Systemic Mycoses Donna Patey, MD

At the end of this session, students must be able to: List the natural habitats, infections and recognition of the tissue form and the mycelial form (in culture) of systemic dimorphic pathogenic fungi: Histoplasma, Blastomyces, Paracoccidioides and Coccidioides. Understand the principle of antifungal therapy, important antifungal agents and their brief mechanism of action.

Systemic Mycoses Inhalation of the spores of dimorphic fungi that have their mold forms in the soil. Within the lungs, the spores differentiate into yeasts or other specialized forms. Most lung infections are asymptomatic some persons - disseminated disease develops in which the organisms grow in other organs, cause destructive lesions, and may result in death. Infected persons do not communicate these diseases to others.

COCCIDIOIDES IMMITIS Disease: Coccidioidomycosis.  Properties: dimorphic fungus exists as a mold in soil and as a spherule in tissue. (arthrospores) cells at the tip of the hyphae differentiate into asexual spore which germinate in the soil to form new hyphae if inhaled the arthrospores differentiate into spherules in tissue.

COCCIDIOIDES IMMITIS Transmission: Arthrospores are very light and carried by the wind. Inhaled and infect the lungs. Pathogenesis: Lungs - arthrospores form spherules (large with a thick, doubly refractive wall, filled with endospores). Upon rupture of the wall, endospores are released and differentiate to form new spherules. Organism spreads via the bloodstream. Granulomatous lesions can occur in virtually any organ but are found primarily in bones and the central nervous system (meningitis).

COCCIDIOIDES IMMITIS: Dissemination Occurs in people who have a defect in cell-mediated immunity. - One way to determine whether a person has produced adequate cell-mediated immunity to the organism is to do a skin test. can occur in almost any organ; the meninges, bone, and skin are important sites. incidence of dissemination in persons infected with C. immitis is 1%, although the incidence in Filipinos and African Americans is 10 times higher. Women in the third trimester of pregnancy also have a increased incidence of dissemination.

COCCIDIOIDES IMMITIS: Skin Test In infected persons, skin tests with fungal extracts (coccidioidin or spherulin) cause at least a 5-mm induration 48 hours after injection (delayed hypersensitivity reaction). positive skin test - reaction has developed sufficient immunity to prevent disseminated disease from occurring. Skin Test becomes positive within 2—4 weeks of infection and remain so for years but are often negative (anergy) in patients with disseminated disease. serologic tests - IgM and IgG precipitins appear within 2—4 weeks of infection and then decline in subsequent months. Complement-fixing antibodies occur at low titer initially, but the titer rises greatly if dissemination occurs. Not used to diagnose acutely ill patients, but rather to determine whether a person has been exposed to Coccidiodes in the past.

COCCIDIOIDES IMMITIS: Clinical Findings: Infection of the lungs is often asymptomatic and is evident only by a positive skin test and the presence of antibodies. Some infected persons have an influenzalike illness with fever and cough. 50% have changes in the lungs as seen on x-ray, and 10% develop erythema nodosum. This syndrome is called “valley fever” or “desert rheumatism” it tends to subside spontaneously.

COCCIDIOIDES IMMITIS: Erythema nodosum (EN) red, tender nodules on extensor surfaces such as the shins. delayed (cell-mediated) hypersensitivity is an indicator of a good prognosis. no organisms in these lesions; they are not a sign of disseminated disease. EN is not specific for coccidioidomycosis; it occurs in other granulomatous diseases, eg, histoplasmosis, tuberculosis, and leprosy.

Coccidioides immitis Title: Lesion on knee Disease(s): Coccidioidomycosis Legend: Lesion on knee resulting from dissemination from the lungs. Genus/Species: Coccidioides immitis Image Type: Clinical Presentation

Erythema Nodosum Erythema nodosum (EN) (red nodules) is an inflammation of the fat cells under the skin (panniculitis). It causes tender nodules[1] that are usually seen on both shins. EN is an immunologic response to a variety of different causes. Erythema nodosum usually resolves itself 3-6 weeks after an event, either internal or external to the body, that initiates a hypersensitivity reaction in subcutaneous fat [2][3]. EN is frequently associated with fever, malaise, and joint pain and inflammation. It presents as tender red nodules on the shins that are smooth and shiny. The nodules may occur anywhere there is fat under the skin, including the thighs, arms, trunk, face, and neck [4][5]. The nodules are 1-5 cm in diameter, and individual nodules may coalesce to form large areas of hardened skin. As the nodules age, they become bluish purple, brownish, yellowish, and finally green, similar to the color changes that occur in a resolving bruise. The nodules usually subside over a period of 2–6 weeks without ulceration or scarring[6]. Dermatophytids are similar skin lesions that result from a fungus infection such as ringworm in another area of the body.

Coccidioides immitis Title: Erythema nodosum Disease(s): Coccidioidomycosis Legend: The rash is a immunologic response to the fungus. It is most commonly seen in caucasion women. Genus/Species: Coccidioides immitis Image Type: Clinical Presentation

COCCIDIOIDES IMMITIS: Laboratory Diagnosis In tissue specimens, spherules are seen microscopically. Cultures on Sabouraud’s agar incubated at 25 0C show hyphae with arthrospores. Cultures are highly infectious; precautions against inhaling arthrospores must be taken. In infected persons, skin tests with fungal extracts (coccidioidin or spherulin) cause at least a 5-mm induration 48 hours after injection (delayed hypersensitivity reaction). Serology is used today instead of culture: complement fixation test.

COCCIDIOIDES IMMITIS: Treatment: Amphotericin B is used for persisting lung lesions or disseminated disease. Nephrotoxicity and magnesium and potassium wasting. Ketoconazole is also effective in lung disease.   Prevention: There are no means of prevention except avoiding travel to endemic areas.

Definitions: Left Shift Increased number of immature neutrophils (band forms) Suggests acute inflammation

Temp. (F)– Children 0-3 months: 99.4 Children 6 months to 1 year: 99.7 Children 1 year to 3 years: 99.0 Children 3 years to 5 years: 98.6 Children 5 years to 9 years: 98.3 Children 9 years to 13 years: 98.0 Children 13 year to adult: 97.8 - 99.1 Normal body temperature varies over a narrow range of 36°C (98.6°F) to 37.5°C (99.5) HR – newborn infants; 100 to 160 beats per minute children 1 to 10 years; 70 to 120 beats per minute children over 10 and adults; 60 to 100 beats per minute well-trained athletes; 40 to 60 beats per minute pH – 7.35-7.45 WBC - 4500-11,000/mm3 BP – 120/80 pCO2 – 33-45 mmHg RR – 20 breaths/min. pO2 – paO2 of 60 to 80 mm is labeled as mild hypoxia < 60 is moderate and < 40 mm of Hg is labeled as severe hypoxia. SaO2 - > 70% is acceptable. Saturation is probably more useful than the pO2

Geographic Location is Important for these three

Left Shift an acute bacterial infection, will cause an increase in both the total number of mature neutrophils and the less mature bands or stabs to respond to the infection. "shift to the left" This term is a holdover from days in which lab reports were written by hand. Bands or stabs, the less mature neutrophil forms, were written first on the left-hand side of the laboratory report. Today, the term "shift to the left" means that the bands or stabs have increased, indicating an infection in progress. For example, a patient with acute appendicitis might have a "WBC count of 15,000 with 65% of the cells being mature neutrophils and an increase in stabs or band cells to 10%". This report is typical of a "shift to the left", and will be taken into consideration along with history and physical findings, to determine how the patient's appendicitis will be treated.

Memory Tool: The Coyboy “cocks” his gun in the old Southwest and “HItS” and “BLASTs” the Mississippi River Valley.

HISTOPLASMA CAPSULATUM Disease: histoplasmosis. Properties: H capsulatum is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue.

HISTOPLASMA CAPSULATUM: It forms two types of asexual spores: (1) Tuberculate macroconidia: with typical thick walls and fingerlike projections that are important in laboratory identification (2) Microconidia: which are smaller, thin, smooth-walled spores that, if Inhaled, transmit the infection.

HISTOPLASMA CAPSULATUM: Transmission: Inhalation of airborne asexual spores (microconidia)   Pathogenesis & Clinical Findings: Inhaled spores are engulfed by macrophages and develop into yeast forms. In tissues H capsulatum occurs as an oval budding yeast inside macrophages!!!!

Histoplasma

Histoplasma spreads widely throughout the body liver and spleen most infections remain asymptomatic, and the small granulomatous foci heal by calcification. With intense exposure (eg, in a chicken house or bat-infested cave), pneumonia may become clinically manifest. Severe disseminated histoplasmosis develops in a small minority of infected persons, especially infants and individuals with reduced cell-mediated immunity, such as AIDS patients. In AIDS patients, ulcerated lesions on the tongue are typical of disseminated histoplasmosis.

Histoplasma capsulatum Title: Histoplasmosis Disease(s): Histoplasmosis Legend: Discoloration of the skin caused by the fungus. Genus/Species: Histoplasma capsulatum Image Type: Clinical Presentation

HISTOPLASMA CAPSULATUM: Laboratory Diagnosis In tissue biopsy specimens or bone marrow aspirates, oval yeast cells within macrophages are seen microscopically. Cultures on Sabouraud’ s agar show hyphae with tuberculate macroconidia. Tests that detect Histoplasma antigens by radioimmunoassay and Histoplasma RNA with DNA probes are also useful. In immunocompromised patients with disseminated disease, tests for antigens in the urine are especially useful because antibody tests may be negative.

HISTOPLASMA CAPSULATUM: Skin test uses histoplasmin (a mycelial extract) becomes positive, ie, shows at least 5 mm of induration within 2—3 weeks after infection and remains positive for many years.  

HISTOPLASMA CAPSULATUM: Treatment: No therapy needed in asymptomatic or mild primary infections. progressive lung lesions - oral itraconazole In disseminated disease, amphotericin B is the treatment of choice. In meningitis, fluconazole - penetrates the spinal fluid well. Oral itraconazole - treat pulmonary or disseminated disease, as well as for chronic suppression in patients with AIDS. Prevention: There are no means of prevention except avoiding exposure in areas of endemic infection.

BLASTOMYCES Disease: blastomycosis Properties: B. dermatitidis is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue. The yeast is round with a doubly refractive wall and a single broad-based bud.

BLASTOMYCES Transmission: Inhalation of airborne asexual spores.   Pathogenesis & Clinical Findings: Infection via the respiratory tract. Asymptomatic or mild cases are rarely recognized. Dissemination - ulcerated granulomas of skin, bone, or other sites. Laboratory Diagnosis: In tissue biopsy specimens, thick-walled yeast cells with single broad-based buds are seen microscopically. Hyphae with small pear-shaped conidia are visible on culture. Skin test lacks specificity and has little value. Serologic tests have little value.

Skin lesion following dissemination from the lungs.

BLASTOMYCES: Treatment: Itraconazole is the drug of choice for most patients. Amphotericin B should be used to treat severe disease. Surgical excision may be helpful.   Prevention: There are no means of prevention.

PARACOCCIDIOIDES BRASILIENSIS   Disease: paracoccidioidomycosis P brasiliensis is a dimorphic fungus that exists as a mold in soil and as a yeast in tissue. The yeast is thick-walled with multiple buds (pilot wheel), in contrast to B. dermatitidis, which has a single bud

PARACOCCIDIOIDES BRASILIENSIS Transmission: Inhalation of airborne asexual spores.   Pathogenesis: The spores are inhaled, and early lesions occur in the lungs. Asymptomatic infection is common. Alternatively, oral mucous membrane lesions, lymph node enlargement, and sometimes dissemination to many organs develop. Laboratory Diagnosis: In pus or tissues, yeast cells with multiple buds (pilot’s wheel) are seen microscopically. A specimen cultured for 2—4 weeks may grow typical organisms. Skin tests are rarely helpful. Serologic testing shows that when significant antibody titers (by immunodiffusion or complement fixation) are found, active disease is present. Treatment: The drug of choice is itraconazole taken orally for several months. Prevention: There are no means of prevention.

Important Summary Sporothrix schenckii: Rose Gardener’ Disease. Local pustule or ulcer with nodules along the draining lymphatics; round or cigar-shaped budding yeasts COCCIDIOIDES IMMITIS: Red, tender nodules on extensor surfaces such as the shins (Erythema Nodosum). Hyphae with arthrospores in culture; spherules in tissue HISTOPLASMA CAPSULATUM: Birds and Bats. Oval budding yeast inside macrophages. BLASTOMYCES: Single broad-based buds are seen microscopically. PARACOCCIDIOIDES BRASILIENSIS: yeast cells with multiple buds (pilot’s wheel) TINEA: 10% KOH on a glass slide show hyphae under microscopy. Tinea capitus, Wood’s Lamp.