1. ASSOC. PROF. DR. FERDA ÖZKAN
FUNGAL DISEASES
ASSOC. PROF. DR. FERDA ÖZKAN

2. Some are members of the normal human microflora.
The fungi are free living, eukaryotic saprophytes found in every habitat on earth.
Some are members of the normal human microflora.
Many of the causative fungi are opportunists and are not usually pathogenic unless they enter a compromised host.

3. Opportunistic fungal infections are particularly likely to occur in patients during therapy with
corticosteroids,
immunosuppressants , or
antimetabolites;
such infections also tend to occur in patients with AIDS,
azotemia,
diabetes mellitus,
bronchiectasis,
emphysema,
TB,
Lymphoma, leukemia, or
burns.

4. Candidiasis, aspergillosis, mucormycosis (phycomycosis), nocardiosis, and cryptococcosis are typical opportunistic infections.

5. In mild immunocompetent patients, disseminated mycoses with pneumonia and septicemia are rare.
Lung lesions may develop slowly in such patients.
Systemic mycoses affecting severely immunocompromised patients often have acute or subacute presentations with rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination.

6. When a fungus disseminates from a primary focus in the lung, the manifestations may be characteristic.
Cryptococcosis usually presents as a chronic meningitis,
progressive disseminated histoplasmosis as generalized involvement of the reticuloendothelial system (liver, spleen, bone marrow), and
blastomycosis as single or multiple skin lesions.
Diagnoses are usually confirmed by isolating causative fungi from sputum, urine, blood, bone marrow, or specimens from infected tissues.

7. In contrast to viral and bacterial diseases, fungal infections often can be diagnosed histopathologically with a high degree of reliability based on distinctive morphologic characteristics of invading fungi rather than assay of specific antibody products.
However, definitive identification may be difficult, especially if few organisms are visible, so that histopathologic diagnoses should be confirmed by cultures whenever possible.

8. Fungi possess thick, ergosterol-containing cell walls and grow as perfect, sexually reproducing forms invitro and as imperfect forms in vivo;
The latter includes budding yeast cells and slender tubes (hyphae).
Some yeast forms produce spores, which are resistant to extreme environmental conditions, while hyphae may produce fruiting bodies.

9. Some fungal species (e. g
Some fungal species (e.g., those of the Tinea group, which cause “athlete’s foot”) are confined to the superficial layers of the human skin;
other “dermatophytes” preferentially damage the hair shafts or nails.
Certain fungal species invade the subcutaneous tissue, causing abscesses or granulomas, as happens in sporotrichosis and in tropical mycoses.

10. Deep Fungi

11. CANDIDIASIS (Candida albicans, Moniliasis)
The most common serious human fungal disease (80 %).
Candida is now the fourth most prevalent organism found in bloodstream infections and is the most common cause of fungal infections in immunocompromised people. The frequency of nosocomial candidiasis has risen at least fivefold in the 1980s, making it one of the most common hospital-acquired infections.

12. Candidiasis
Invasive infections caused by Candida sp, most often C. albicans, manifested by fungemia, endocarditis, meningitis, and/or focal lesions in liver, spleen, kidneys, bone, skin, and subcutaneous or other tissues.

13. Candida albicans
Is the usual agent (the pseudohyphae, from which bud off small yeasts).
A normal commensal in the oral cavity, gastrointestinal tract, and vagina,
Which overgrows when the normal flora are destroyed by
antibiotics, or
changes in pH (i.e., in diabetes, in the vagina during pregnancy or when "on the pill") or
when patients are immunocompromised.

14. Three disease patterns are:
1. Superficial proliferation occurs at sites normally colonized by fungus,
2. Deep invasion occurs from surface lesions when there is a systemic impairment of host defense; widespread dissemination of the fungus may follow,
3. Direct inoculation into the blood stream can give rise to severe disseminated candidiasis in immunocompromised patients (iv lines, catheters, peritoneal dialysis, cardiac surgery, iv drug abuse).

15. Neonates commonly have perianal infection (diaper rash) and oral thrush.
In adults, oral candidiasis increases in incidence with age; the elderly are affected most.
Gastrointestinal (GI) candidiasis also increases in incidence with age.

16. 1. Superficial proliferation (Mucocutaneous candidiasis)
Frequently complicates AIDS, but hematogenous dissemination is unusual until immunocompromise becomes profound.
Common first symptoms of HIV infection.
Oral candidiasis (thrush) commonly affects patients with AIDS or with other causes of compromised T-cell-mediated immune defense mechanisms and occasionally affects others (in newborns who are bottle-fed, in adults during therapy with wide-spectrum antibiotics).
Candidiasis involving the esophagus, trachea, bronchi, or lungs is a defining opportunistic infection in AIDS.

17. Candidiasis on the mucosal surfaces (mouth, vagina, conjunctiva) appears as white patches.
Candida also causes cutaneous eczematoid lesions in moist areas (groin, between fingers and toes, anorectal region).
Vaginal candidiasis (vaginitis; vulvar rash) commonly affects women, including those with normal immunity, especially after antibiotic use.

18. 2. Deep invasion (Invasive infections)
Invasive candidiasis usually occurs in immunosuppressed patients and is most often caused by C. albicans or C. tropicalis.
Neutropenic patients receiving cancer chemotherapy are at high risk for developing life-threatening disseminated candidiasis.
Fungemia may lead to meningitis as well as to focal involvement of skin, subcutaneous tissues, bones, joints, liver, spleen, kidneys, eyes, and other tissues.

19. Renal involvement, seen in 90% of invasive cases, is characterized by the presence of innumerable microabscesses in both the cortex and the medulla.
Candidiasis of the esophagus usually means serious immune compromise.
Candida endocarditis resulting from direct inoculation of the fungi into the bloodstream give rise to large, friable vegetations that frequently break off and occlude large arterial branches.

20. In the lungs, candida lesions are often extensive, spherical or irregular, and hemorrhagic.
Meningitis, intracerebral abscesses, enteritis, endophthalmitis, multiple subcutaneous abscesses, arthritis, and osteomyelitis are some of the presentations of disseminated candidiasis.

21. 3. Direct inoculation into the blood stream
Candidemia and especially hematogenous endophthalmitis are frequent nosocomial infections in non-neutropenic patients who have prolonged hospitalizations;
Infection is often related to multiple trauma or surgical procedures, multiple courses of broad-spectrum antibacterial therapy, and/or IV hyperalimentation.

22. IV lines and the GI tract are the usual portals of entry.
Endocarditis may occur in relation to IV drug abuse, valve replacement, or intravascular trauma.

23. Moniliasis

24. Moniliasis
CNS infection by Candida (cerebral moniliasis) usually manifests itself as diffuse cerebral involvement. Cerebral moniliasis is often associated with patients who are on multiple antibiotics. The organisms are often found in small cerebral vessels, and, as in this section, have the appearance of budding yeasts which stain dark brown

25. Histology
Microscopically, these lesions show nonspecific, acute, and chronic inflammation with microabscesses.
The fungi can be seen in the center of the abscesses, with a surrounding area of necrosis and a polymorphonuclear infiltrate.
In chronic states granulomatous reactions may develop.

27. Severe candidiasis of the distal esophagus

28. Silver stain of esophageal candidiasis

30. CRYPTOCOCCOSIS (Torulosis)
An infection acquired by inhalation of soil contaminated with the encapsulated yeast Cryptococcus neoformans, which may cause a self-limited pulmonary infection or disseminate, especially to the meninges, but sometimes to the skin, bones, viscera, or other sites.

31. Cryptococcus neoformans, a yeast which abounds in bird (especially pigeon) droppings.
Cryptococcocis more commonly occurs in patients with AIDS, sarcoidosis, leukemia, lymphoma, or Hodgkin’s diesase or those receiving long-term corticosteroid therapy are also at increased risk.

32. In such cases, chronic meningitis is most common, usually without clinically evident pulmonary lesions.

33. The yeast has a polysaccharide-rich capsule (the basis for the India Ink test), and it reproduces by narrow-based budding.
Capsular antigen diffuses into the spinal fluid and serum, where it can be detected by specific antibodies to facilitate early diagnosis.

34. PATHOLOGY
In the immunosuppressed patient, there is usually no inflammatory reaction, and gelatinous masses of fungi may develop as through in a culture medium.

35. The most common site of infection is the meninges, and the underlying cerebral cortex may be infected via the Virchow-Robin spaces and turned into swiss cheese (multifocal intracerebral lesions).
In normal man, the fungi often induce a chronic granulomatous reaction composed of macrophages, lymphocytes and foreign body giant cells.

36. Neutrophils and suppuration may occasionally be seen.
The lung and regional lymph node involvements show one or more circumscribed foci or a diffuse pattern of infiltration. Chronic infection may produce solid lesions (cryptococcomas) that remain stationary and may be mistaken for tumors.

38. Mucicarmine stain of cryptococci (staining red) in a Virchow-Robin perivascular space of the brain

39. ASPERGILLOSIS
Opportunistic infections caused by Aspergillus sp and inhaled as mold conidia, leading to hyphal growth and invasion of blood vessels, hemorrhagic necrosis, infarction, and potential dissemination to other sites in susceptible patients.

40. Invasive fungus infection in hospitals, usually by Aspergillus fumigatus or niger,
ubiquitous fungi with septate, narrow-angle branching hyphae and characteristic fruiting bodies.
It can also cause hypersensitivity reactions in normal individuals either by inhalation of their spores or by noninvasive mycelial proliferation in the lumen of previously damaged airways.

41. Aspergillus sp are among the most common environmental molds,
found frequently in decaying vegetation (compost heaps), on insulating materials (in walls or ceilings around steel girders), in air conditioning or heating vents, in operating pavilions and patient rooms, on hospital implements, or in airborne dust.
Invasive infections are usually acquired in susceptible patients by inhalation of conidia or, occasionally, by direct invasion at sites of damaged skin.

42. Major risk factors are
neutropenia,
long-term high-dose corticosteroid therapy,
organ transplantation (especially bone marrow transplantation),
hereditary disorders of neutrophil function, such as chronic granulomatous disease,
AIDS,
thrombocytopenia,
respiratory insufficiency.

43. 1-Allergic aspergillosis: It manifests itself as bronchial asthma (clinically extrinsic asthma).
People also get allergic to aspergillus, i.e., to airborne spores, which can produce type I (asthma; allegic alveolitis), type III and/or type IV (allergic bronchopulmonary aspergillosis) immune injury, and may result chronic obstructive lung disease.
Aspergillus commonly infects people who already have allergic asthma.

44. 2-Colonizing aspergillosis (aspergilloma) :
implies growth of the fungus in pulmonary cavities with minimal or no invasion of the tissues.
Proliferating masses of fungal hyphae called fungus balls can be seen as brownish masses lying free within the cavities.

45. 3-Invasive aspergillosis:
3-Invasive aspergillosis:
is an opportunistic infection confined to immunosupressed and debilitated hosts.
The primary lesions are usually in lungs.
Widespread hematogenous dissemination with involvement of the heart valves, brain, liver and kidneys is common (extrapulmonary disseminated aspergillosis).

46. The pulmonary lesions are the form of necrotizing pneumonia (target lesions), rounded gray foci with hemorrhagic borders.
Primary superficial invasive aspergillosis is uncommon but may occur in burns, beneath occlusive dressings, after corneal trauma (keratitis), or in the sinuses, nose, or ear canal.

47. Its fruting body resembles a water sprinkler (aspergillus).
Microscopically, Aspergillus appears as septate filaments of phycomycetes.
Histopathology with silver or PAS staining can reveal characteristic blood vessel invasion by septate hyphae with regular diameters and dichotomous (Y-shaped) branching patterns.
Its fruting body resembles a water sprinkler (aspergillus).
Aspergillus is more pathogenic than mucor, it also invades blood vessels, and thus areas of hemorrhage and infarction are usually superimposed on the necrotizing, inflammatory tissue reactions.

48. Microscopically, the changes of aspergillosis consist of granulomatous inflammation which is exhibited in the left panel.

49. The morphology of the Aspergillus organisms is quite characteristic and can be easily appreciated with silver stains as shown in the left panel. The hyphae are branched at a 45 degree angle and show prominent septae

50. Histologic sections from this case, stained with Gomori methenamine-silver (GMS) stain

51. Aspergillosis

52. An abscess in the centrum semiovale of the right cerebral hemisphere that formed secondary to infection with Aspergillus. Note the many small satellite lesions, a finding common to most fungal abscesses.

53. MUCORMYCOSIS (mucor, zygomycosis, phycomycosis)
Infection with tissue invasion by broad, nonseptate, irregularly shaped hyphae of diverse fungal species, including Rhizopus, Rhizomucor, Absidia, and Basidiobolus.
Infection by such bread molds as the Phycomycetes. The spores germinate best at low pH, and the hyphae then invade vessels.

54. Many of these infections are nosocomial.
Infection is most common in immunosuppressed persons, in patients with poorly controlled diabetes, and in patients receiving the iron-chelating drug desferrioxamine.
These fungi are widely distributed in the nature but cannot harm immunocompetent individuals and infect even immunosupressed persons less frequently than Candida or Aspergillus.
Many of these infections are nosocomial.

55. PATHOLOGY
Because the spores most often land in the nose, the nasal sinuses are most often involved.
Necrotic lesions usually appear on the nasal mucosa or sometimes the palate.

56. Pulmonary infections resemble invasive aspergillosis.
Lungs and gastrointestinal tract infections due to the spores, inhaled or digested.
Lung invasion may be secondary to rhinocerebral mucormucosis.
The lung lesions combine areas of hemorrhagic pneumonia with multiple infarctions.

57. GI mucormycosis occurs in severe malnutrition in children.
Cutaneous Rhizopus infections have developed under occlusive dressings.

58. PAS stain of mucormycosis showing hyphae, which have an irregular width and right-angle branching, invading an artery wall.

59. MUCORMYCOSIS

60. The hyphal forms are seen in the center of the slide surrounded by lymphocytes. In contrast to Aspergillus, the hyphae of mucor are nonseptate and branch at 90 degrees.

61. BLASTOMYCOSIS
A disease caused by inhalation of mold conidia (spores) of Blastomyces dermatitidis, which convert to yeasts and invade the lungs, occasionally spreading hematogenously to the skin or focal sites in other tissues.
Blastomycosis is a chronic infection characterized by focal suppurative and granulomatous lesions, principally in the lungs and skin.

62. Pulmonary blastomycosis may take one of several forms:
-  solitary focus,
-  progressive lung disease.
Skin infections feature a chronic dermatitis, with overgrowth of the epidermis (pseudoepitheliomatous hyperplasia) that will almost always be mistaken clinically for cancer.

63. BLASTOMYCOSIS

64. HISTOPLASMOSIS
A disease caused by Histoplasma capsulatum, causing primary pulmonary lesions and hematogenous dissemination.
Infection by Histoplasma capsulatum, a tiny non-encapsulated yeast.
The organism is found primarily in the U.S., in the Mississippi River valley, and it is ubiquitous in Kansas City. The organism is inhaled from bird (especially starling) or bat guano, or from soil where these have been deposited. Only the spores produced by the mycelium are contagious.

65. The disease has three main forms:
1. Acute primary histoplasmosis is usually asymptomatic.
2. Progressive disseminated histoplasmosis follows hematogenous spread from the lungs that is not controlled by normal cell-mediated host defense mechanisms.
Characteristically, generalized involvement of the reticuloendothelial system, with hepatosplenomegaly, lymphadenopathy, bone marrow involvement, and sometimes oral or GI ulcerations occurs, particularly in chronic cases.

66. 3. Chronic cavitary histoplasmosis is characterized by pulmonary lesions that are often apical and resemble cavitary TB.
When most people meet the histoplasma fungus, they develop only a mild fever and chest cold (primary pulmonary histoplasmosis).
Latent histoplasmosis is the residue of an old, healed infection.
Tiny calcified granulomas are found in the lungs, and often in the spleen and even the liver.

67. Chronic pulmonary histoplasmosis is a cavitating, granulomatous disease of the lungs, while disseminated histoplasmosis kills the immunosuppressed and those who, for some reason, cannot mount an immune response. The diagnosis is generally a surprise at autopsy.

68. Single organ histoplasmosis has been reported for many locations, notably the adrenal glands.
A histoplasmoma is a calcified histoplasmosis granuloma, while "sclerosing mediastinitis" is the result of serious histoplasmosis in the chest.

69. Histoplasmosis

70. Superficial Fungi (Dermatophytosis)
These infections of the epidermis, hair, or nails by fungi cause skin lesions, hair loss, and itching.
Some fungal species (e.g., those of the Tinea group, which cause “athlete’s foot”) are confined to the superficial layers of the human skin.

71. THANK YOU