MUCOCUTANEOUS CANDIDIASIS Dr. Riina Rautemaa-Richardson Infectious Diseases Consultant Wythenshawe Hospital, Manchester University NHS FT

Intended Learning objectives To understand the morphology, pathogenesis and spread of Candida species. To identify the various clinical syndromes caused by Candida species. To know the different presentations of oropharyngeal candidiasis. To know how to diagnose oropharyngeal candidiasis. To be aware of the various options of treatment.

Introduction Over 20 species of Candida yeasts can cause infection in humans. Divided into Candida albicans and Non-Candida albicans species (NAC). Normal resident yeasts on skin, mucous membranes, GI tract without symptoms. 30-50% of healthy individual have Candida in mouth & GI tract. The fungal infection caused by Candida can be called ‘candidiasis’ or ‘candidosis’.

Candida species Candida albicans Most prevalent and pathogenic of all the Candida species. Non Candida albicans (NAC) C. glabrata - commonest C. parapsilosis C. tropicalis C. krusei Rarer species C. orthopsilosis (parapsilosis complex) C. guilliermondii C. rugosa. C. lusitaniae C. kefyr C. zeylanoides C. dubliniensis (albicans complex) The photo shows C. albicans on cornmeal agar, which is the best medium for conventional identification of different species.

morphology Pinched cells that fail to separate. Source: Delma et al . Eukaryot Cell. 2011; 10(9): 1173–1182 Coevolution of Morphology and Virulence in Candida Species Pinched cells that fail to separate.

Morphological evolution Ability to change morphological forms confers increased virulence Delma et al . Eukaryot Cell. 2011 Sep; 10(9): 1173–1182 Coevolution of Morphology and Virulence in Candida Species Delma et al. Eukaryot Cell. 2011;10(9): 1173–1182

Characteristics of Candida species Dimorphic (ability to exist as hyphae or yeast cells) Versatile and adaptable to different anatomical sites. Commonly found as commensals on skin, GIT & vagina. Individuals often colonized by 1 strain in different anatomical sites. Ability to cause disease due to weakened host immune system and virulence factors. Immunity is site-specific.

Transmission Endogenous. Exogenous Overgrowth of commensal yeasts and translocation through the gut wall into the bloodstream. Persistent Candida species carriage in the oral cavity is common with higher colonization rate in young children and denture wearers. Exogenous Hands of health care workers Vaginal canal during birth Devices e.g. urinary catheters & IV cannula

Pathogenesis Overgrowth of commensal yeasts which adhere to various medical devices surfaces or host tissues & have ability to evade host defences Majority of infections are associated with biofilm growth which can be drug resistant. Morphological transformation of C. albicans species Production of hydrolytic and phospholipase enzymes that damage tissues Host factors that impair immunity or critically ill patients

Virulence factors Adherence to host tissue and medical devices. Biofilm formation Hydrolytic enzymes.

Colonisation or infection? Fungal load? Formation of hyphae? Presence of biofilms? Invasion? Elicitation of immune responses? Tissue damage?

What is a biofilm? Highly structured communities of microorganisms that are surface- associated or attached to each other. They have a protective extracellular matrix that encloses them which is self produced. Over 80% microorganisms exist in biofilms and majority of human infections involve a biofilm. source: Eukaryotic Cell April 2005 vol. 4 no. 4 633-638

Changing Epidemiology Increase in prevalence of candidiasis. Likely relationship with increased use of medical devices. Increase infections due to Non-Candida albicans (NAC) species. Increase in antifungal resistant yeasts. Geographical variations in infections due to NAC species.

Clinical syndromes Candida vulvo-vaginitis. Hypersensitivity Candida vulvo-vaginitis. Candida perianal dermatitis. Candida balanitis. Skin and nail infections. Oral candidiasis. Sepsis and disseminated disease. Immune-suppression

Oropharyngeal candidiasis

Etiology of oral candidiasis Candida albicans - most prevalent. Rare causes C. glabrata (increases with increasing age) C. krusei C. tropicalis

Risk factors (1) Impaired systemic defense mechanism: Infancy Diabetes Malnutrition Immunosuppression: Primary. Acquired.eg medications, cancer, HIV Impaired local defense: Decreased saliva production. Topical corticosteroids including inhalers. Radiotherapy to head and neck

Risk factors (2) Altered normal flora: Antibiotics Reflux Diabetes Infancy High carbohydrate diet Poor oral hygiene: Mixed oral biofilm on non-renewing surfaces like endotracheal tubes (ETT), nasogastric tubes (NGT)

Significance of oral candidiasis Potential for systemic invasion. Can facilitate mucosal invasion by other microbes including S. aureus. Symptom causation - nutrition, impaired speech. Development of resistance, especially associated with biofilm formation.

Clinical presentation

Clinical forms THREE distinct clinical forms: Pseudomembranous candidiasis (thrush) Erythematous candidiasis (atrophic) Hyperplastic candidiasis (Candida leukoplakia) Denture stomatitis?

Pseudomembranous candidiasis Most common form. White raised lesions on tongue, mucosa, palate, tonsils. May become confluent plaques. Painless. Can be dislodged or Scraped off to reveal Bleeding base. Source: slide share

Thrush

Erythematous candidiasis (1) Often associated with broad spectrum antibiotics, steroids and HIV infection. Flat red lesion usually on tongue or palate. Painful with difficulty feeding especially swallowing solids. Pain maybe worsened by hot or cold liquids.

Erythematous candidiasis (2) Almost symmetric, asymptomatic red lesion involving the midline of the posterior dorsal tongue. Palatal erythematous candidiasis

Hyperplastic candidiasis Often on the buccal mucosa. Rarely on tongue Often asymptomatic and associated with smoking or local trauma Can undergo malignant transformation Possibility of hyperplastic lesion with C. albicans superinfection

Angular cheilitis Usually develops in association with other forms of oral candidiasis. Scaling, erythematous fissures at the corners of the mouth associated with infection by Candida albicans Source of picture 1: Wanda et al. Common Oral Lesions: Part I. Superficial Mucosal Lesions Am Fam Physician. 2007;75(4):501-506

Differential Diagnoses Contact dermatitis to oral hygiene product. All-cause cheilitis Herpes labialis Lichen planus

Herpes infections Herpes labialis Herpes simplex Source: DermNet New Zealand. Source: Ruderfer D. Herpes Simplex 1& 2 paediatrics in Review 2015; 36 (2) :

Apthous ulcers

Lichen planus Source: DermNet New Zealand.

DIAGNOSIS

Diagnosis Clinical - mainly Microbiological. White plaques Localized erythema & inflammation Essential to rule out other causes of similar presentation Microbiological.

Microbiologic Diagnosis Microscopy after staining. Fungal culture to identify yeast species and conduct drug susceptibility tests. Quantity of yeast helps differentiate colonizer from pathogen though not very precise

Microscopy: Direct smear examination Scrape the material with a spatula. Spread on glass slide then air dry. Fix with alcohol Stain with periodic Acid Schiff reagent (PAS) or potassium hydroxide (KOH) 10%. Examine under a microscope

Direct smear exam Staining with KOH PAS staining Source : Slideshare.net & PAS staining

Culture Specimen collection: - oral swab. - imprint culture. - oral rinse - Direct sonication of foreign body e.g. ETT, nasogastric tube etc. Culture media - Sabouraud dextrose agar (SDA) University of Adelaide mycology online

Biopsy Especially for diagnosis of hyperplastic candidiasis. Mainly to rule out squamous cell carcinoma. Histopathological exam shows epithelial parakeratosis with polymorphonuclear leukocytes in the superficial layers. PAS-stained slides show the presence of Candida hyphae. Candida albicans in a section of lung, confirming an invasive Candida pneumonia. Both yeasts and hyphae are visible. Candida is staining Gram positive. Source:://www.life-worldwide.org/fungal-diseases/histopathology

MANAGEMENT

Goals of management Address underlying condition/risk factor Appropriate antifungal agents through the proper route Considering alternative diagnosis Prevention

Underlying conditions Mechanical/surgical disruption of biofilm Proper management of underlying disease or condition. Proper glycemic control in diabetes Improved oral self-care Proper steroid inhaler use with mouth rinsing

Disrupting the biofilm Drugs penetrate biofilm poorly Azoles do not inhibit biofilm formation on surfaces and have no activity against preformed biofilms Potential for selection of resistant strains Mouth washes (especially those containing chlorhexidine) disrupt biofilm formation Ramage G et al Commercial mouthwashes are more effective than azole antifungals against Candida albicans biofilms in vitro. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111:456-60 Ramage et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:456-60

Suggested management algorithm Source: Rautemaa & Ramage.Crit Rev Microbiol. 2011 Nov;37(4):328-36

Antifungal Drug therapy Topical Systemic Minimal absorption from GI tract. Few drug to drug interactions Safe in children. High local drug levels achieved. Examples: nystatin, buccal miconazole Can be used in combination with topical antifungals. Need high concentrations and adequate saliva to reach adequate local levels. Preferred for immunocompromised due to high relapse rates with topical agents. Oral: fluconazole, itraconazole, posaconazole. IV: fluconazole & amphotericin B

Options for immunocompetent infants & neonates Nystatin oral suspension Dose: 1ml (100,000units/ml) every 4 -6 hours Oral Fluconazole Dose: 3mg/kg daily Miconazole gel Apply 2-4 times daily Spontaneous cure in neonates by 3-8 weeks has been reported

Options for immunocompetent older children & Adolescents Clotrimazole troches Dose: 1troche (10mg) five times daily Nystatin Suspension Dose: 4-6ml (100,000units/ml) every 6 hours Miconazole Buccal tablet Dose: 50mg once daily Fluconazole Dose: 100-200mg daily

Options for patients with immunosuppression Fluconazole- preferred agent. Dose: 100-200mg/ day for 7-14 days Itraconazole suspension (or capsules) Dose: 200-400mg/day for 14 days. Other options for fluconazole refractory disease: oral posaconazole suspension, oral amphotericin B.

Response to treatment Oral symptoms resolve in 2-5 days. Relapse is common especially for HIV infected not on ART. Managing underlying condition is KEY.

Unresponsive oral candidiasis Why? Resistant organism. Uncontrolled underlying condition e.g. HIV/Diabetes. Failure to remove/eradicate biofilm. Alternative diagnosis. Chronic mucocutaneous candidiasis.

Managing resistant organisms Increasing the dose of fluconazole to 400-800mg for adults. Oral itraconazole or posaconazole suspension for prolonged period (up to 4 weeks) Amphotericin B oral suspension (500mg 4x daily) may be used. IV amphotericin B or IV caspofungin

Chronic mucocutaneous candidiasis (CMC) Recurrent persistent superficial candidiasis often caused by C. albicans. Genetic defect in STAT1 (AIRE) or CARD9 most common. They are IL17 deficient But may be sporadic and not linked to genetics Onset in infancy for majority. Significant morbidity. Rarely disseminates

Prevention Good oral self-care including use of chlorhexidine mouth washes when necessary. Rinse the mouth after steroid inhaler use HAART if HIV positive. Smoking cessation. Prophylactic antifungals for secondary prevention. Avoid azoles due to resistance selection. Pulse therapy with nystatin or amphotericin solutions. Probiotics and alternative agents

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