patoloji-ders-notlari

Title

Serdar Balcı

Pathology of Fungal and Parasitic Infections

Serdar BALCI, MD

FUNGAL INFECTIONS

Fungus

Eukaryotes
Grow as
- Molds (multicellular filaments, hyphae)
- Yeast (chain of cells)
  - **Budding **
- Elongated yeast (pseudohyphae)
  - C.albicans
They can be seen on routine H&E sections
They are highlighted by special stains
- GMS, PAS
Definitive diagnosis may require cultures

Mycoses (Fungal Infections)

Superficial and cutaneous mycoses
- Common
- Limited to the very superficial or keratinized layers of skin, hair, and nails
Subcutaneous mycoses
- Involve the skin, subcutaneous tissues, and lymphatics
- Rarely disseminate systemically
Endemic mycoses
- Dimorphic fungi
- Serious systemic illness
- Healthy individuals
Opportunistic mycoses
- Life-threatening systemic diseases
- Immunosuppressed patients
- Implanted prosthetic devices
- Vascular catheters

Candidiasis

Adhesion
- Integrin-like protein, which binds arginine-glycine-aspartic acid (RGD) groups on fibrinogen, fibronectin, and laminin
- Protein that resembles transglutaminase substrates and binds to epithelial cells
- Several agglutinins that bind to endothelial cells or fibronectin
Enzymes
- Degrading extracellular matrix proteins
Catalases
- Resist oxidative killing by phagocytic cells
Adenosine
- Blocks neutrophil oxygen radical production and degranulation
Grow as biofilms
Innate immunity and T-cell responses are important for protection against Candida infection
Oral Cavity
- Superficial infection
- Thrush (Pamukçuk)
- Newborns, debilitated people, children receiving oral steroids for asthma, broad-spectrum antibiotics, HIV-positive patients

Rubin’s Pathology 7th Ed, Clinicopathologic Foundations Of Medicine

Candida esophagitis
- AIDS patients, hematolymphoid malignancies
- Dysphagia (painful swallowing) and retrosternal pain
- White plaques and pseudomembranes resembling oral thrush

Robbins and Cotran’s Pathological Basis of Disease

Candida vaginitis
- Diabetic, pregnant, oral contraceptive pills
- Intense itching and a thick discharge
- Can be diagnosed in a PAP-smear test
Cutaneous candidiasis
- Nail proper (onychomycosis)
- Nail folds (paronychia)
- Hair follicles (folliculitis)
- Moist, intertriginous skin such as armpits or webs of the fingers and toes (intertrigo)
- Penile skin (balanitis)
- Perineum of infants (Diaper rash)
Invasive candidiasis
- Renal abscesses
- Myocardial abscesses and endocarditis
  - prosthetic heart valves or in intravenous drug abusers
- Brain microabscesses and meningitis
- Endophthalmitis
- Hepatic abscesses
Invasive candidiasis
Depending on the immune status of the infected person
- Little inflammatory reaction
- Suppurative response
- Occasionally produce granulomas

Cryptococcosis

Cryptococcus neoformans
- Present in the soil and in bird (pigeon) droppings
- Infects people when it is inhaled
Virulence factors
- Polysaccharide capsule
  - inhibits phagocytosis by alveolar macrophages, leukocyte migration, and recruitment of inflammatory cells
  - phenotype switching
- Melanin production
- Enzymes

Robbins and Cotran’s Pathological Basis of Disease

Rubin’s Pathology 7th Ed, Clinicopathologic Foundations Of Medicine

Grow as yeasts (5- to 10-μm)
Highly characteristic thick gelatinous capsule
- Stains intense red with periodic acid–Schiff and mucicarmine
- Antibody-coated beads in an agglutination assay
- India ink preparations create a negative image, visualizing the thick capsule as a clear halo within a dark background
Lung is the primary site of infection
- Pulmonary involvement is usually mild and asymptomatic
- May form a solitary pulmonary granuloma similar to the circumscribed (coin) lesions caused by Histoplasma
Central Nervous System
- Meninges, cortical gray matter, and basal nuclei
Response is extremely variable
Immunosuppressed people
- No inflammatory reaction
- Grow in the meninges or expand the perivascular Virchow-Robin spaces within the gray matter (soap-bubble lesions)
Severely immunosuppressed persons
- Skin, liver, spleen, adrenals, and bones
Nonimmunosuppressed people or in those with protracted disease
- Chronic granulomatous reaction composed of macrophages, lymphocytes, and foreign body–type giant cells
- Suppuration
- Granulomatous arteritis of the circle of Willis.

Aspergillosis

Aspergillus is transmitted by airborne conidia

Lung is the major portal of entry

A. fumigatus spores small enough (2-3 μm) to reach alveoli

Conidia germinate into hyphae, then invade tissues

Host defenses against Aspergillus

Alveolar macrophages ingest and kill the conidia

Neutrophils produce reactive oxygen intermediates that kill hyphae

Invasive aspergillosis is highly associated with neutropenia and impaired neutrophil defenses.

Aspergillus Virulence Factors

Adhesins
Antioxidants
- melanin pigment, mannitol, catalases, and superoxide dismutases
Enzymes
Toxins

Aflatoxin

Carcinogen

Made by Aspergillus species growing on the surface of peanuts

Cause of liver cancer in Africa

Allergic alveolitis
- Sensitization to Aspergillus spores
Allergic bronchopulmonary aspergillosis, associated with hypersensitivity arising from superficial colonization of the bronchial mucosa, often occurs in asthmatic people

Colonizing aspergillosis (aspergilloma)

Growth of the fungus in pulmonary cavities

Minimal or no invasion of the tissues

Nose is often colonized

Cavities are result of prior tuberculosis, bronchiectasis, old infarcts, abscesses

Masses of hyphae form brownish “fungal balls” lying free within the cavities

Surrounding chronic inflammation and fibrosis

Invasive aspergillosis

Opportunistic infection
Lung, heart valves, brain
Necrotizing pneumonia
- Sharply delineated, rounded, gray foci and hemorrhagic borders
- Target lesions

Robbins and Cotran’s Pathological Basis of Disease

Rubin’s Pathology 7th Ed

Robbins and Cotran’s Pathological Basis of Disease

Aspergillus

Fruiting bodies and septate filaments

5 to 10 μm thick

Branching at acute angles (40 degrees)

Robbins and Cotran’s Pathological Basis of Disease

Zygomycosis (mucormycosis, phycomycosis)

**Widely distributed in nature **

No harm to immunocompetent individuals

Infect immunosuppressed people

Zygomycosis

Transmitted by airborne asexual spores
- Produce infection in the sinuses and the lungs
Percutaneous exposure
Ingestion
Thermotolerance contribute to their spread
Host defense
- Macrophages
  - phagocytose, oxidative killing of germinating spores
- Neutrophils
  - role in killing fungi during established infection

Nonseptate

Irregularly wide (6 to 50 μm) fungal hyphae

Frequent right-angle branching

Demonstrated in necrotic tissues by H&E and special stains

Robbins and Cotran’s Pathological Basis of Disease

Rubin’s Pathology 7th Ed, Clinicopathologic Foundations Of Medicine

Sites of invasion
- Nasal sinuses
- Lungs
- Gastrointestinal tract
In diabetics
- Spread from nasal sinuses to the orbit and brain
- Rhinocerebral mucormycosis
Brain involvement
- Local tissue necrosis in nose
- Invade arterial walls
- Penetrate the periorbital tissues and cranial vault
- Meningoencephalitis
- Cerebral infarctions (invade arteries and induce thrombosis)
Lung involvement
- Secondary to rhinocerebral disease
- Primary in people with severe immunodeficiency
- Hemorrhagic pneumonia, vascular thrombi, distal infarctions

Rubin’s Pathology 7th Ed Clinicopathologic Foundations Of Medicine

PARASITIC INFECTIONS

PROTOZOA

Unicellular

Eukaryotic organisms

Transmitted by insects, fecal-oral route

Robbins and Cotran’s Pathological Basis of Disease

Malaria

Rubin’s Pathology 7th Ed Clinicopathologic Foundations Of Medicine

Robbins and Cotran’s Pathological Basis of Disease

Spleen in Malaria

Initially causes congestion and enlargement of the spleen (1000 gm)

There is increased phagocytic activity of the macrophages in the spleen

Spleen becomes increasingly fibrotic and brittle

A thick capsule and fibrous trabeculae

Parenchyma is gray or black because of phagocytic cells containing granular, brown-black, faintly birefringent hemozoin pigment

Macrophages with engulfed parasites, red blood cells, and debris are numerous

Liver in Malaria

Liver becomes progressively enlarged and pigmented
Kupffer cells contain
- Malarial pigment
- Parasites
- Cellular debris
Some pigment is also present in the parenchymal cells

Pigmented phagocytic cells also found
- bone marrow
- lymph nodes
- subcutaneous tissues
- lungs

Kidneys in Malaria

Enlarged

Dusting of pigment in the glomeruli

Hemoglobin casts in the tubules

Malignant cerebral malaria

**Brain vessels are plugged with parasitized red cells **
Around the vessels there are ring hemorrhages, related to local hypoxia incident to the vascular stasis
Small focal inflammatory reactions (called malarial or Dürck granulomas)
More severe hypoxia
- degeneration of neurons
- focal ischemic softening
- inflammatory infiltrates in the meninges

Robbins and Cotran’s Pathological Basis of Disease

Malaria

Nonspecific focal hypoxic lesions in the heart
- Progressive anemia
- Circulatory stasis in chronically infected people
- Myocardium shows focal interstitial infiltrates
In the nonimmune patient
- Pulmonary edema
- Shock with DIC
- Death

Babesia microti, Babesia divergens

Malaria like parasite live in RBC in humans
In fatal cases the anatomic findings are related to shock and hypoxia
- Jaundice
- Hepatic necrosis
- Acute renal tubular necrosis
- Adult respiratory distress syndrome
- Erythrophagocytosis
- Visceral hemorrhages

Robbins and Cotran’s Pathological Basis of Disease

Leishmaniasis

Robbins and Cotran’s Pathological Basis of Disease

Visceral leishmaniasis

L. donovani or L. chagasi

Invade macrophages, mononuclear phagocyte system

Hepatosplenomegaly, lymphadenopathy, pancytopenia, fever, and weight loss

The spleen -> 3 kg, lymph nodes -> 5 cm

Liver becomes increasingly fibrotic

Hyperpigmentation of the skin
- The disease is called kala-azar or “black fever” in Urdu
Kidneys
- Immune complex–mediated mesangioproliferative glomerulonephritis
- In advanced cases there may be amyloid deposition
Secondary bacterial infections
- Macrophages cannot function well
- The usual cause of death
Hemorrhages
- Related to thrombocytopenia
- May also be fatal

Cutaneous leishmaniasis

L. major, L. mexicana, L. braziliensis

Relatively mild

Localized disease

Ulcers on exposed skin

Papule surrounded by induration, a shallow and slowly expanding ulcer, heaped-up borders, usually heals by involution within 6 to 18 months without treatment

On microscopic examination, the lesion is granulomatous, usually with many giant cells and few parasites.

Mucocutaneous leishmaniasis

L. braziliensis

Moist, ulcerating or nonulcerating lesions in the nasopharyngeal areas

Progressive and highly destructive

Microscopic examination parasite-containing macrophages with lymphocytes and plasma cells

Inflammatory response becomes granulomatous, and the number of parasites declines

Lesions remit and scar

Reactivation may occur after long intervals

Diffuse cutaneous leishmaniasis

A rare form of dermal infection

Begins as a single skin nodule, which continues spreading until the entire body is covered by nodular lesions

Microscopically, they contain aggregates of foamy macrophages stuffed with leishmania

African Trypanosomiasis

Parasites that proliferate extracellularly in the blood
Variant Surface Glycoprotein
- Continuously undergo genetic rearrangement and escape from immune response

Robbins and Cotran’s Pathological Basis of Disease

Large, red, rubbery chancre forms at the site of the insect bite
- Large numbers of parasites
- Dense, predominantly mononuclear, inflammatory infiltrate
Lymph nodes and spleen enlarge
Trypanosomes concentrate in capillary loops
- choroid plexus
- glomeruli
Breach the blood-brain barrier and invade the CNS
- Leptomeningitis
- Extends into the perivascular Virchow-Robin spaces
- Demyelinating panencephalitis occurs
Chronic disease leads to progressive cachexia
Acute myocarditis
- Clusters of amastigotes cause swelling of individual myocardial fibers and create intracellular pseudocysts
- Focal myocardial cell necrosis
- Extensive, dense, acute interstitial inflammatory infiltration throughout the myocardium
- Associated with four-chamber cardiac dilation
Chronic Chagas disease
- Heart is typically dilated, rounded, and increased in size and weight
- Mural thrombi
- Pulmonary or systemic emboli or infarctions
- Interstitial and perivascular inflammatory infiltrates
  - Lymphocytes, plasma cells, and monocytes
- Scattered foci of myocardial cell necrosis, interstitial fibrosis
- Aneurysmal dilation and thinning
- Dilation of the esophagus or colon, related to damage to the intrinsic innervation of these organs
- Often treated by cardiac transplantation.

Metazoa

Multicellular, eukaryotic organisms

Strongyloidiasis

Worms, mainly larvae, present in the duodenal crypts
- Eosinophil-rich infiltrate in the lamina propria with mucosal edema
Hyperinfection results in invasion of larvae
- Colonic submucosa
- Lymphatics
- Blood vessels
- Associated mononuclear infiltrate
Many adult worms, larvae, and eggs in the crypts of the duodenum and ileum
Worms of all stages may be found in other organs
- Skin
- Lungs
- may even be found in large numbers in sputum

Robbins and Cotran’s Pathological Basis of Disease

Cysticercosis

Taenia solium, Taenia saginata, Diphyllobothrium latum
More common locations
- brain
- muscles
- skin
- heart

Robbins and Cotran’s Pathological Basis of Disease

cysticercus cyst in the skin

Cerebral symptoms depend on the location of the cysts
- The cysts are ovoid and white to opalescent, often grape-sized, and contain an invaginated scolex with hooklets that are bathed in clear cyst fluid
The cyst wall
- More than 100 μm thick
- Rich in glycoproteins
- Little host reaction when it is intact
When cysts degenerate
- there is inflammation, followed by focal scarring, and calcifications, which may be visible by radiography

Rubin’s Pathology 7th Ed Clinicopathologic Foundations Of Medicine

Hydatid Disease

Echinococcus granulosus

2/3 of cysts are found in the liver

5% to 15% in the lung

Rest in bones and brain or other organs

Larvae lodge within the capillaries

Inflammatory reaction mononuclear leukocytes and eosinophils

Many such larvae are destroyed, but others encyst

The cysts begin at microscopic levels, progressively increase in size

In 5 years or more they may have achieved dimensions of more than 10 cm in diameter

Enclosing an opalescent fluid
An inner, nucleated, germinative layer
An outer, opaque, non-nucleated layer
- Innumerable delicate laminations
Outside this opaque layer, there is a host inflammatory reaction
- A zone of fibroblasts, giant cells, and mononuclear and eosinophilic cells
- A dense fibrous capsule forms
Daughter cysts often develop within the large mother cyst
Degenerating scolices of the worm produce a fine, sandlike sediment within the hydatid fluid (“hydatid sand”)

Trichinosis

Trichinella spiralis
preferentially encysts in striated skeletal muscles with the richest blood supply
- diaphragm, extraocular, laryngeal, deltoid, gastrocnemius, and intercostal muscles

Robbins and Cotran’s Pathological Basis of Disease

Schistosomiasis

Granuloma forms

At the center of the granuloma is the schistosome egg

Degenerates over time and calcifies

Granulomas are composed of macrophages, lymphocytes, neutrophils, and eosinophils

Eosinophils are distinctive for helminth infections

Robbins and Cotran’s Pathological Basis of Disease

Lymphatic Filariasis

**Wuchereria bancrofti and Brugia species **
Hydrocele and lymph node enlargement
In severe and long-lasting infections
- Chylous weeping of the enlarged scrotum
- Chronically swollen leg (elephantiasis)
- Subcutaneous fibrosis
- Epithelial hyperkeratosis

Robbins and Cotran’s Pathological Basis of Disease

Onchocerciasis

Onchocerca volvulus
Chronic, itchy dermatitis
Subcutaneous onchocercoma
- Fibrous capsule surrounding adult worms
- Mixed chronic inflammatory infiltrate that includes fibrin, neutrophils, eosinophils, lymphocytes, and giant cells

Robbins and Cotran’s Pathological Basis of Disease

The progressive eye lesions
Punctate keratitis
- Caused by degenerating microfilariae
- Eosinophilic infiltrate
- Sclerosing keratitis
- Opacifies the cornea
Anterior chamber
- Iridocyclitis, glaucoma
Choroid and retina
- Atrophy and loss of vision