Candidiasis

CANDIDIASIS
Dr P MIKITHA
2nd YEAR POST GRADUATE
AECS MAARUTI COLLEGE OF DENTAL SCIENCES AND RESEARCH CENTRE

CONTENTS
 Introduction to mycology
 Candidiasis
 History of candidiasis
 Epidemiology
 Predisposing factors
 Pathogens
 Pathophysiology
 Classification of candidiasis
 Candida in HIV immuno-compromised patients
 Diagnosis
 Treatment
 Conclusion
 References

INTRODUCTION TO MYCOLOGY
 Fungi are eukaryotic microorganisms (eukaryotic -true
nucleus) i.e. has a membrane bound nucleus seen in fungi,
algae, protozoa, plants and animals.
 Prokaryotes---- (Primitive nucleus) --- does not have a
membrane bound nucleus - e.g. true bacteria.
 Study of fungi is called mycology. In Greek Mykos- meaning
mushroom.
Ananthanarayan, Panicker. Textbook of microbiology, fourth edition. Chapter The mycology. 432-455.

MORPHOLOGY OF FUNGI
Rippon J. Textbook of Medical Mycology – The pathogenic fungi and the pathogenic actinomycetes, Third Edition. Chapter
fungal infection. 237-252.

CANDIDIASIS
Oral candidiasis is a collective term given to a group of disorders
caused by the yeast candida and its species.
 An older name for this disease is moniliasis.
 Like many other pathogenic fungi, candida albicans may
exist in two forms, a trait known as dimorphism.
 The yeast form of the organism is believed to be relatively
innocuous, but the hyphal form is usually associated with
the invasion of host tissue.

HISTORY OF CANDIDIASIS
 The descriptions oral thrush go back to the time of hippocrates.
 Vulvovaginal candidiasis was first described in 1849 by Wilkinson.
 In 1875, Hausmann demonstrated the causative organism in both
vulvovaginal and oral candidiasis is the same
 With the advent of antibiotics following World War II, the rates of
candidiasis increased.
 The rates then decreased in 1950s following the development of
nystatin.

EPIDEMIOLOGY
 Incidence of candida albicans isolated from the oral cavity
has been reported to be neonates - 45%
 Healthy children - 45% - 65%
 Healthy adults - 30% - 45%
 People wearing removable dentures -50% - 65%
 Acute leukemia patients on chemotherapy – 90%
 HIV patients ->95%
 Effects of oral candidiasis may range form localized
infections to acute systemic disseminated disease.

PREDISPOSING FACTORS
 Candida species are normal oral commensals
 It is generally accepted that candidiasis as an opportunistic
infection affecting individuals who were debilitated by
another disease. It is also known that they develop in normal
healthy individuals. The transition of this innocuous
commensal to the disease causing parasite may be associated
with the virulence attributes of the organism.
Greenberg, Glick, Ship et al., Textbook of oral medicine diagnosis and treatment, Twelfth edition, Chapter 12. 320-332

 Neville et al, have identified three general factors
that may lead to clinically evident oral candidiasis.
These factors are
 The immune status of the host.
 The oral mucosal environment.
 The particular strain of C.albicans (the hyphae
form is usually associated with pathogenic
infection).
Shafer, Hine, Levy, Textbook of Oral Pathology, Sixth edition, Elsevier; 2009. Keratotic lesions. 613-623.

 Factors that alter the immune status of the host.
 Blood dyscrasis / advanced malignancy.
 Old age / infancy.
 Radiation therapy / chemotherapy
 HIV inf. / other immuno deficiency disorders.
 Endocrine abnormalities like
 Diabetes mellitus
 Hypothyroidism or Hypoparathyrodisim
 Pregnancy
 Corticosteroid therapy / hypoadrenalism

 Factors that alter the oral mucosal environment
 Xerostomia
 Prolong antibiotic therapy.
 Poor oral or denture hygiene
 Mal nutrition / gastro intestinal absorption.
 Iron, folic acid or vitamin def.
 Acidic saliva / carbohydrate rich diets
 Heavy smoking.
 Oral epithelial dysplasia.
 Chronic local irritants.

PATHOGENS
 Candida spp are asexual yeast of genus ascomycetes and
genetically diploid with presence of 8 chromosomes.
 They are small( 4-6 um) thin walled ovoid cells(
blastospores) that reproduce by budding.
 The important candidal species are C.albicans (commonest)
C.tropicalis, C.glabrata, C. pseudotrophicalis, C.
guilleierimondii, C. krusei.
 C.albicans, C. glabrata and C .tropoicalis represent more
than 80% of isolates from clinical infection.

MICROCOPIC VIEW

PATHOPHYSIOLOGY
 Establishment of the infection requires thigmotropism
(contact sensing) and attachment to epithelial cells.
 Also intercellular penetration through secretions of protease
enzymes, specifically secretory aspartyl proteinases and
phospholipase B.
 A. host factors.
 B. virulence factors.
Janaina C. O. Sardi et. al. candida spp. In periodontal disease – a review. J Oral Sci 52, 177-185, 2010

HOST FACTORS
 To colonize and infect the oral tissues candida requirs specific local and
systemic defects in host immune responses.
 Among healthy people, several immunological and non-immunological
defense mechanism are collectively responsible for antifungal properties
of the oral enviornment.
 The host factors include:
A. properties of saliva
B. oral keratinocytes
C. T-cell mediated responses.

1. Properties of saliva:
 Mechanical debridement, facilitated by salivary mucins and
proteoglycans.
 A close to neutral pH that reduces fungal adherence to
epithelial surfaces and also reduces the expression of C
albicans virulence genes.
 Antibacterial proteins such as lysozyme, lactoferrin, histatins,
calprotectin, and secretory leukocyte protease inhibitor.

2. Oral keratinocytes:
 Provides a physical barrier to candida
 Secrete a number of growth factors and cytokines thus playing
a crucial role in the inflammatory response on the epithelial
cells.
3. T-Cell mediated response:
 An intact T-helper cell 1(Th1) CD4+ response to c. albicans
and a CD4+ T-cell augmentation of monocyte/macrophage
and PMN functions appear to be necessary for the clearance
of oropharyngeal candidiasis.

VIRULENCE FACTORS
 Adhesins
 Polymorphism
 Biofilm
 Secreted hydrolases
 Invasins
 Metabolic adaptation

Adhesins
 They have special sets of (GPI) linked cell surface glycoproteins that
allow it to adhere to the surface of microorganisms.
 These glycoproteins are encoded by 8 sets of agglutinin-like
sequence (ALS) genes, ranging from Als1-7 and Als9.
 For adhesion, the Als3 gene appears to be the most important as it is
upregulated during an infection of oral and vaginal epithelial cells.
 Also, it helps with biofilm formation by helping with adhesion to
each other.

Polymorphism
 Polymorphic fungus that can grow in several different forms, primarily yeast,
pseudohyphae, and hyphae.
 For its pathogenicity, its ovoid-shaped budding yeast and parallel walled true
hyphae forms are the most important.
 The hyphae form is more prevalent for an infection, while the yeast form is
believed to be important in the spread.
 The role of pseudohyphae is not very well understood, other than being an
intermediate form between yeast and hyphae.
 Several factors can cause a change in morphology, such as pH differences,
temperature changes, CO2 levels, starvation and quorum-sensing molecules.

Biofilm
 Candida albicans have the ability to form biofilms on living and
non-living surfaces, such as mucosal membranes and catheters,
respectively.
 After the adherance of yeast cells to the surface, there is
development of hyphae cells in the upper part of the biofilm.
 Eventually, this leads to a more resistant, mature biofilm and
dispersion of yeast cells- both contributing to the pathogens
virulence.

 In the process of biofilm formation, Bcr1, Tec1 and Efg1
function as important transcriptional factors.
 Recent studies show that biofilms protect C.albicans
colonization from neutrophil attack and deter the formation of
ROS.0

Invasins
 Along with adhesion, Als3 proteins can function as invasins
that help with the invasion of C.ablicans into host epithelial and
endothelial cells.
 Another important invasin gene is Ssa1, which normally codes
for heat shock proteins.

 Basically, these specialised proteins on the pathogens surface
mediate binding to host ligands, such as E-cadherin on
epithelial cells and N-cadherin on endothelial cells, and it
induces host cells to engulf the fungal pathogen (induced
endocytosis).
 Another method of invasion is the active penetration of
C.albicans into host cells by an unknown mechanism
involving hyphae (active penetration)

Secreted hydrolases
 Secrete 3 main classes of hydrolases: proteases, phospholipase, and
lipases.
 It is proposed that these hydrolases help facilitate the pathogens active
penetration into host cells and the uptake of extracellular nutrients from
the enviornment.
 There are about 10 known secreted aspartic proteases ( Sap 1-10).
 Their exact contribution to the pathogenicity is controversial.
 For phospholipases, there are 4 major classes (A,B,C,D) and all 5
members of the B class are involved with the disruption of the host cell
surface.

Metabolic adaptation
 Are usually found in the gastrointestinal microbiome of healthy
individuals and in this enviornment nutrient levels are relatively
high.
 During niche changes in the course of infection, available nutrient
levels will also change.
 Consequently the fungus can quickly undergo metabolic adaptation,
such as their glycolysis, gluconeogenesis, and starvation responses.
 For example, in the case of candidemia, C. albicans infect the blood
stream which is typically rich in glucose.

 Neverthless, it might be phagocytosed into a macrophage or
neutrophil, where its surrounded by ROS, AMP’s.
 In response C. albicans quickly switch the glycolysis to
starvation response with the activation of glyoxylate cycle.
 Due to this flexibility, C. albicans can infect almost every organ
in a human host through bloodstream, providing candidemia’s
higher mortality rate.

CLASSIFICATION OF
CANDIDIASIS

 Tony Axell, Samaranayaka and Reichart (1997) have proposed a re classification.
One of reasons being unusual clinical variants have appeared with the pandemic
progression of the HIV infection.
 I. Primary oral candidiasis
Acute forms - Pseudomembranous
Erythematous
Chronic types -hyperplastic - Nodular.
- Plaque Like
-Erythematous
-Pseudomembranous.

II. Secondary oral candidiasis - Oral manifestations of systemic
mucocutaneous candidiasis as a result of diseases such as thymic
aplasia and candidiasis endocrinopathy syndrome.
III. Candida associated lesions - Angular cheilitis
Denture stomatitis
Median rhomboid glossitis
IV. Keratinised primary lesions super infected with candida:
Leukoplakia
Lichen planus
Lupus erythematosus

PRIMARYACUTE/CHRONIC
ORALCANDIDIASIS
1.Pseudomembranous candidiasis:
 Also known as thrush.
 Clinical appearance
 Semi adherent, whitish, slightly elevated confluent patches or
plaques resembling milk curds or cottage cheese.
 Plaques can be easily removed by wiping with a gauze swab,
leaving a red and slightly bleeding surface or even a shallow
ulceration.

 Site of occurrence - Buccal mucosa
Mucobuccal folds
Oropharynx.
Dorsal tongue
 White plaque are composed of tangled masses of hyphae
yeasts, desquamated epithelial cells and debris.
H/P:
 There is hyphae penetration and colonization, but without
significant or no inflammatory response either in the
epithelium / connective tissue.
• Clinical sign distinguishing from leukoplakia is it cannot be
scraped / rubbed off.

2. Erythematous candidiasis.
 Oral symptoms of acute erythematous form are quite marked
because of numerous erosions and intense inflammation.
 White flecks or plaque is not seen in this type of lesion.
 Site of occurance : Tongue, gingiva, Palate.
 Tongue typically shows depapillation and dekeratinisation.
 Predisposing factors - Antibiotics ,Corticosteroid aerols.

 Other forms of erythematous candidasis -central papillary
atrophy
 In some patients acute atrophic form develops when the
pseudomembrane is shed.
Histopathology –
 Epithelium - Hyperplastic with superficial necrotic and
desquamating parakeratotic layer infiltrated both by hyphae and
yeasts and by inflammatory cells. Predominantly neutrophil
leucocytes. Neutrophils may accumulate to form micro abscesses.

Pseudomembranous candidiasis Erythematous candidiasis

PRIMARY CHRONIC
CANDIDIASIS
1. Hyperplastic candidiasis
 Also referred as candidal leukoplakia.
 Clinical appearance :
 Persistent white patch on the oral mucosa indistinguishable from
leukoplakia.
 Characteristically the lesions present as dense, opaque white
patches of irregular thickness and density with a rough or nodular
surfaces.

 Site of occurrence
 Buccal mucosa adjacent to the commmissure of the lips and
present as roughly triangular, often bilateral white plaques
tapering posteriorly.
 Often associated with angular cheilitis.
 In many patients there is a strong association with tobacco
smoking.

Histo pathology :
 Epithelium is parakeratinized and is generally marked and
hyperplastic and acanthotic.
 Many of the cell in the para keratinized surface of the
epithelium are separated by oedema and numerous neutrophil
leucocytes, the neutrophils together collecting together as
micro abscesses.
 Chronic hyper plastic candidosis is considered to be a pre
malignant lesion and epithelial dysplasia is seen in about 50%
of cases.

CANDIDIASISASSOCIATED
LESIONS
1.Candida associated lesions denture stomatitis.
Chronic inflammatory changes of the denture bearing mucosa.
 Occurs in the confined space between the mucosa and the
upper denture
 Inadequate cleaning of the fitting surface.
 Wearing the denture throughout the night all appear to
favor the over growth of candida resulting in a local
imbalance of the host parasite relationship.

Histo pathology :
 The epithelium shows hyperplasia / atrophy.
 Surface being either parakeratinized or non keratinised.
 Leucocytes infiltrate the epithelium forming micro
abscesses.

2. Angular Chelitis / Perleche / Angular stomatitis.
 Multifactorial disease of infectious origin.
 Occurs predominantly in denture wearers.
 Commonly caused by >yeasts, staphylococci, β-Streptococci
Clinical appearance
 Soreness.
 Erythema
 Crust formation
 Fissuring at the corners of the mouth.

 Seen on deep folds of skin at the angles of the mouth, which
may be associated with loss of occlusal height in old age or
due to decrease vertical height in dentures.
 Nutritional deficiencies -Thiamine. ,Riboflavin ,Folic acid,
Iron deficiency anemia

3. Median Rhomboid glossitis
 In the past, this was thought to be a developmental defect of
the tongue. Investigators have noted a consistent relationship
between the lesion and candida albicans.
Clinical appearance
 Diamond shaped depapillated erythematous patch on the
midline of the tongue dorsum.
 Erythema is due in part of the loss of the filiform papillae in
this area.
 Mixed microbiological etiology

MUCO CUTANEOUS CANDIDIASIS
(CHRONIC MUCOCUTANEOUS
CANDIDIASIS -CMC)
 Several oral candidiasis may also be seen as a component of a
relatively rare group of immunologic disorders known as
mucocutaneous candidiasis.
 Result of a defect in cell mediated immunity or structure of the
epidermis. Several distinct immunologic dysfunctions have been
identified and severity of the candidal infection correlates with the
immunologic defect.

Types
 Familial CMC.
 Diffuse CMC
 Candidiasis endocrinopathy syndrome.
 CMC of late onset > 35 yrs.
Clinical appearance
 Thick white plaque that cannot be scraped / rubbed off.
 Usually associated with endocrine abnormalities
 Nutritional def. >Iron deficiencies.

ID REACTION
 Some persons with chronic candida infections develop a secondary
skin response characterized by a localized or generalized sterile
vesiculopapular rash that is believed to be an allergic response to
candida antigens.
 These lesions referred to as monilids, id reaction, usually resolve
with treatment of the candida infection.

AIDS related oral candidiasis
Primary HIV infection is associated with
 Severe aphthous stomatitis
 Oropharyngeal and oesophageal candidiasis.
Clinical variants of oral candidiasis seen are
 Pseudomembranous
 Erythematous.
 Hyperplastic
 Angular chelitis.

 The pseudomembranous and erythematous variants forms the
most common clinical presentations of the mucosal candidiasis
associated with HIV-infection.
 Symptoms include burning pain, altered taste sensation, difficulty
swallowing liquids and solids.
 Immunodeficiency T-helper cells predisposes to secondary
infections (fungi being fairly common)
 C. albicans serotype B is prevalent.
Spampinoto C, Leonardi D. Candida infections, causes, targets and resistance mechanisms: traditional and alternative
antifungal agents. BioMed Research Internation, 2013 june 6, vol. 10, 230-245.

 The pseudomembranous form can be easily diagnosed by
demonstrating the presence of candidal yeast and pseudohyphae
on wet mounts or stained smears of material obtained by
swabbing the lesions.
 Confirmed by the isolation of candida species on culture.
 In erythematous form, the sparse presence of candida at the
mucosal surface frequently requires a biopsy and PAS ataining
to establish a formal diagnosis.
 Candidiasis can occur at any time during the course of HIV
infection.

 Oral burdens of C. albicans are augmented in HIV-infected
patients even prior to the first episode of candidiasis and the
intensity of carriage increases significantly in the progression
from asymptomatic candida carrier to an episode of candidiasis.
 Pseudomembranous form of OPC and oesophageal candidiasis
increases dramatically in advanced HIV disease associated with
CD4+ cell counts of <200/mm3, while erythematous candidiasis
and angular chelitis are less strongly associated with late disease.

Histopathology
 Candida infection in HIV infected persons show weak
inflammatory reaction.
 Epithelium invaded by numerous hyphae or Pseudo hyphae
without the characteristic massive infiltrate of
polymorphonuclear leucocytes.
 Areas of sub epithelial inflammation often contain few or no
leucocytes.

CLINICAL EXPRESSION OFCANDIDA
INFECTION IN HIV – IMMUNO
COMPROMISED PATIENTS.
 Reichart et al (1994) reported on seven dentate homosexual
AIDS patients who developed inflammatory papillary hyperplasia
of the palate in association with candida infections.
 A characteristic form of periodontal disease: linear gingival
erythema, is clinically expressed as a gingival erythematous band
of at least 2mm extending to adjacent papilla.

 Grbic et al (1995) have studied the presence of linear gingival
erythema in two groups of patients. One group was composed of
homosexual men and other group was composed of parenteral
drug users.
 Both groups, included HIV sero positive and HIV sero negative
patients. Linear gingival erythema was present in greater numbers
in the drug user group. (Statistically significant) irrespective of
serostatus

 The authors suggest that this finding may be related to the
extremely poor oral hygiene observed in the parenteral drug user
group.
 The presence of candidiasis in homo sexual men was related with
true HIV associated linear gingival erythema. The authors
hypothesis that HIV positive patients may be more sensitive to
certain bacterial pathogens that, in the presence of candida would
notice them prone to developing linear gingival erythema.

DIAGNOSIS
 Laboratory tests: direct microscopy
 Culture
 Serology
 Biopsy
 Skin test
 Imprint culture technique
 Oral rinse technique
 Salivary culture technique

Direct microscopy:
 gram stained smears & KOH mounts from lesions of skin, nail
or mucous membrane shows budding gram positive yeast
cells.
 Other stains: PAS and Gomori’s methenamine silver stain.

CULTURE
 Cultures are obtained on sabourad’s dextrose agar (SDA) and
on ordinary bacteriological culture media, eg: blood agar at
room temperature or at 37 degrees celsius.
 Colonies are creamy white, smooth with a yeast odour.
 Gram stained smears from colonies shows gram positive
budding yeast cells.

Cornmeal agar:
for identification of characteristic terminal chlamydospores,
incubation at 25 degree celsius.
Blood agar:
non hemolytic, smooth, moderate colonies, resemble staph.
Colonies.

Sabouraud’s agar
Cornmeal agar Blood agar

Chromagar:
 this is special media for candida, use to identify the different
species, each species colonies have a characteristic color.
 C.albicans- light green to bluish green
 C.glabrata-rose
 C.krusei-rose pale
 C.tropicalis-blue-violet

IDENTIFICATION
Germ tube test:
 C.albicans has ability to germ tubes within two hours when
incubated in human serum at 37 degree celsius.
(REYNOLDS-BRAUDE PHENOMENON)

Chlamydospore formation:
 When C.albicans cultured on cornmeal agar and incubate at
26 degree celsius for 48-96 hrs, it produces chlamydospores,
while the other species are non producing.

SEROLOGY
 Agglutins appear in the sera of pt. But as they are frequent in
normal persons also, they are not helpful in diagnosis.
 The detection of circulating cell wall mannan, using a latex
agglutination test or an enzyme immunoassay, is much more
specific, but the test lacks senstivity.

BIOPSY
 A biopsy of affected tissue may be indicated, especially when
candidiasis is suspected in conjunction with some concurrent
pathology, such as candidal leukoplakia, epithelial dysplasia,
squamous cell carcinoma or lichen planus.
 The section should be stained with PAS or Gridley’s or Gomori
methenamine silver(GMS), because candida species stain poorly
by hematoxylin and eosin.

SKIN TEST
 Delayed hypersenstivity to candida is so universal that skin
testing with candida extracts is used as an indicator of the
functional integrity of cell mediated immunity

IMPRINT CULTURE TECHNIQUE
 This technique uses a sterile plastic foam pad of known size
(2.5*2.5) dipped in sabourard’s broth and placed on the
suspect mucosal surface for 60 sec.
 Then this plastic foam is placed directly on sabouraud’s or
Pagano-Levin agar.

 Candida density at each site is determined by a GallenKamp
colony contcat and expressed as CFU/mm2.
 ≥30 CFU/mm2 of mucosa in dentate.
 ≥ 49 CFU/mm2 in denture wearers.

ORALRINSE TECHNIQUE
 Here the pt. is asked to rinse the mouth for 60 sec. with 10ml of
sterile phosphate buffered saline or sterile water. The oral rinse is
centrifuged at 1700g for 10min and the deposit resuspended in
1ml of sterile PBS.
 The concetrated oral rinse is now inoculated on apropriated media
to assess CFU/mm of rinse sample using a spiral plate prior to
incubation.

SALIVARY CULTURE TECHNIQUE
 This involves pt. 2ml of mixed unstimulated saliva into a
sterile, universal container.
 The number of canida expressed as CFU/mm of saliva is
estimated by counting the resultant growth of sabouraud’s
agar.

TREATMENT
 Cutaneous candidiasis: most localized cutaneous candidiasis
infections may be treated with any number of topical
antifungal agents.
 If the infection is paronychia, the most important aspect of
therapy is drainage of abscess, followed by oral antifungal
therapy with either fluconazole or itraconazole.

 Chronic mucocutaneous candidiasis - I.V. Fluconazole
Amphotericin B.
 Acute oral candida infection - topical nystatin. Oral Susp
USP. 100,000 units/ml.
 More effective treatment of acute and chronic candidasis
can usually obtained by a once daily dose of 200 mg
ketoconazole or 100 mg fluconazole for 2 weeks.

 Treatment of denture base mouth and angular chelitis must
include elimination of candida from the denture surface either by
making a new denture or by relining an existing denture.
 Nystatin applied as a cream under a denture or to the lesions of
angular chelitis will eliminate redness and promote shrinkage of
mucosa and healing of fissures.

CONCLUSION
 Fungal infections aptly recognized as “Diseases of the
diseased” is increasingly alarmingly due to the pandenic of
AIDS. Advances in medical and pharmacological treatment
have resulted in greater life expectancy for patients with
malignant and metabolic disease and other systemic,
conditions, which can predispose patients to oral and systemic
fungal infections.

REFERENCES
 Greenberg, Glick, Ship et al., Textbook of oral medicine
diagnosis and treatment, Twelfth edition, Chapter 12. 320-
332.
 Joklik, Willett, Amos et al., Textbook of Zinsser
Microbiology, Ninth edition, Jaypee brothers medical
publishers; Mycoplasma and ureaplasma. 210-237.

•Shafer, Hine, Levy, Textbook of Oral Pathology, Sixth
edition, Elsevier; 2009. Keratotic lesions. 613-623.
•Harsh Mohan, Textbook of Pathology, fourth edition,
Jaypee Brothers Medical Publishers; 2003. Chapter 8. 227-
232.
•Rippon J. Textbook of Medical Mycology – The pathogenic
fungi and the pathogenic actinomycetes, Third Edition. Chapter

 Ananthanarayan, Panicker. Textbook of microbiology, fourth
edition. Chapter The mycology. 432-455.
 Spampinoto C, Leonardi D. Candida infections, causes, targets
and resistance mechanisms: traditional and alternative antifungal
agents. BioMed Research Internation, 2013 june 6, vol. 10, 230-
245.
 Janaina C. O. Sardi et. al. candida spp. In periodontal disease –
a review. J Oral Sci 52, 2010, 177-185.

Candidiasis

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