INTRODUCTION

Some 50% of the normal population harbour (carry) the fungus Candida albicans as a normal oral commensal mainly on the posterior dorsum of tongue (without any disease) and are therefore termed ‘Candida carriers’. The opportunistic pathogen grows either as yeasts or hyphae (i.e. it is a dimorphic fungus). Actual infection with Candida (usually Candida albicans) is common mainly in people who are otherwise unwell; candidosis is thus called a ‘disease of the diseased’. The importance of Candida has increased greatly, particularly as the HIV pandemic extends since, when host defences are compromised, Candida typically colonizes mucocutaneous surfaces and causes only superficial infections but in immunocompromised people candidosis is commonly oro-pharyngeal and can be a portal for entry into deeper tissues and invasive candidosis (see Chs 53 and 54).

AETIOLOGY

Host defences against Candida species include the following:

PATHOGENESIS

 C. albicans can switch frequently and reversibly between several variant, heritable, phenotypes associated with changes in micromorphology, physiology and virulence (‘colony switching’).

 C. albicans adhere to the oral epithelial surface via extracellular polymeric materials, including mannoprotein and adhesins.

 Adhesins, such as HWP1 (hyphal wall protein 1), originating from the yeast cell surface, appear important in making hyphal forms adhere more strongly than do yeast forms.

 Hyphae invade the superficial epithelium and penetrate, via enzymes such as the phospholipases, lysophospholipases and aspartyl proteinase (secretory aspartyl proteinases; SAP) (Fig. 39.1) as far as the stratum spinosum.

 Epithelial endocytic pathways are key innate immune mechanisms in host defence. Defective endolysosomal maturation may partially explain the inability of oral epithelial cells to kill C. albicans.

 C. albicans invades oral epithelial cells by inducing its own endocytosis by the adhesin and invasin Als3 and gains access to epithelial vacuolar compartments. C. albicans is internalized by oral epithelial cells through actin-dependent clathrin-mediated endocytosis and is taken into vacuolar compartments immediately following its internalization. Candida-containing endosomes transiently acquire early endosomal marker EEA1, but show marked defects in acquisition of late endosomal marker LAMP1 and lysosomal marker cathepsin D.

 The innate immune system is a first-line defence and involves pattern recognition receptors such as Toll-like receptors and C-type lectin-receptors that not only induce innate immune responses but also modulate cellular and humoral adaptive immunity.

 IL-12: a cytokine family which includes IL-12, IL-23, IL-27, and IL-35 – links to both innate and adaptive immunity systems. An essential component of the response that leads to the generation of Th1-type cytokine responses and protection activity against disseminated candidosis.

 CD4 T-cells are crucial in the regulation of immunity and inflammation; Th1/2, helper cells, together with Th17 and Treg cells are important.

 Th17 and release IL-17 (which recruits neutrophils), IL-21 (which stimulates CD8 or NK cells) and IL-22, the latter stimulating epithelial cells to produce proteins with antimicrobial activity against Candida.

 Fungal pattern-recognition receptors such as C-type lectin receptors trigger protective Th17 responses which play the predominant role against mucosal candidiasis. IL-17A and IL-17 F are essential for mucocutaneous immunity against C. albicans

 Dectin-1, a C-type lectin that recognizes 1,3-beta-glucans from fungi, including Candida, is involved in the initiation of the immune response against fungi. Patients bearing the Y238X polymorphism in the DECTIN-1 gene are more likely to be colonized with Candida species, compared with patients bearing wild-type DECTIN-1.

 Oral epithelial cells orchestrate an innate response to C. albicans via NF-κB and a biphasic MAPK response.

 Activation of NF-κB and the first MAPK response, constituting c-Jun activation, is due to fungal cell wall recognition while the second MAPK phase, constituting MKP1 and c-Fos activation, depends upon hypha formation and fungal burdens – and correlates with the pro-inflammatory responses.

 Activation of the kallikrein–kinin system and other factors result in an inflammatory response in the connective tissue comprising lymphocytes, plasma cells and other leukocytes.

 PMNL migrate into the epithelium in defensive mode, but candidal cell-wall mannans and glycans may impair PMNL chemotaxis, phagocytosis, respiratory burst, T lymphocyte reactivity and the macrophage secretion of tumour necrosis factor (TNF).

 Defective cell-mediated immune responses are commonly associated with mucocutaneous Candida infections.

CLINICAL FEATURES

Candidosis (candidiasis; moniliasis) is the state when Candida species cause lesions or symptoms:

Symptomatic oral candidosis presents as mainly:

Factors that can increase the liability to oral candidosis are shown in Box 39.1. Candidosis may also affect or spread from or to the mouth, from:

By tradition, the most frequently adopted classification of oral candidosis has been into (Box 39.2):

A newer classification categorizes candidosis into:

DIAGNOSIS OF CANDIDOSIS

Diagnosis can, if necessary, be supported by:

However, the diagnosis of candidosis in most instances is clinical and investigations can be complicated by the facts that:

Since oral candidosis is occasionally associated with nutritional deficiencies or blood dyscrasias, estimates of haemoglobin, white blood cell counts, corrected whole blood folate, vitamin B₁₂ and serum ferritin can be important.

Tests of immune function are indicated mainly in HIV disease or chronic mucocutaneous candidosis.

Since some endocrine disorders may be associated with chronic mucocutaneous candidosis, tests of thyroid, parathyroid and adrenocortical function are warranted in selected individuals (Table 39.1).

TREATMENT OF CANDIDOSIS (see also Chs 4 and 5)

Few patients have spontaneous remission unless the condition is solely related to, for example, the use of an antimicrobial, or a topical corticosteroid, and thus, in other cases, treatment is often indicated (Table 39.2). Often, in the treatment of fungal infections, attention to the underlying cause will avoid the need for prolonged or repeated courses of treatment. Intermittent or prolonged topical antifungal treatment may be necessary where the underlying cause is unavoidable or incurable. Treatment includes the following measures: