Fungal Infections

Dr Bahaushe Nanisi Zorto

Senior Registra Anatomic pathology and forensic medicine.
Jos university teaching hospital
Introduction
• Fungi are eukaryotes that grow as multicellular filaments (mold) or
individual cells alone or in chains (yeast).Cell walls give fungi their
shape.
• Yeasts are round to oval and mainly reproduce by budding. Some
yeasts, such as C.albicans, can produce buds that fail to detach and
become elongated, producing a chain of elongated yeast cells called
pseudohyphae.
• Molds consist of threadlike filaments (hyphae) that grow and divide
at their tips. They can produce round cells called conidia that easily
become airborne, disseminating the fungus.
Introduction….
• Many medically important fungi are dimorphic, existing as yeast or
molds, depending on environmental conditions

• (yeast forms at human body temperature and mold forms at room

temperature).

• Fungal infections can be diagnosed by histologic examination,

although definitive identification of some species requires culture
Introduction
• Fungal infections, also called mycoses, are of four major types:
• Superficial and cutaneous mycoses are common and limited to the
very superficial or keratinized layers of skin, hair, and nails.
• Subcutaneous mycoses involve the skin, subcutaneous tissues, and
lymphatics and rarely disseminate systemically.
• Endemic mycoses are caused by dimorphic fungi that can produce
serious systemic illness in healthy individuals.
• Opportunistic mycoses can cause life-threatening systemic diseases in
individuals who are immunosuppressed or who carry implanted
prosthetic devices or vascular
Yeasts infection…….Candidiasis
• C. albicans is the most prevalent fungal pathogen of
• humans.
• Although there are more than 200 species of Candida, and are about
15 to 20 species that are frequently seen in human infections, with C.
glabrata, C. tropicalis, C. parapsilosis, and C. krusei being more
frequent.
• This class will focus on C. albicans
• Most C. albicans infections originate when these normal commensal microbiota breach
the skin or mucosal barriers.
• Residing normally in the skin, mouth, gastrointestinal tract, and vagina, Candida spp.
usually live as benign commensals and seldom produce disease in healthy people.
• These infections may be confined to the skin or mucous membranes or may disseminate
widely. In otherwise healthy people, C.albicans causes vaginitis and diaper rash.
• Individuals with diabetes and burn patients are particularly susceptible to superficial
candidiasis.
• In individuals with indwelling intravenous lines or catheters, or undergoing peritoneal
dialysis, C. albicans can spread to the bloodstream.
• Severe disseminated candidiasis most commonly occurs in patients who are neutropenic
due to leukemia, chemotherapy, or hematopoietic stem cell transplantation, and may
cause shock and DIC.
Pathogenesis….
• A single strain of C. albicans can be successful as a commensal or a pathogen. There is no known
environmental reservoir for C. albicans, unlike other Candida spp., and C. albicans has
developed multiple adaptive mechanisms to complete its life cycle fully within the human host.
• C. albicans can shift between nine distinct cell shapes. Phenotypic switching involves
coordinated transcriptional regulation of phase specific genes and provides a way for C. albicans
to adapt to changes in the environment such as temperature nutrient availability, antibiotic
therapy, or the host immune response.
• These variants can exhibit altered colony morphology, cell shape, antigenicity, and virulence.
• C. albicans produces a large number of functionally distinct adhesins involved in binding to
fibrinogen, fibronectin, laminin, epithelial cells, and endothelial cells.
• C.albicans also produces 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, and catalases, which may enable the organism to resist oxidative
killing by phagocyticcells.
• The ability of C. albicans to grow as biofilms also contributes to its
capacity to cause disease, with at least 30 factors identified to play a
role in adhesion, maturation,and dispersion that affect biofilm
formation.
• The 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 the organism’s susceptibility to immune responses and
antifungal drug therapy.
• Neutrophils, macrophages, and Th17 cells are important for protection against Candida
infection.
• Neutrophils and macrophages phagocytose C. albicans,and oxidative killing by these
phagocytes is a first line of host defense. The important role of neutrophils and macrophages is
illustrated by the increased risk of C.albicans infection in individuals with neutropenia or defects
in NADPH oxidase or myeloperoxidase. Filamentous forms, but not yeast, can escape from
phagosomes and enter the cytoplasm and proliferate.
• C. albicans yeast forms activate dendritic cells through multiple pathways, more so than do
the filamentous forms of the fungi. For example, β-1,3-glucan expressed by the yeast engages
dectin on dendritic cells and induces IL-6 and IL-23 production, which promotes Th17 responses.
• The Th17 responses elicited by C. albicans promote the recruitment of neutrophils and
monocytes. These responses are critical for protection against C. albicans infection, as shown
by recurrent mucocutaneous candidiasis in individuals with either low T-cell counts due to HIV
infection or inherited defects in Th17 cell development.
Morphology
• In tissue sections, C. albicans can appear as yeast, pseudohyphae,and, less commonly, true hyphae, defined by the presence
of septae, such as under reduced oxygen tension (Pseudohyphae, an important diagnostic clue, are a chain of buddingyeast
cells joined end to end at constrictions. All forms may be present together in the same tissue. The organisms may be seenin
routine hematoxylin and eosin stains, but a variety of specialfungal stains (Gomori methenamine-silver, periodic acid-
Schiff)are commonly used to better visualize them.
• 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 under the surface, there is mucosal hyperemia andinflammation. This form of candidiasis is seen
in newborns, debilitated people, children receiving oral steroids for asthma, and following a course of broad-spectrum
antibiotics that destroys competing normal bacterial microbiota. The other major risk group includes HIV-positive patients;
people with oral thrush for no obvious reason should be evaluated for HIV infection.
• C. albicans esophagitis is commonly seen in AIDS patients and in those with hematologic malignancies. These patients
present with dysphagia (painful swallowing) and retrosternal pain; endoscopy demonstrates white plaques and
pseudomembranes resembling oral thrush on the esophageal mucosa
• C. albicans vaginitis is common, especially in women who are diabetic, pregnant, or on oral contraceptive pills. It is usually
associated with intense itching and a thick, curdlike discharge.
• Cutaneous candidiasis can present in many different forms, including infection of the nail proper (onychomycosis); nail folds
• (paronychia); hair follicles (folliculitis); moist, intertriginous skin, such as armpit.web of fingers, toes and penile skin
• Diaper rash is a cutaneous candidal infection seen in the perineum of infants, the region in contact
with wet diapers.
• Invasive candidiasis is caused by blood-borne dissemination of organisms to various tissues or organs.
Common patterns include
(1) renal abscesses,
(2) myocardial abscesses and endocarditis,
(3) brain microabscesses and meningitis,
(4) endophthalmitis(virtually any eye structure can be involved), and
(5) hepatic abscesses.
• In any of these locations, depending on the immune status of the infected person, the fungus may
evoke little inflammation, cause the usual suppurative response, or occasionally produce granulomas.
• People with acute leukemias who are profoundly neutropenic after chemotherapy are particularly
prone to developing systemic disease.
• Candida spp. endocarditis is the most common fungal endocarditis, usually occurring in the setting of
prosthetic heart valves or in intravenous drug abusers. In the latter group, the tricuspid valve is
involved.
Cryptococcus
• Two species of cryptococcus are known to cause disease in humans, C. neoformans
and C. gattii, both of which grow as encapsulated yeasts.
• It has long been recognized that although C. neoformans may cause
meningoencephalitis in otherwise healthy individuals, it more frequently presents as
an opportunistic infection in people with AIDS, leukemia,lymphoma, systemic lupus
erythematosus, or sarcoidosis, as well as in immunosuppressed transplant recipients.
• Many of these patients receive high-dose corticosteroids, a major risk factor for C.
neoformans infection. It is estimated that there are more than 220,000 cases of
cryptococcal meningitis occurring worldwide each year, with more than 180,000
• associated deaths.
• C. neoformans is present in the soil and in bird (particularly pigeon) droppings and
infects people when it is inhaled.
• C. gattii is an obscure infectious agent that was classically viewed as a tropical or subtropical
fungus until 1999, when it was identified as the cause of an outbreak of cryptococcal disease
in the American Pacific Northwest and contiguous areas of British Columbia.
• It has subsequently been linked to cryptococcal infections in other regions of the
world,because most current tests used to diagnose cryptococcal infections do not
distinguish between C. gatti and C. neoformans, the true incidence of infections caused by
these two agents is currently uncertain.
• Based on findings from areas where C. gattii is now specifically monitored, it appears that C.
gattii is more likely than C. neoformans to cause disease in immunologically normal
individuals and to present with large lesions that produce mass effects or that mimic the
radiologic appearance of a neoplasm.
• C. gattii is associated with certain species of trees, is found in soil, and, like C.neoformans, is
acquired by inhalation.
• Cryptococcus spp. have several virulence factors that enable it to evade host defenses, as follows: •
• Polysaccharide capsule. Glucuronoxylomannan inhibits phagocytosis by alveolar macrophages, leukocyte migration, and
recruitment of inflammatory cells. Cryptococcus spp. can block dendritic cell maturation by reducing MHC class II–dependent
antigen presentation and inhibiting the production of IL-12 and IL-23. It Can make large cells, called Titan cells, that are greater
than 12 μm and have a thickened cell wall.It also produce small (micro) cells of 2 to 4 μm that may be adapted for growth in
macrophages.
• Melanin production; Laccase in the yeast catalyzes the formation of melanin which
(1) has antioxidant properties,
(2) decreases antibody-mediated phagocytosis
(3) counteracts the effects of antifungal agents,
(4) binds iron,
(5)and provides cell wall integrity.
• Enzymes. Phospholipases degrade cell wall components and may aid tissue invasion. Urease helps neutralize the reactive oxygen
species and pH of the phagocytic cell.
• Differential cellular response to phagocytes. A mechanism has been hypothesized to explain the success of the C. gattii strain in the
Northwestern U.S. outbreak: In response to reactive oxygen species in the phagocyte, some cells stop growing and acquire an
unusual morphology with tubularization of mitochondria, and other cells rapidly divide.
• Further investigation of these pathogenic pathways is needed for complete understanding.
• Cryptococcus spp. have yeast forms, but not pseudohyphal or hyphal forms, in
human hosts.
• The typically 5- to 10-μm cryptococcal yeast form has a highly characteristic
thick gelatinous capsule containing a polysaccharide that stains intense red
with periodic acid-Schiff and mucicarmine in tissues
• it can be detected in blood or CSF with various immunoassays.
• Although the lung is the primary site of infection,pulmonary involvement is
usually mild and asymptomatic, even while the fungus is spreading to the CNS.
• C. gattii appears to be particularly likely to form a solitary pulmonary
granuloma similar to the circumscribed (coin) lesions caused by Histoplasma
spp.
• The major lesions caused by Cryptococcus spp. are in the CNS, involving the meninges,
cortical gray matter, and basal nuclei.
• The host response to cryptococci is extremely variable.
• 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
• In severely immunosuppressed persons, C. neoformans may disseminate widely to the
skin, liver, spleen, adrenals, and bones.
• In immunocompetent 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 of willis
Histoplasmosis
• H. capsulatum infection is acquired by inhalation of dustparticles from soil contaminated with bird or bat
droppings that contain small spores (microconidia), the infectious form of the fungus. It is endemic along
the Ohio and Mississippi rivers and in the Caribbean. It is also found in Mexico, Central and South America,
parts of eastern and southern Europe, Africa, eastern Asia, and Australia
• Like M. tuberculosis, H.capsulatum is an intracellular pathogen that is found mainly in phagocytes. The
clinical presentations and morphologic lesions of histoplasmosis bear a striking resemblance to those of
tuberculosis, including
• (1) a self-limited and often latent primary pulmonary involvement, which may result in coin lesions on
chest radiography;
• (2) chronic, progressive, secondary lung disease, which is localized to the lung apices and causes cough,
fever, and night sweats;
• (3) spread to extrapulmonary sites, including mediastinum, adrenal glands, liver, or meninges; and
• (4) widely disseminated disease in immunocompromised patients.
• Histoplasmosis can occur in immunocompetent individuals but as per usual is more severe in those with
depressed cell mediated immunity.
Pathogenesis
• The pathogenesis of histoplasmosis is incompletely
• Macrophages ingest but cannot kill the organism without T-cell help, and
this allows the organism to multiply within phagolysosomes and
disseminate prior to the development of T-cell immunity, which takes 1
to 2 weeks.
• In individuals with adequate cell-mediated immunity, the infection is
controlled by Th1 helper T cells that recognize fungal antigens and
subsequently secrete IFN-γ, which activates macrophages and enables
them to kill intracellular yeasts.
• In addition, Histoplasma induces macrophages to secrete TNF, which
recruits and stimulates other macrophages to kill Histoplasma
Pathogenesis
• In the lungs of otherwise healthy adults, Histoplasma infections produce
granulomas, which usually become necrotic and may coalesce to produce areas
of consolidation.
• With spontaneous resolution or effective treatment, these lesions undergo
fibrosis
• and concentric calcification (tree-bark appearance)
• Histologic differentiation from tuberculosis, sarcoidosis, and coccidioidomycosis
requires identification of the 3- to 5-μm thin-walled yeast forms, which may
persist in tissues for years.
• In fulminant disseminated histoplasmosis, which occurs in immunosuppressed
individuals, granulomas do not form; instead, there are focal accumulations of
mononuclear phagocytes filled with fungal yeasts throughout the body
• The diagnosis of histoplasmosis may be established by serologic tests
for antibodies and fungal antigens, culture,or identification of the
fungus in tissue biopsies.

• The majority of cases resolve spontaneously. Progressive disease or

disease in immunocompromised patients is treated with antifungal
agents.
Blastomycosis
• Blastomyces dermatitidis is a soil-inhabiting dimorphic fungus.
• It causes disease in the central and southeastern United
States,infection also occurs in Canada, Mexico, the Middle East,
Africa, and India.
• There are three clinical forms: pulmonaryblastomycosis, disseminated
blastomycosis, and a rare primary cutaneous form that results from
direct inoculation of organisms into the skin.
• The pneumonia most often resolves spontaneously, but it may persist
or progress to a chronic lesion.
morphology
• In the normal host, the lung lesions of blastomycosis are suppurative
• granulomas.
• Macrophages have a limited ability to ingest and kill B. dermatitidis,
and the persistence of the yeast cells leads to the recruitment of
neutrophils. In tissue,
• B. dermatitidis is a round, 5- to 15-μm yeast cell that divides by broad-
based budding. It has a thick, double-contoured cell wall, and visible
nuclei
• Involvement of the skin and larynx is associated with marked epithelial
hyperplasia, which may be mistaken for squamous cell carcinoma.
Aspergillosis
• Aspergillus is a ubiquitous mold that causes allergies(allergic
bronchopulmonary aspergillosis) 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 use of corticosteroids.
• Aspergillus fumigatus is the most common pathogenic species of the
fungus.
Pathogenesis
• Aspergillus spp. are transmitted as 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 are coated in hydrophobic proteins that mask the microbial
molecules from innate immune recognition.
• As conidia grow and form hyphae, these molecules are exposed. Alveolar macrophages
recognize Aspergillus through TLR2 and the lectin dectin-1, which recognizes β-1,3-glucan
in the fungal cell wall. Both receptors activate phagocytes to ingest and kill the conidia. In
immunosuppressed states, conidia can germinate into hyphae, which then invade tissues.
• TLRs can recognize products of the fungal hyphae and trigger the release of pro-
inflammatory mediators, including TNF, IL-1, and chemokines.
• 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. The antioxidant defenses include melanin pigment, mannitol,
catalases, and superoxide dismutases. This fungus also produces phospholipases,
proteases, and toxins, but their roles in pathogenicity are not clear.
• Aflatoxin is made by Aspergillus spp.that grow on the surface of some crops,
including corn and
• peanuts, particularly in warm regions if the crops are not stored or inspected
appropriately. Aflatoxin causes acute and chronic hepatotoxicity and is associated
with increased risk of liver cancer.
• 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.
Morphology
• Colonizing aspergillosis (aspergilloma) refers to growth of the fungus in the
respiratory tract with minimal or no invasion of the tissues.
• Colonized lung cavities are usually the result of prior tuberculosis, bronchiectasis,
old infarcts, or abscesses.Proliferating masses of hyphae within proteinaceous
debris form brownish “fungus balls” 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.
• 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.
Morphology
• 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 hyphae without the distinct fruiting body cannot be
distinguished from Pseudallescheriaboydii and Fusarium spp. by
morphology alone.
• Aspergillus has a tendency to invade blood vessels, therefore areas of
haemorrhage and infarction are usually superimposed on the necrotizing,
inflammatory tissue reactions.