Infectious Diseases

1. Dr. Sobia Khalid

2. PATHOGENESIS AND DIAGNOSIS
OF COMMON FUNGAL INFECTIONS

3. FUNGAL INFECTIONS
 Fungi are eukaryotes with cell walls that give
them their shape.
 Fungal cells can grow as
 Multicellular filaments called molds or as
 Single cells or chains of cells called yeast.

4. TYPES OF FUNGAL INFECTIONS
Fungal infections, also called mycoses, are of four major
types:
 Superficial and cutaneous mycoses, which are
common and limited to the very superficial or
keratinized layers of skin, hair, and nails.
 Subcutaneous mycoses, which involve the skin,
subcutaneous tissues, and lymphatics and rarely
disseminate systemically.
 Endemic mycoses, which are caused by dimorphic
fungi that can produce serious systemic illness in
healthy individuals.
 Opportunistic mycoses, which can cause life-
threatening systemic diseases in individuals who are
immunosuppressed or who carry implanted
prosthetic devices or vascular catheters.

5. YEASTS
CANDIDIASIS
 Residing normally in the skin, mouth,
gastrointestinal tract, and vagina, Candida species
usually live as benign commensals and seldom
produce disease in healthy people.
 Most often C. albicans, is the most frequent cause
of human fungal infections.
 Most types of Candida infections originate when
the normal commensal flora breach the skin or
mucosal barriers.

6. Pathogenesis
 Candida can shift between different phenotypes in a
reversible and apparently random fashion.
 Candida lead to disease state because of the following:
 Adhesins
 Enzymes
 Adenosine
 Ability to grow as biofilms
 Candida produce a large number of functionally distinct
adhesins that mediate adherence to host cells, some of
which also function in Candida morphogenesis or
signaling.These adhesins include
 An integrin-like protein, which binds arginine-glycine-aspartic
acid (RGD) groups on fibrinogen, fibronectin, and laminin
 A protein that resembles transglutaminase substrates and binds
to epithelial cells

7.  Several agglutinins that bind to endothelial cells or
fibronectin.
 Adhesion is an important determinant of virulence,
since strains with reduced adherence to cells in vitro
are avirulent in experimental models in vivo.
Differential expression of adhesins by yeast and
filamentous forms leads to recognition of distinct
receptors on host cells.
 Candida produce a number of enzymes that
contribute to invasiveness, including
 At least nine secreted aspartyl proteinases, which may
promote tissue invasion by degrading extracellular matrix
proteins
 Catalases, which may enable the organism to resist
oxidative killing by phagocytic cells.
 Candida also secrete adenosine, which blocks
neutrophil oxygen radical production and
degranulation.

8.  Candida biofilms are microbial communities
consisting of mixtures of yeast, filamentous forms,
and fungal-derived extracellular matrix. C. albicans
can form biofilms on implanted medical devices that
reduce susceptibility of the organism to immune
responses and antifungal drug therapy.
 Innate immunity and T-cell responses are important
for protection against Candida infection.
 Neutrophils and macrophages phagocytose
Candida, and oxidative killing by these phagocytes is
a first line of host defence.
 Filamentous forms, but not yeast, can escape from
phagosomes and enter the cytoplasm and
proliferate.

9.  Candida yeast activate dendritic cells to produce
IL-12 more than do the filamentous forms of the
fungi. As a result, the yeast forms elicit a
protective antifungal TH1 response, while
filamentous forms tend to stimulate a
nonprotectiveTH2 response.
 Candida also elicit TH17 responses, which are
responsible for recruiting neutrophils and
monocytes.
 Candida T-cell responses are particularly
important for protection against mucosal and
cutaneous Candida.

10. Morphology
 C. albicans can appear as yeastlike forms
(blastoconidia), pseudohyphae, and, less commonly,
true hyphae, defined by the presence of septae.
 Pseudohyphae, an important diagnostic clue,
represent budding yeast cells joined end to end at
constrictions.
 All forms may be present together in the same
tissue.
 The organisms may be visible with routine
hematoxylin and eosin stains, but a variety of special
“fungal” stains (Gomori methenamine–silver,
periodic acid–Schiff) are commonly used to better
visualize them.

13.  Most commonly candidiasis takes the form of a
superficial infection on mucosal surfaces of the oral
cavity (thrush).
 Florid proliferation of the fungi creates gray-white,
dirty-looking pseudomembranes composed of
matted organisms and inflammatory debris. Deep to
the surface, there is mucosal hyperemia and
inflammation.
 This form of candidiasis is seen in
 Newborns
 Debilitated people
 Children receiving oral steroids for asthma
 Following a course of broad-spectrum antibiotics that
destroy competing normal bacterial flora.
 HIV-positive patientspeople with oral thrush for no
obvious reason should be evaluated for HIV infection.

14. Candida esophagitis
 It is commonly seen in AIDS patients and in those
with hematolymphoid malignancies.
 These patients present with
 Dysphagia (painful swallowing)
 Retrosternal pain
 Endoscopy demonstrates white plaques and
pseudomembranes resembling oral thrush on
the esophageal mucosa

16. Candida vaginitis
 It is a common form of vaginal infection in women,
especially those who are diabetic, pregnant, or on oral
contraceptive pills.
 It is usually associated with intense itching and a thick,
curdlike discharge.
Cutaneous candidiasis
 It can present in many different forms:
 Infection of the 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”).
 “Diaper rash” is a cutaneous candidial infection seen in
the perineum of infants, in the region of contact with wet
diapers

17. Invasive candidiasis
 It is caused by blood-borne dissemination of
organisms to various tissues or organs. Common
patterns include
 Renal abscesses
 Myocardial abscesses and endocarditis
 Brain microabscesses and meningitis
 Endophthalmitis (virtually any eye structure can be involved)
 Hepatic abscesses.
 Candida pneumonia, which usually presents as bilateral
nodular infiltrates.
 In any of these locations, depending on the immune
status of the infected person, the fungus may evoke
little inflammatory reaction, cause the usual
suppurative response, or occasionally produce
granulomas.

18.  People with acute leukemias who are profoundly
neutropenic after chemotherapy are particularly
prone to developing systemic disease.
 Candida endocarditis is the most common fungal
endocarditis, usually occurring in the setting of
prosthetic heart valves or in intravenous drug
abusers.
Chronic Mucocutaneous Candidiasis
 It is a chronic refractory disease aflicting the mucous
membranes, skin, hair and nails.
 It is associated with underlyingT-cell defects.
 Predisposing conditions include endocrinopathies (
mostly hypoparathyroidism and Addison’s disease).

19. Diagnosis
 Both yeasts and pseudohyphae are Gram +ve
 Grows well on Sabouraud’s agar

20. CRYPTOCOCCOSIS
 Cryptococcus neoformans grows as an encapsulated
yeast that causes meningoencephalitis in otherwise
healthy individuals.
 More frequently, it presents as an opportunistic
infection in people with AIDS, leukemia, lymphoma,
systemic lupus erythematosus, or sarcoidosis, as well
as in transplant recipients.
 Many of these patients receive high-dose
corticosteroids, a major risk factor for Cryptococcus
infection.
 Cryptococcus neoformans is present in the soil and in
bird (particularly pigeon) droppings and infects people
when it is inhaled.

21. Pathogenesis
 Virulence factors include:
 A polysaccharide capsule
 Melanin production
 Enzymes
 These mechanisms are effective only in and can lead
to disseminated disease in immunosuppressed
individuals.
 Glucuronoxylomannin, the principal capsular
polysaccharide of C. neoformans, is a major virulence
factor that inhibits phagocytosis by alveolar
macrophages, leukocyte migration, and recruitment
of inflammatory cells.
 C. neoformans can undergo phenotypic switching,
which leads to changes in the structure and size of
the capsule polysaccharide, providing a means to
evade immune responses

22.  Cryptococcus neoformans makes laccase, which
catalyzes the formation of a melanin-like
pigment.
 These fungi also make a number of other
enzymes, including a serine proteinase that
cleaves fibronectin and other basement
membrane proteins, which may aid tissue
invasion.
 C. neoformans can establish latent infections
accompanied by granuloma formation that can
reactivate in immunosuppressed hosts.
 The effects of melanin may be related to its
antioxidant properties.

23. Morphology
 Cryptococcus has yeast but not pseudohyphal or
hyphal forms.
 The 5- to 10-μm cryptococcal yeast has a highly
characteristic thick gelatinous capsule.
 Capsular polysaccharide stains intense red with
periodic acid–Schiff and mucicarmine in tissues
and can be detected with 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.

24.  Lung is the primary site of infection, however,
pulmonary involvement is usually mild and
asymptomatic, even if the fungus is spreading to
the CNS. C. neoformans, however, may form a
solitary pulmonary granuloma.
 The major lesions caused by C. neoformans are in
the CNS, involving the meninges, cortical gray
matter, and basal nuclei.
 In immunosuppressed people, organisms may
evoke virtually no inflammatory reaction, so
gelatinous masses of fungi grow in the meninges
or expand the perivascular Virchow-Robin spaces
within the gray matter, producing the so-called
soap-bubble lesions.

25.  In severely immunosuppressed persons, C.
neoformans may disseminate widely to the skin,
liver, spleen, adrenals, and bones.
 In nonimmunosuppressed people or in those with
protracted disease, the fungi induce a chronic
granulomatous reaction composed of
macrophages, lymphocytes, and foreign body–
type giant cells.
 Suppuration also may occur, as well as a rare
granulomatous arteritis of the circle ofWillis.

27. Diagnosis
 Yeast cells can be detected microscopically in
 Sputum
 CSF
 Pus
 Occasionally in blood culture from AIDS patients
 Gram +ve, but stain poorly and unevenly
 Grow well on Blood and Sabouraud agar

28. MOLDS
ASPERGILLOSIS
 Aspergillus is a ubiquitous mold that causes
allergies (allergic bronchopulmonary aspergillosis-
Brewer’s Lung) in otherwise healthy people and
serious sinusitis, pneumonia, and invasive disease in
immunocompromised individuals.
 The major conditions that predispose to
Aspergillus infection are neutropenia and
corticosteroids.
 Aspergillus fumigatus is the most common species
to cause disease, and it produces severe invasive
infections in immunocompromised individuals.

29. Pathogenesis
 Aspergillus species are transmitted by airborne
conidia, and the lung is the major portal of entry.
 The small size of A. fumigatus spores, approximately
2 to 3 μm, enables them to reach alveoli.
 Conidia germinate into hyphae, which then invade
tissues.
 Neutrophils and macrophages are the major host
defenses against Aspergillus. Alveolar macrophages
ingest and kill the conidia, while neutrophils produce
reactive oxygen intermediates that kill hyphae.
 Invasive aspergillosis is highly associated with
neutropenia and impaired neutrophil defenses.
 Aspergillus produces several virulence factors,
including adhesins, antioxidants, enzymes, and
toxins.

30.  Conidia can bind to fibrinogen, laminin, complement,
fibronectin, collagen, albumin, and surfactant
proteins.
 Aspergillus produces several antioxidant defenses,
including melanin pigment, mannitol, catalases, and
superoxide dismutases. This fungus also produces
phospholipases, proteases, and toxins.
 Restrictocin and mitogillin are ribotoxins that inhibit
host-cell protein synthesis by degrading mRNAs.
 Sensitization to Aspergillus spores produces an
allergic alveolitis.
 Allergic bronchopulmonary aspergillosis, associated
with hypersensitivity arising from superficial
colonization of the bronchial mucosa, often occurs in
asthmatic people.

31. Morphology
Colonizing aspergillosis (aspergilloma)
 It usually implies growth of the fungus in
pulmonary cavities with minimal or no invasion of
the tissues (the nose also is often colonized).
 The cavities are usually the result of prior
tuberculosis, bronchiectasis, old infarcts, or
abscesses.
 Proliferating masses of hyphae form brownish
“fungal balls” lying free within the cavities.
 The surrounding inflammatory reaction may be
sparse, or there may be chronic inflammation and
fibrosis. People with aspergillomas usually have
recurrent hemoptysis.

33.  Invasive aspergillosis is an opportunistic infection that is
confined to immunosuppressed hosts.
 The primary lesions are usually in the lung, but
widespread hematogenous dissemination with
involvement of the heart valves and brain is common.
 The pulmonary lesions take the form of necrotizing
pneumonia with sharply delineated, rounded, gray foci
and hemorrhagic borders; they are often referred to as
target lesions.
 Aspergillus forms fruiting bodies (usually in lung cavities)
and septate filaments, 5 to 10 μm thick, branching at
acute angles (40 degrees).
 Aspergillus has a tendency to invade blood vessels;
therefore, areas of hemorrhage and infarction are usually
superimposed on the necrotizing, inflammatory tissue
reactions. Rhinocerebral Aspergillus infection may occur
in immunosuppressed individuals

34. Diagnosis
 KOH preparation of sputum in aspergilloma
and invasive aspergillosis
 Flourescence microscopy

35. ZYGOMYCOSIS(MUCORMYCOSIS)
 Zygomycosis (mucormycosis, phycomycosis) is an
opportunistic infection caused by “bread mold fungi,”
including Mucor, Rhizopus, Absidia, and
Cunninghamella, which belong to the class
Zygomycetes.
 These fungi are widely distributed in nature and infect
immunosuppressed people.
 Major predisposing factors are
 Neutropenia
 Corticosteroid use
 Diabetes mellitus
 Iron overload
 Breakdown of the cutaneous barrier (e.g., as a result of burns,
surgical wounds, or trauma).

36. Pathogenesis
 Zygomycetes fungi are transmitted by airborne
asexual spores.
 Most commonly, inhaled spores produce infection
in the sinuses and the lungs, but percutaneous
exposure or ingestion can also lead to infection.
 The thermotolerance of the spores of some
species of zygomycetes might contribute to their
spread.
 Macrophages provide the initial defenses by
phagocytosis and oxidative killing of germinating
spores.
 Neutrophils have a key role in killing fungi during
established infection.

37. Morphology
 Zygomycetes form nonseptate, irregularly wide (6
to 50 μm) fungal hyphae with frequent right-angle
branching, which are readily demonstrated in
necrotic tissues by hematoxylin and eosin or
special fungal stains.
 Depending on whether the spores (which are
widespread in dust and air) are inhaled or
ingested, the three primary sites of invasion are
 Nasal sinuses
 Lungs
 Gastrointestinal tract

38.  Most commonly in diabetics, the fungus may spread
from nasal sinuses to the orbit and brain, giving rise
to rhinocerebral mucormycosis.
 The zygomycetes cause local tissue necrosis, invade
arterial walls, and penetrate the periorbital tissues
and cranial vault.
 Meningoencephalitis follows, sometimes
complicated by cerebral infarctions when fungi
invade arteries and induce thrombosis.
 Lung involvement with zygomycetes may be
secondary to rhinocerebral disease, or it may be
primary in people with severe immunodeficiency.
 The lung lesions combine areas of hemorrhagic
pneumonia with vascular thrombi and distal
infarctions.

40. Diagnosis
 KOH preparations of exudates from infected
lesions or tissue

41. HISTOPLASMOSIS
 Caused by
 Histoplasma capsulatum( classical or small form)
 Histoplasma duboisii( African or large form)
 Histoplasma capsulatum
 Asymptomatic
 Acute- symptoms similar to pneumonia
 Chronic- resembles pulmonary tuberculosis
 Generalized infections are rare, occuring mostly
in infants and immunocompromised patients.

42.  Histoplasma duboisii
 Occurs in tropicalAfrica
 Infection may take form of
 A localized skin nodule which may ulcerate
 Bone abscess
 Generalized infection
 Lungs are only occasionally infected

43. Diagnosis
 Yeast forms can be found in
 Sputum( H.capsulatum)
 Pus from lesions( H.duboisii)
 Bone marrow aspirates
 Blood cultures-in generalized infections
 Yeast seen in cytoplasm of endothelial and
mononuclear cells in Giemsa stained
preparations
 Flourescence microscopy