Systematic-Mycoses

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Fungi Causing Systemic Mycoses : 

Fungi Causing Systemic Mycoses Majority causes in apparent infection Causative organism are dimorphic fungi

True Systemic (Endemic) Mycoses : 

True Systemic (Endemic) Mycoses Coccidioidomycosis Histoplasmosis Blastomycosis Paracoccioidomycosis

General Features : 

General Features Causative Agents thermally dimorphic fungi that exist in nature, soil Geographic distribution varies Inhalation  pulmonary infection  dissemination No evidence of transmission among humans or animals Otherwise healthy individuals are infected

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Blastomycosis (Gilchrist’s Disease) (North-American Blastomycosis) Chicago Disease A chronic infection characterized by formation of suppurative and granulomatous lesion found mainly in the lungs and disseminate throughout the body MOT = Inhalation of airborne spore (conidia)

North American Blastomycosis : 

North American Blastomycosis Cutaneous form exhibits sporotricoid spread and if chronic almost always originates in the lungs. Most common site of dissemination from lung is the skin. (80% of cases) Mainly on hands and feet, nodular, draining sinuses or papillomatous and crusted. LESIONS ARE USUALLY MULTIPLE

North American BlastomycosisDistribution : 

North American BlastomycosisDistribution Endemic in North, Central and Southeastern USA, Quebec province of Canada V. few cases from India 1st in 1983 (U.P.) Scattered cases Mumbai and Vellore.

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Blastomyces dermatitides Characteristics: Dimorphic Can exist as mold in soil, yeast in tissue Yeast form is round-shaped with a thick refractile wall and a single broad-based bud Natural habitat is soil rich in organic material

Pathogenesis : 

Pathogenesis Infection occurs mainly in the respiratory tract Inhaled conidia differentiate into yeast cell which initially cause abscesses Followed by formation of granuloma Dissemination is rare, but when it occurs skin and bone are the most commonly involved.

Clinical features : 

Clinical features Weight loss Fever Malaise Fatigue More in males and adults

Types : 

Types Pulmonary –self limiting Cutaneous-most common, over exposed parts like face, neck and hands. Disseminated-in AIDS,transplant, immunocompromised Miscellaneous-rare eg laryngeal, CNS, osteomyelitis

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Laboratory Diagnosis: Samples:- sputum,BAL, biopsy, pus from abcess Direct microscopic examination (KOH mount) and calcoflour white = demonstrate characteristic thick walled “yeast cell with single broad-based bud”

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Broad Based Budding yeast Blastomyces dermatitides KOH will show single or singly budding ovoid/ spherical cells with refractile walls

2.Culture is difficult, Sabouraud’s dextrose agar, Mycosel and a brain-heart infusion agar to which blood has been added. grows as fluffy, brownish to white fungus which produces pyriform spores : 

2.Culture is difficult, Sabouraud’s dextrose agar, Mycosel and a brain-heart infusion agar to which blood has been added. grows as fluffy, brownish to white fungus which produces pyriform spores

Lab diagnosis cont… : 

Lab diagnosis cont… 3. Hypersensitivity test – Blastomycin test 4. Serological test not useful 5. DNA probe assay is commercially available 6. Animal pathogenicity-g.pig,rats,hamster

Treatment : 

Treatment Itraconazole (drug of choice)200-400mg/day for 6mths Amphotericin B - used to treat severe cases Surgical excision helpful Prevention: No vaccine or prophylactic drug available

North American Blastomyces BLASTO = BROAD BASED BUDS : 

North American Blastomyces BLASTO = BROAD BASED BUDS TX: Itraconazole, Amphotericin B, Fluconazole

Coccidioidomycosis : 

Coccidioidomycosis

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Coccidiodes immitis Coccidiodomycosis San Joaquin Valley Fever, Desert Fever, Desert Rheumatism Endemic in southwest USA, NW Mexico and parts of Central and South America It is a normal inhabitant of sandy and somewhat saline soil Disease simulates pneumonia wherein large part of the lung becomes consolidated

History : 

History It is the oldest of the major human mycoses First case reported by a medical student Alejandro Posadas in 1892 Coccidia-derived from protozoa Immitis-im+mitis=not mild

Characteristics : 

Characteristics Dimorphic fungus that exist as: Spherules in tissues containing endospores Mold at 250C in soil which forms hyphae with alternating arthrospores Natural habitat is soil

Pathogenesis : 

Pathogenesis MOT: Inhalation of airborne arthrospores Arthrospores inhaled to the lungs  forms spherules filled with endospore  rupture  endospore release  forms new spherules  disseminate throughout the body

Coccidioidomycosis occurs in two forms: : 

Coccidioidomycosis occurs in two forms: 1) Mild lung infection (acute primary coccidioidomycosis): The infection disappears without treatment. It accounts for about half of cases. 2) Severe, progressive infection (progressive coccidioidomycosis): The infection spreads throughout the body and is often fatal. It is more common among men and among blacks, Filipinos, and Native Americans. This form is more likely to occur in AIDS pts or in immunosuppression of the immune system.

Symptoms : 

Symptoms Most people with acute primary coccidioidomycosis have no symptoms. If symptoms develop, they appear 1 to 3 weeks after people are infected. Symptoms are usually mild and often flu-like. They include a cough, fever, chills, chest pain, and sometimes shortness of breath. The cough may produce sputum and occasionally blood..

Symptoms cont… : 

Symptoms cont… Some people develop desert rheumatism, which includes Conjunctivitis Arthritis and Formation of skin nodules (erythema nodosum). These effects, which can be painful and are allergic reactions to the fungus

Severe, progressive infection : 

Severe, progressive infection Unusual and may develop weeks, months, or even years after the initial infection. Symptoms include mild fever and loss of appetite, weight, and strength. The lung infection may worsen, causing increased shortness of breath. The infection may also spread from the lungs to the bones, joints, liver, spleen, and kidneys. Joints may become swollen and painful.

Severe, progressive infection cont.. : 

Severe, progressive infection cont.. The fungi can also infect the brain and the tissues covering the brain (meninges), causing meningitis. This infection is often chronic, causing headaches, confusion, loss of balance, double vision, and other problems. Untreated meningitis is always fatal

Tissue section showing typical endosporulating spherules of Coccidioides immitis. Young spherules have a clear centrewith peripheral cytoplasm and a prominent thick-walled : 

Tissue section showing typical endosporulating spherules of Coccidioides immitis. Young spherules have a clear centrewith peripheral cytoplasm and a prominent thick-walled

Serology : 

Serology Tube precipitin (IgM) test Complement fixation Skin Test ( Coccidioidin and Spheruline antigens) Negative results may rule out the diagnosis ELISA-to detect IgM Abs positve in 85% of cases and are found within the 1st wk of illness DNA probe

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Laboratory Diagnosis: Samples Sputum, tissue, gastric contents, csf A) Microscopic examination of tissue scrapings or sputum (KOH mount) = demonstrate the characteristic spherules containing endospores. Spherule refractile double walled thick globular 30-60µm contain endospores. B) Culture Sabouraud medium – colonies appear in 3-5days- white tan cottony M/E--presence of hyphae containing arthrospores.

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Septate hyphae Arthroconidia Septate hyphae

C) Serological test : 

C) Serological test a)Precipitin test– demonstrate a rising titer of IgM Ab (indicates recent infection) b) CF test - a rising titer IgG antibody indicates dissemination of infection D) Skin test – Coccidioidin test – using mycelial extract or spherulin (an extract from spherules) as antigen = (+) test(>5mm in 24-48 hrs) indicate prior infection but not necessarily active disease = useful in determining whether patient has been infected

Coccidioides immitis : 

Coccidioides immitis Arthrospores Endospores

Slide 38: 

Coccidio “endospores” PAS + Surrounded by infectious granulomatous pattern, ie neuts, plasma cells, epithelioid and giant cells

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Treatment Ketoconazole (for primary infection) Amphotericin B/Itraconazole (for disseminated infection Fluconazole - drug of choice in cases of meningitis Prevention: No vaccine and Prophylactic drug available

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Paracoccidiodes brasiliensis Paracoccidioidomycosis (South American Blastomycosis) Brazil, Argentina, Venezuela, US, Mexico and Central America Chronic granulomatous disease of the skin, mucous membrane, lymph node and internal organs.

Characteristics : 

Characteristics Dimorphic fungus exist as: Mold in soil and Yeast in tissue (yeast form is thick walled with multiple buds) Resembling a ship steering-wheel Habitat – soil Natural infection in armadillos Bats may serve as reservoirs

Pathogenesis: : 

Pathogenesis: MOT : inhalation of airborne conidia from contaminated soil conidia are inhaled and deposited in the lung alveoli (primary site of infection) Then disseminates to other organs through venous and lymphatic systems

Clinical Findings : 

Clinical Findings ASYMPTOMATIC INFECTION LATENT FORM (duration variable) SYMPTOMATIC INFECTION Nodular lesions in lungs Dissemination to other organs (rare) Mucocutaneous para coccidioidomycosis showing extensive destruction of facial features. Mucocutaneous paracoccidioidomycosis showing an ulcerated lesion on the pharyngeal mucosa.

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Laboratory Diagnosis: A) Direct microscopic examination from pus or tissues (KOH mount) = presence of large yeast cell with multiple buds B) Culture SDA agar – growth occurs after 20 -30 days On M/E--presence of septate hyphae with microconidia

Paracoccidioides brasilensis : 

Paracoccidioides brasilensis “MARINER’S WHEEL”

C.Serology : 

C.Serology CF/Immunodiffusion test - rise in AB titer significant ELISA detect Abs to gp43, the main antigenic determinant of P.brasiliensis Newer tests detect Ag7 i.e Ag found after 7 days. D. Skin test -not useful

Treatment : 

Treatment Itraconazole –drug of choice and effective in 95% of the pts Amphotericin B Prevention: No vaccine available, No prophylactic drug available

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Histoplasma capsulatum Histoplasmosis (Darling’s Disease) Acute, benign pulmonary disease acquired by inhalation of airborne spores (microconidia) which are present from dropping of birds. The ecological niche of H. capsulatum is in blackbird roosts, chicken houses and bat guano Inhaled spore are engulfed by macrophages which develop into yeast forms. In tissue the organism occurs as oval body yeast cell inside macrophages which spread throughout the body especially liver and spleen.

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Natural reservoir soil, bat and avian habitats Location May be prevalent all over the world, but the incidence varies widely Endemic in Ohio, Kentucky, Mississippi.

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Dimorphic fungus that exist as 1) Yeast cell in tissue and 2) Mold in soil enriched with bird droppings Forms 2 types of asexual spore a) Tuberculate macroconidia (thick-walled finger like projection) b) Microconidia - thin, small, smooth-walled

Pathogenesis : 

Pathogenesis Inhalation of microconidia / primary Cutaneous inoculation Conversion to budding yeast cells Phagocytosis by alveolar macrophages Restriction of growth or dissemination to RES by bloodstream Suppression of cell-mediated immunity

Clinical Findings : 

Clinical Findings ACUTE PULMONARY INFECTION Asymptomatic (95%) / mild / moderate / severe /chronic cavitary CHRONIC PULMONARY PROGRESSIVE DISSEMINATED INFECTION RES (liver, spleen, lymph nodes, bone marrow), mucocutaneous infection PRIMARY CUTANEOUS INFECTION

Acute Pulmonary histoplasmosis : 

Acute Pulmonary histoplasmosis Majority are asymptomatic. incubation period-3-14 days Fever, chills Headache Malaise Myalgia Abdominal pain Cough, Hemoptysis. Dyspnea may also be present

Chronic Pulmonary Histoplasmosis : 

Chronic Pulmonary Histoplasmosis In pts with underlying pulmonary disease. Cough Weight loss Fever Malaise Hemoptysis dyspnea

Progressive Disseminated Histoplasmosis : 

Progressive Disseminated Histoplasmosis In pts who are immunocompromised. Mucosal ulcers in the -mouth, -gums and -on surfaces of the skin.

Laboratory Diagnosis : 

Laboratory Diagnosis Samples Sputum, tissue, bone marrow, CSF, blood 1. Direct Examination 2. Culture 3. Serology 4. Skin Test (Histoplasmin antigen) Limited diagnostic value. 5. DNA probe and PCR

Direct Examination : 

Direct Examination Intracellular (within macrophages) and extracellular oval yeast cells Stained by H&E for tissue biopsy smear Yeast may br detected in areas of caseation necrosis and calcified lymph nodes by Gomori Methenamine silver stain.

H&E stain (left) shows macrophages filled with organisms giving the cytoplasm a slightly vacuolated appearance. A GMS (Gomori methenamine stain) (right) shows clustered organisms in cytoplasm. : 

H&E stain (left) shows macrophages filled with organisms giving the cytoplasm a slightly vacuolated appearance. A GMS (Gomori methenamine stain) (right) shows clustered organisms in cytoplasm.

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Budding yeast cell inside macrophages

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Geimsa stain: intracellular oval bodies surrounded by an artefactual “capsule”

Culture : 

Culture Culture of sputum and blood on SDA at 25 C shows cottony mycelial growth. Thin branching septate hyphae with tuberculoid macroconidia and microconidia Macroconidia-8-20µm in diameter with fingerlike projections. At 37 C shows yeast cells.

Tuberculate macroconidia : 

Tuberculate macroconidia

Serology : 

Serology Complement fixation test Immunodiffusion test:- detect antibodies to two glycoprotein's, H and M Anti-H Ab is more specific and positive in 50-80% of pts Detection of specific H.capsulatum Ag in urine and serum in immunocompromised pts when Ab production may be impaired

C. Skin test : 

C. Skin test Histoplasmin test Mycelial extract as antigen Useful for epidemiologic determination of incidence of infection Not used to diagnose actual disease

Treatment: : 

Treatment: Amphotericin B – for disseminated infection Itraconazole - for pulmonary infection Fluconazole for meningitis. Prevention: None (no vaccine available)

AFRICAN HISTOPLASMOSIS : 

AFRICAN HISTOPLASMOSIS Etiology Histoplasma capsulatum var. duboisii Differentiation from Classical Histoplasmosis Larger, thick-walled yeast cells Pronounced giant cell formation in infected tissue Diminished pulmonary involvement Greater frequency of skin and bone lesions Treatment Not required for several cases Amphotericin B Itraconazole Surgical resection of pulmonary lesions

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Fungi Causing Opportunistic Mycoses = produce disease in those individual with impaired host defenses 1. Candida albicans Characteristics: = is an oval yeast cell with a single bud = part of the normal flora of the mucous membrane of the upper respiratory tract, gastrointestinal and female genital tract = in tissues can appear as yeast cell or as psuedohyphae (which are elongated yeast that visually resembles hyphae but are not true hyphae) = CHO fermentation reaction differentiate C-albicans from other specie of Candida

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MOT: - part of the normal of the skin, mucous membrane and gastrointestinal tract of human = no person to person transmission Pathogenesis: Opportunistic pathogen = disease may results when host defenses are impaired Diseases: 1. Thrush (Moniliasis) 2. Vulvovaginitis 3. Infection of the Nail (Paronychia) 4. Skin lesion occurs frequently in moisture-damage skin 5. Systemic Candidiasis (disseminated form)

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Laboratory Diagnosis: A. Direct microscopic examination (KOH mount) = presence of budding yeast cell w/pseudohyphae B. Culture SDA – presence of yeast cell, pseudohyphae and large chlamydospore Germ tube form in serum at 370C differentiate albicans from other species C. Skin test with candida antigen = (+) among immunocompetent adult and are used as indicator that a person can mount a cellular immune response

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Treatment: Nystatin / Miconazole oral/topical for skin and mucous membrane disease Amphotericin B - disseminated infection Ketoconazole – for chronic mucocutaneous candidiasis Prevention: No vaccine available = predisposing factors should be reduced or eliminated = Clotrimazole trochis / Nystatin–used for prevention of oral thrush

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2. Aspergillus fumigatus/Aspergillus flavus/Aspergillus niger Characteristics: = exist only as mold with septate hyphae that branch at a V-shaped angle = monomorphic = organism is normally found in soil Diseases: 1. Aspergillosis (major disease) = a granulomatous necrotizing disease of the lung which often disseminates hematogenously to various organs of the body = involving the skin, eyes, ear, and other vital organ = acquired by inhalation by airborne conidia = can colonize and invade abraded skin and paranasal sinuses causing fungal sinusitis 2. Allergic bronchopulmonary aspergillosis 3. Aspergilloma (fungus ball in the lung)

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Pathogenesis: = opportunistic pathogen = produce invasive disease among immunocompromised individual = organism can invade bloodvessels causing thrombosis and infarction = patient with lung cavity (tuberculosis) may develop fungal ball (Aspergilloma) = allergic patient with bronchial asthma can develop allergic bronhopulmonary aspergillosis Laboratory Diagnosis: A. Microscopic examination (KOH mount) = presence of hyaline septate hyphae, dichotomously branched B. Culture – SDA – shows colonies with characteristic radiating chain of conidia C. Serological – detect IgG precipitin in patient with aspergilloma and IgE antibody in patient with bronchopulmonary aspergillosis D. Skin test – not available

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Treatment: Amphotericin B – for invasive aspergillosis Surgical removal – for aspergilloma (fungus ball) Steroid – recommended for allergic bronchopulmonary aspergillosis Prevention: No vaccine / Prophylactic drug available

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3. Rhizopus/Mucor Characteristic: = mold with non-septate hyphae w/ sporangiospore that typically branch at 90O angle = monomorphic = habitat in soil MOT: inhalation of airborne spores Disease: Mucormycoses (Zygomycoses; Phycomycoses) = is a systemic disease cause by saprophytic mold (Mucor, Rhizopus and Absidia) found widely in the environment = acquired by inhalation of airborne asexual spore

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Laboratory Diagnosis: 1. Microscopic examination of tissue (KOH mount) = presence of non-septate hyphae that branch at wide right angle 2. Culture – SDA - large hyaline coenocytic hyphae with spores found inside sporangium 3. Serologic test – not available Treatment: Amphotericin B Prevention: No vaccine / Prophylaxis drug available

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4. Cryptococcus neoformans = is an oval yeast-like budding cell surrounded by a wide polysaccharide capsule = not dimorphic = habitat soil enriched with pigeon droppings Disease: Cryptococcosis(Torulosis, European Blastomycosis) = most common life-threatening fungal disease in AIDS patient MOT: inhalation of airborne yeast cell = no human to human transmission Pathogenesis: = lung infection as a result of inhalation is often asymptomatic or may produce pneumonia = disease occurs in patient with altered cell mediated immunity especially AIDS patient = spread via blood stream to the CNS and result to Cryptococcal Meningitis

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Laboratory Diagnosis: = Direct visualization of the encapsulated yeast-like budding cell from spinal fluid by India Ink staining (yeast cell surrounded by a wide unstained capsule) = Culture (spinal fluid/sputum) SDA – presence of encapsulated yeast cell. = Serological – Latex particle agglutination test - detects polysaccharide capsular antigen in spinal fluid Treatment: Amphotericin B plus Flucytosine for meningitis Prevention: No vaccine = Cryptococcal meningitis can be prevented in AIDS patient by oral Fluconazole

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Capsule Budding yeast

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