in Th1 cytokines, however.

    Neutrophils appear to react to coccidioidal infection but are not fungicidal.

    Natural killer cells reduce fungal viability, but this appears to be lost once spherules mature.

    Although a humoral response is seen, it appears to have little effect on pathogenicity of the organism.

  • Cryptococcosis

    Cryptococcus neoformans var. neoformans and C. neoformans var. gattii cause disease primarily through environmental exposure to the organism.

    Virulence factors:

    Capsule: the attached capsule has been shown to act as an antiphagocytic barrier, deplete complement, produce antibody unresponsiveness, interfere with antigen presentation, alter cytokine secretion, and enhance HIV replication

    Melanin may act as an antioxidant

    High-temperature growth ability

    A Th1 cellular immune response is required for adequate control of the disease: as CD4 cell count decreases to less than 100, a sparse inflammatory response occurs at the site of infection

    Humoral immunity is important to reduce yeast burden and improve survival; it enhances phagocytosis, natural killer cell function, and clearing of capsular polysaccharide. <

  • Histoplasmosis

    Histoplasma capsulatum causes disease primarily through environmental exposure to the organism in the soil or bird/bat droppings.

    Transition from mycelial to yeast form is essential for infectivity.

    Once transitioned, the yeast, within macrophages, enters the lymphatics to the reticuloendothelial system where they grow.

    Macrophages from HIV infected patients engulf less yeast and inhibit yeast growth less well than those from patients without HIV.

    Cellular immunity is required for control and clearance of the infection.

    T-cells release cytokines to promote phagocytosis.

    TNF-α and IFN-γ are likely important.

    Coordinate granuloma formation appears important.

    Mechanisms of reactivation are not completely understood.

    TNF-α may play a role.

  • Paracoccidioidomycosis

    Paracoccidioides brasiliensis causes disease primarily through environmental exposure to the organism in endemic regions, although microniche has not been established.

    The fungus may lay dormant for many years only to reactivate as the immune system wanes from HIV/AIDS or malnutrition.

    The patient’s immune system influences disease severity and clearance of the fungus.

    Innate immunity inhibits fungal growth to control the initial infection.

    A strong Th1 response is required to control the fungus.

    Macrophages act as the key cell to kill both conidia and yeast.

    Well-formed granulomas are required.

    Th2 type response is seen in patients with disseminated disease.

    Increased IL-4, -5, -10

    Decreased IL-12, IFN-γ

    IgA, IgE, and IgG are significantly increased in the juvenile form and may have accompanying eosinophilia.

  • Sporotrichosis

    Sporothrix schenckii causes disease primarily through direct inoculation from minor trauma associated with soil, plants, and plant products.

    The host immune response helps to determine the extent of disease.

    The fungal resistance and susceptibility mechanisms are not understood.

  • Penicilliosis

    Penicillium marneffeii causes disease primarily through environmental exposure to the organism in the endemic region. It is thought that inhalation of the conidia into the lungs is the initial site of infection.

    The organism’s virulence factors and host immune response are not elucidated.

What other clinical manifestations may help me to diagnose and manage a disseminated fungal infection?

  • Blastomycosis

    The lesions tend to progressively increase in size with crusting and associated seropurulent exudate.

    Should be considered with:

    Exposure to an endemic location

    Appropriate clinical setting

  • Coccidioidomycosis

    Lesions favor the face, especially the melolabial folds.

    Incubation period is most commonly 1 to 3 weeks.

    Should be considered with:

    History of travel to or residence in an endemic region

    Appropriate clinical setting

    Complications and dissemination usually occur within weeks to a few months after the initial infection but can arise years after exposure with immunosuppression from medications, underlying malignancy, or HIV/AIDS.

  • Cryptococcosis

    Cutaneous manifestations can resemble many other diseases; a high index of suspicion is required for diagnosis.

  • Histoplasmosis

    Cutaneous manifestations can resemble many other diseases; a high index of suspicion is required for diagnosis.

    The oral manifestations, along with cutaneous disease, should be helpful in raising histoplasmosis as a possible diagnosis in the right clinical setting.

  • Paracoccidioidomycosis

    The prominent mucosal involvement, accompanied by pulmonary and cutaneous findings in a patient from an endemic region, should raise the possibility of this diagnosis

  • Sporotrichosis

    Extensive cutaneous involvement with osteoarticular disease in a patient with the appropriate exposure should raise the possibility of this diagnosis.

    The pathology specimen will often appear consistent with a fungal infection, but the organism is not seen even with special stains; a high index of suspicion is necessary to continue to consider sporotrichosis.

  • Penicilliosis

    Disseminated fungal infection in an HIV-positive patient from or who visited the endemic region should strongly suggest this diagnosis.

What other additional laboratory findings may be ordered?

  • Blastomycosis

    Chemiluminescent DNA probe may be used for early identification of mycelial growth in culture.

    Serum complement fixation, immunodiffusion, and ELISA assays are available but, because of low sensitivity and specificity, should only be used to stimulate further evaluation in a patient suspected of having blastomycosis, not for definitive diagnosis.

  • Coccidioidomycosis

    PCR may be used on sputum or other tissue samples for identification but is not commonly available.

    Cytology staining may be used to identify spherules in sputum.

  • Histoplasmosis

    PCR of tissue samples may be helpful but is not commonly available.

  • Paracoccidioidomycosis

    PCR of sputum or tissue sample may be helpful but is not commonly available.

  • Sporotrichosis

    Serum agglutination tests have been developed but are not commonly used in diagnosis.

  • Penicilliosis

    Serum antibody and antigen testing is still experimental.

    Serum galactomannan testing for Aspergillus was positive in two-thirds of patients with penicilliosis in one study.

How can a disseminated fungal infection be prevented?

  • Coccidioidomycosis

    Primary prophylaxis is not recommended for those with a CD4 greater than 250, regardless of region of residence.

    In those with CD4 less than 250 and residing in an endemic region yearly IgM and IgG testing is reasonable.

    In those with a positive test, most recommend treating with fluconazole or itraconazole.

  • Cryptococcosis

    At risk individuals should avoid contact with birds and soils contaminated with bird droppings.

    Antifungal prophylaxis is not recommended in the United States or Europe. It may be considered in areas where disease burden is high with limited HAART availability.

  • Histoplasmosis

    Itraconazole 200mg/day is useful in HIV positive patients with CD4 less than 150 cells/mL.

For further details on the systemic manifestations, pathogenesis and treatment please see the individual chapters for each fungus discussed herein.

  • Blastomycosis

  • Coccidioidomycosis

  • Cryptococcosis

  • Histoplasmosis

  • Paracoccidioidomycosis

  • Penicilliosis

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Ameen, M, Robles, WS., Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Coccidioidomycosis”. Treatment of skin disease comprehensive therapeutic strategies. 2010. pp. 149-51. (This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A, double-blind studies; B, clinical trial with greater than or equal to 20 subjects; C, clinical trial with less than 20 subjects; D, case series of more than 4 subjects; and E, anecdotal case reports.)

Ameen, M, Robles, WS., Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Histoplasmosis”. Treatment of skin disease comprehensive therapeutic strategies. 2010. pp. 311-3. (This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A, double-blind studies; B, clinical trial with greater than or equal to 20 subjects; C, clinical trial with less than 20 subjects; D, case series of more than 4 subjects; and E, anecdotal case reports.)

James, WD, Berger, TG, Elston, DM.. Andrews' diseases of the skin. 2011. pp. 304-19. (This is an excellent review of the salient features of mucocutaneous candidiasis.)

Robles, WS, Ameen, M., Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Blastomycosis”. Treatment of skin disease comprehensive therapeutic strategies. 2010. pp. 101-3. (This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A, double-blind studies; B, clinical trial with greater than or equal to 20 subjects; C, clinical trial with less than 20 subjects; D, case series of more than 4 subjects; and E, anecdotal case reports.)

Robles, WS, Ameen, M., Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Cryptococcosis”. Treatment of skin disease comprehensive therapeutic strategies. 2010. pp. 152-4. (This book evaluates the evidence for treatments for many different diseases of the skin. It grades them as A, double-blind studies; B, clinical trial with greater than or equal to 20 subjects; C, clinical trial with less than 20 subjects; D, case series of more than 4 subjects; and E, anecdotal case reports.)

Smith, JA, Kauffman, CA.. “Blastomycosis”. Proc Am Thorac Soc. vol. 7. 2010. pp. 173-80.

Sobera, JO, Elewski, BE., Bolognia, JL, Jorizzo, JL, Rapini, RP. “Fungal diseases”. Dermatology. 2008. pp. 1152-61. (This is a review of epidemiology, clinical manifestations, pathology, and treatment of numerous fungal infections that involve the skin.)

Bennett, JE, Dolin, R, Blaser, MJ.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 2015. (The most recent edition of this standard textbook contains excellent reviews on all pathogens mentioned here, see section O. Mycoses, chapters 256 to 271.)

ICD-9 Codes

114: Coccidioidomycosis

115: Histoplasmosis

116: Blastomycotic infection

117: Other mycosis; 118: Opportunistic mycosis

  • Cryptococcosis

  • Paracoccidioidomycosis

  • Penicilliosis

Jump to Section