Disseminated fungal infection

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

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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

Verrucous, crusted plaque with red-brown border

Umbilicated skin-colored papules, central crust

Large painful ulceration overlying painful ankle joint

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

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 (T_h2) 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 T_h1 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 T_h1 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 T_h1 response is required to control the fungus.

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

Well-formed granulomas are required.

T_h2 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

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Infectious Diseases

Disseminated fungal infection

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

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