Systemic

Question 1

Also known as San Joaquin Valley fever, Valley fever, or Desert Rheumatism,

Answer 1

Coccidioidomycosis

Question 2

coccidioidomycosis is a fungal infection caused by (2)

Answer 2

Coccidioides immitis and Coccidioides posadasii.

Question 3

It primarily affects the lungs and can cause systemic disease in immunocompromised individuals.

Answer 3

COCCIDIOIDOMYCOSIS

Question 4

COCCIDIOIDOMYCOSIS

Causative Agents
• – Endemic in Central and Southern California, Northern Mexico.
• – Found in Arizona, Texas, Mexico, and parts of South America.

•	Both species are ***phenotypically indistinguishable*** but can be differentiated by genotyping.

Answer 4

Coccidioides immitis
Coccidioides posadasii

Question 5

COCCIDIOIDOMYCOSIS

History & Discovery
• 1891: (a medical student) first observed Coccidioides in a soldier with a verrucous facial lesion.
• 1892: described it as a coccidia-like parasite.
• 20 years later: The fungal dimorphism and endemicity in California were confirmed.

Answer 5

Alejandro Posadas

Posadas and Wernicke

Question 6

COCCIDIOIDOMYCOSIS

Pathogenesis & Clinical Features

Transmission & Infection
• Mode of entry:_______

Answer 6

Inhalation of airborne arthroconidia from disturbed soil.

Question 7

• Primary pulmonary infection – Spores enter the lungs, where they enlarge and form spherules filled with endospores.
• Rupture of spherules releases endospores, which mature into new spherules, continuing the infection cycle.

Answer 7

COCCIDIOIDOMYCOSIS

Question 8

Asymptomatic infection (60%)
• No symptoms, but a positive skin test (delayed hypersensitivity) within 2-4 weeks.
• Recovery often leads to lifelong immunity.

Answer 8

COCCIDIOIDOMYCOSIS

Question 9

Self-limiting respiratory illness (40%)
• Flu-like symptoms: fever, malaise, cough, headache, and arthralgia.
• “Valley Fever” - a term for this acute form.
• Lasts for weeks to months.

Answer 9

COCCIDIOIDOMYCOSIS

Question 10

COCCIDIOIDOMYCOSIS

Hypersensitivity reactions (15%)
• _______ (“desert bumps”) – Red, tender nodules on the shins.
• _______– Target-like skin lesions.
• _______(desert rheumatism) – Joint pain and swelling.

Answer 10

Erythema nodosum

Erythema multiforme

Arthritis

Question 11

COCCIDIOIDOMYCOSIS

Disseminated coccidioidomycosis (<3%)
• Spreads beyond lungs to (4)

•	Skin: Ulcerated nodules or plaques.
•	Meningitis: Headache, stiff neck, confusion, seizures.
•	Risk factors: Filipinos, African Americans, men, pregnant women, AIDS, immunosuppression.

Answer 11

skin, bones, joints, meninges.

Question 12

COCCIDIOIDOMYCOSIS

•	Cavitary lung lesions that may rupture, leading to hemoptysis (coughing up blood).
•	Can mimic tuberculosis on chest X-ray.

Answer 12

Chronic pulmonary coccidioidomycosis (5%)

Question 13

Highest risk: Filipinos and Blacks, favor males

Remissions and relapses occur

Answer 13

COCCIDIOIDOMYCOSIS

Question 14

Pathogenesis & Clinical Findings
• Radiographic exam: hilar adenopathy, pulmonary infiltrates, pneumonia, pleural effusions, or nodules; pulmonary residua (solitary nodule or thin-walled cavity) in about 5%

• Risk factors:
heredity, sex, age, and compromised immune response, pregnant women,
AIDS, other conditions of cellular immunosuppression

Answer 14

COCCIDIOIDOMYCOSIS

Question 15

Epidemiology & Control
• Endemic in low rainfall, semiarid regions (Lower Sonoran life zone)

• Highly endemic - Southwest, San Joaquin Valley of California, and southern Arizona; Mexico, parts of Central and South America;

It can be isolated from the soil and indigenous rodents.

Answer 15

COCCIDIOIDOMYCOSIS

Question 16

More males at risk: digging, excavation, construction, archaeology, agriculture, firefighting, mining, gas or oil extraction

Answer 16

COCCIDIOIDOMYCOSIS

Question 17

COCCIDIOIDOMYCOSIS
Diagnostic Laboratory Tests
• Specimens for culture: (6)

• Examined fresh (after centrifuging, if necessary) for typical spherules

Answer 17

sputum, exudate from cutaneous lesions, spinal fluid, blood, urine, tissue biopsies

Question 18

COCCIDIOIDOMYCOSIS
Diagnostic Laboratory Tests

• _______ or _______; H&E, GMS, or PAS
• Cultures: ____ or _____ w/ or w/o antibiotics & cycloheximide, 30C or 37C, examine only in level____ biosafety cabinet.

Answer 18

20% KOH or calcofluor white stain

Level 3 biosafety cabinet

Question 19

COCCIDIOIDOMYCOSIS
Diagnostic Laboratory Tests

• Confirm by detection of a________ or by animal inoculation or use of a specific DNA probe

Answer 19

C. immitis-specific antigen

Question 20

Morphology & Identification

• Culture:22C, a rapid grower, within a week; white to gray/tan/brown cottony colony in circular bloom;

hyaline septate hyphae form chains of arthroconidia,

chains fragment into individual arthroconidia (airborne, highly resistant to adverse environmental conditions);

small arthroconidia (ave. 3 x 6 um) remain viable for years, highly infectious

Answer 20

COCCIDIOIDOMYCOSIS

Question 21

COCCIDIOIDOMYCOSIS
Morphology & Identification

Following inhalation of arthroconidia - become_______

Answer 21

spherical, enlarged - SPHERULES

Question 22

Morphology & Identification

• Mature: thick, doubly refractile walls, a size of 30-80 um in diameter, packed with endospores (2-5 um);

• Rupture releases endospores, develop into new spherules

• Young spherules: have a clear center with peripheral cytoplasm & a prominent thick wall.

Answer 22

COCCIDIOIDOMYCOSIS

Question 23

COCCIDIOIDOMYCOSIS
Morphology & Identification

• Use_____ medium to produce spherules in the laboratory, 40°C at 20% carbon dioxide

• On wet mount/histologic sections of tissue, sputum, other specimens: Spherules are diagnostic of (2)

Answer 23

Converse

C immitis/ C posadasii.

Question 24

COCCIDIOIDOMYCOSIS
Antigenic Structures
• 2 clinically useful antigens:

________
• An antigen preparation extracted from the filtrate of a liquid mycelial culture of C immitis

_______
• Produced from a filtrate of a broth culture of spherules
• Coccidioidin skin test: (≥5 mm in diameter) maximum induration between 24 and 48 hours after cutaneous injection of 0.1 ml standardized dilution; spherulin is more sensitive

Answer 24

Coccidioidin

Spherulin

Question 25

COCCIDIOIDOMYCOSIS Antigenic Structures ________ : (_____in diameter) maximum induration between 24 and 48 hours after cutaneous injection of 0.1 ml standardized dilution; spherulin is more sensitive

Answer 25

Coccidioidin skin test ≥5 mm

Question 26

COCCIDIOIDOMYCOSIS Diagnostic Laboratory Tests • ________– Rapid screening test. • Immunodiffusion (ID) test: • Positive exoantigen F precipitin line confirms diagnosis. • – Indicates acute infection. • – Suggests chronic or past infection.

Answer 26

EIA (IgM & IgG) IgM IgG

Question 27

COCCIDIOIDOMYCOSIS Diagnostic Laboratory Tests Antigen Detection Tests • – Useful in early stages, but cross-reactivity with other fungi. • – Low specificity, not used for definitive diagnosis.

Answer 27

Urine & Serum Antigen Test (1→3)-β-D-Glucan Test

Question 28

COCCIDIOIDOMYCOSIS Diagnostic Laboratory Tests Complement Fixation (CF) Test: • Rising titers (_____) = progressive disease. • Declining titers = resolution. • Cross-reactions with other fungi possible.

Answer 28

≥1:32

Question 29

COCCIDIOIDOMYCOSIS Diagnostic Laboratory Tests • Detects Coccidioides DNA– Rapid (~4 hours), but requires specialized facilities. • More reliable than serology in AIDS patients, where antibody tests often fail

Answer 29

Molecular Diagnosis (PCR-based tests)

Question 30

COCCIDIOIDOMYCOSIS TREATMENT • Symptomatic primary infection, self limiting: only supportive treatment,_____ may reduce symptoms •_____: most commonly prescribed • Severe cases:______(nephrotoxic), intravenous administration, followed by several months of oral therapy with itraconazole (higher efficacy) • Coccidioidal meningitis: oral fluconazole, long-term therapy • Surgical resection of pulmonary cavities sometimes necessary and often curative.

Answer 30

itraconazole Fluconazole amphotericin B

Question 31

• The ***most prevalent pulmonary intracellular mycosis worldwide,*** endemic in the Ohio - Mississippi River valleys of North America

Answer 31

HISTOPLASMOSIS

Question 32

is the ***most common endemic mycosis in AIDS patients.***

Answer 32

HISTOPLASMOSIS

Question 33

HISTOPLASMOSIS • Causative agent:_______ (Hc) (Dr. Samuel Darling, 1906) • a dimorphic soil saprophyte, a mold in soil and avian habitats enriched by alkaline nitrogenous substrates in guano. • Initiated by inhalation of the conidia.

Answer 33

Histoplasma capsulatum

Question 34

HISTOPLASMOSIS • In humans: Two distinct varieties

Answer 34

• Histoplasma capsulatum var. capsulatum • Histoplasma capsulatum var. duboisii

Question 35

HISTOPLASMOSIS • In humans: Two distinct varieties •________ • Found globally (mainly North, South, Central America, Southeast Asia, and Africa) • Pulmonary (resembles TB) & systemic histoplasmosis • ***Darling's disease, cave or spelunker's disease***

Answer 35

Histoplasma capsulatum var. capsulatum

Question 36

HISTOPLASMOSIS • In humans: Two distinct varieties •________ • Predominant in ***Western and Central Africa*** • Causes skin and bone lesions • ***African histoplasmosis***

Answer 36

Histoplasma capsulatum var. duboisii

Question 37

HISTOPLASMOSIS • In horses: Hc var.________, lymphangitis

Answer 37

farciminosum

Question 38

HISTOPLASMOSIS Morphology and Identification •_______ (gold standard):

Answer 38

CULTURE

Question 39

Morphology and Identification CULTURE • Mold: ***white suede surface & pale yellow brown reverse colonies,*** varying appearance, 4-12 weeks (slow)

Answer 39

HISTOPLASMOSIS

Question 40

Morphology and Identification • Morphology: ***hyaline, septate hyphae produce microconidia*** (2-5 um) & large, spherical thick-walled macroconidia with peripheral projections of cell wall material (8-16 um); ***"tuberculate macroconidia"***

Answer 40

HISTOPLASMOSIS

Question 41

Morphology and Identification • Tissue culture/ in vitro-rich medium, 37°C: convert to small, oval yeast cells (2 x 4 um) • In tissue biopsy: yeasts ***typically seen within macrophages*** • Its teleomorph: BHIA, 5% sheep blood, 37C: Yeast colonies Ajellomyces capsulatus, produce ascospores

Answer 41

HISTOPLASMOSIS

Question 42

Facultative intracellular

Answer 42

Histoplasmosis

Question 43

HISTOPLASMOSIS Antigenic Structure •________ • crude but standardized mycelial broth culture filtrate antigen • In skin test: positive soon after infection, remains positive for years • 95% asymptomatic - positive delayed hypersensitivity type skin test • In progressive disseminated histoplasmosis - may become negative

Answer 43

Histoplasmin

Question 44

HISTOPLASMOSIS Antigenic Structure • A positive "________" indicates past or present infection, but ***does not differentiate active and past infections.*** • Rarely used today, replaced by blood and urine tests. • Antibodies to yeast and mycelial antigens measurable

Answer 44

histoplasmin skin test

Question 45

HISTOPLASMOSIS Pathogenesis & Clinical Findings Initial inflammatory reaction becomes granulomatous (over 95% CMI response, cytokines activate macrophages, inhibit intracellular growth)

Question 46

HISTOPLASMOSIS Pathogenesis & Clinical Findings • With heavy inoculum: Acute pulmonary histoplasmosis, resolves without therapy, lung nodules heal with calcification • Chronic pulmonary: mostly men, reactivation of a dormant lesion (lung damage like emphysema)

Question 47

HISTOPLASMOSIS Pathogenesis & Clinical Findings Severe disseminated: infants, elderly, immunosuppressed (AIDS) • RES - lymphadenopathy, enlarged spleen, liver, anemia, high mortality without antifungal therapy (Reticuloendothelial cytomycosis • Mucocutaneous ulcers of nose, mouth, tongue, intestine

Question 48

HISTOPLASMOSIS Diagnostic Laboratory Tests A. Specimens & Microscopic Examination • Specimens for culture - (5) • Stain (GMS, PAS, Giemsa) blood films, bone marrow slides, biopsy specimens • Disseminated histoplasmosis - bone marrow often positive

Answer 48

sputum, urine, scrapings from lesions, bone marrow aspirates, buffy coat blood cells.

Question 49

HISTOPLASMOSIS Diagnostic Laboratory Tests B. Culture •________ at 37C • ______at 25-30C • Alert lab if histoplasmosis is suspected to perform special blood culture methods such as lysis centrifugation or fungal broth medium to enhance recovery • Confirm by in-vitro ***conversion to the yeast form*** • Detection of a species-specific antigen, or PCR testing for specific DNA sequences

Answer 49

Glucose-cysteine-blood agar SDA or IMA

Question 50

Diagnostic Laboratory Tests C. Serology • CF tests - positive within 2-5 weeks after infection; • titers rise during progressive disease (≥1:32), declines when inactive • Cross reactions occur • ID tests antigens detecteins to two H-specific Astopdiests H antigen - active • Antibodies to M antigen - repeated skin testing or past exposure

Answer 50

HISTOPLASMOSIS

Question 51

HISTOPLASMOSIS Diagnostic Laboratory Tests _____ and______: most sensitive tests • Circulating polysaccharide antigen of Hc • Nearly all with disseminated form - positive test for antigen in the serum or urine • Antigen level drops after successful treatment and recurs during relapse • More sensitive than conventional antibody tests in AIDS patients with histoplasmosis

Answer 51

RA or EIA

Question 52

Epidemiology and Control • Acute outbreaks - highest in the US, Ohio-Mississippi River valleys o Disturbed soil mixed with bird feces (starling roosts, chicken houses, or bat guano in caves) • Birds not infected, their increment provides superb culture conditions • Conidia spread by wind and dust • 80-90% residents have positive skin test. • Not communicable from person-to-person. • Spraying formaldehyde on infected soil may destroy Hc.

Answer 52

HISTOPLASMOSIS