Primary Fungal Infections
Etiology: dimorphic fungus (mycelial form in environment, yeast form in host); endemic to Ohio and Mississippi River valleys; Natural habitat is soil, decaying buildings, and bird droppings.
Pathogenesis: Inhalation of micronidia (small spores) Þ germinate into yeast in pulmonary tissue Þ disseminate by lymphohematogenous route Þ 2 to 3 weeks after infection, neutrophils, NK cells and reticuloendothelial system contain the pathogen.
Clinical Disease: depends on:
- (1) intensity of initial inoculum
- (2) host immune status
- (3) pre-existing pulmonary disease
Diagnosis: Histopathology and special stains are important. Includes cultures, detection of antibody, immunodiffusion testing and immunologic testing.
- Attack rate is near 100% in endemic areas, but most infections are self-limited.
- White older males with lung conditions develop chronic pulmonary histoplasmosis which resembles tuberculosis.
- Immunocompromised hosts most frequently develop disseminated histoplasmosis.
Etiology: dimorphic soil fungus endemic to Southwestern US, Mexico and South America; cycles of heavy rains followed by drought facilitate the growth and dispersion of this pathogen.
Pathogenesis: Inhalation of spores (arthroconidia) Þ germination into spherules (which contain endospores) in lung tissues Þ cell mediated immune response occurs as in the previous fungus.
Clinical Disease: Infection is asymptomatic in 60%, while 40% experience self-limiting flu-like illness for 1 to 3 weeks (dry cough, pleuritic chest pain, fever, sweats, anorexia); Complications include formation of immune complexes (erythema nodosum, macular rash, erythema multiforme); 5% will have persisting nodules or thin walled cavitaries in chest; Immunocompromised Þ pulmonary disease or disseminated disease (bone, soft tissues, meninges).
Diagnosis: spherules are diagnostic (on histopathology). Includes cultures, serology and skin testing.
Etiology: dimorphic fungus that inhabitates soil with decaying vegetations or decomposing woods found in Southeastern US, the Midwest, and Northern Canada. Growth is enhanced in warm humid areas.
Pathogenesis: Inhalation of conidia Þ intense pulmonary inflammation Þ yeast form which is resistant to phagocytosis and killing Þ cell mediated immune response develops for containment of infection and prevention of dissemination
Clinical Disease: Self-limited in 50% or self-limited flu-like illness. Not a common disease of the immunocompromised. Lobar or segmental consolidation. Pulmonary disease may be progressive. Extrapulmonary manifestations include soft tissue abscesses, genitourinary disease, and osteomyelitis.
Diagnosis: broad-based buds (on histopathology). Cultures are positive.
used for the last 30 years against invasive mycosis and still remains treatment of choice despite its toxicity
binds to ergosterol in fungal cell wall Þ steric hinderance
induces oxidative damage Þ fungal cell death
Not absorbed orally so given topically, intravenously, or intrathecally
First line treatment for deep fungal infections in severely ill patients
Side effects include nephrotoxicity, fever, chills, nausea, vomiting, hypotension, thrombophlebitis
Azoles (Fluconazole, Itraconazole, Miconazole, Ketoconazole):
non-toxic, readily bioavailable to the tissues, and active against a variety of fungi.
Inhibit P-450 cytochrome system which is needed for synthesis of ergosterol of the cell membrane
Miconazole – 1st systemic azole, seldom used because of toxicity and lack of efficacy.
Ketoconazole – oral agent effective in treatment of candidal stomatitis and esophagitis. Side effects include endocrine hypoplasia and hepatotoxicity.
Fluconazole, Itraconazole (new azoles) – do not affect mammalian sterol synthesis. Well absorbed and distributed (including CSF) and excreted in urine. Fluconazole used for Coccidiomycosis and Itraconazole used for Histoplasmosis and Blastomycosis.