Oral Candidiasis in Children. Etiology and Causes, Clinical Symptoms and Diagnosis, Treatment and Prevention

In recent years, the prevalence of diseases caused by opportunistic microorganisms has significantly increased, with oral candidiasis taking center stage. Studies reveal that fungal flora is present in around 50% of otherwise healthy individuals. Moreover, fungal infections are playing an increasingly prominent role in pediatric health issues. This rise is linked to advancements in neonatal care technologies, frequent and sometimes unjustified antibiotic use, and medications with cytotoxic or immunosuppressive properties used in intensive care. Additional contributing factors include environmental challenges and the high overall morbidity among children.

Among pediatric patients, especially infants, oral candidiasis is the most commonly diagnosed fungal infection. Pediatric dentists must be well-versed in recognizing its clinical manifestations, diagnostic techniques, treatment options, and prevention strategies.

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Etiology and Causes of Candidiasis. Candida Species

Fungal infections are among the most widespread human diseases, with candidiasis occupying a leading position. Historically, thrush was first described by Hippocrates, and its causative agent, Candida, was identified by Langenbeck in 1839. Over the past two decades, fungal infections have shown a steady global increase, particularly among neonates. Key factors contributing to this trend include:

• The widespread adoption of advanced care technologies for premature and immunocompromised newborns.
• Frequent and often unwarranted antibiotic use, disrupting the establishment of normal oral and intestinal microbiota in children.
• Intensive therapy with cytotoxic and immunosuppressive drugs.
• Environmental challenges and elevated child morbidity rates.

Candida species are opportunistic pathogens, thriving in various environments, including the human body. While they are part of the normal microbiota in 40–50% of the population, their overgrowth leads to candidiasis, a condition often affecting infants’ oral mucosa.

The genus Candida comprises more than 100 species, of which around 30 can cause candidiasis. Key pathogenic species include Candida albicans, C. tropicalis, C. krusei, C. lusitaniae, C. parapsilosis, C. pseudotropicalis, C. stellatoidea, and C. glabrata.

Candida thrives in acidic environments (pH 5.8–6.5) at temperatures of 30–37°C. It displays a preference for stratified squamous epithelium due to its glycogen content. Additionally, Candida species produce enzymes that break down proteins, lipids, and carbohydrates, facilitating tissue invasion.

Despite their ubiquity, Candida fungi remain saprophytic under normal conditions, with their pathogenicity triggered by host vulnerabilities such as immunosuppression or dysbiosis.

Risk Factors of Candidiasis in Children

Candida colonization begins early in life. Primary infection can occur in utero, during birth through infected maternal birth canals, or via postnatal contact with caregivers. Rapid colonization of the oral cavity in newborns is driven by:

• High adhesive properties of Candida.
• Immature immune responses (e.g., low levels of immunoglobulin A and lysozyme activity).
• Lack of stabilizing microbial flora in the oral cavity.
• Vulnerable mucosal surfaces with reduced protective factors.

Microbial Imbalance. Dysbiosis and its Consequences

The normal oral microbiota of children represents a dynamic and integrated system whose qualitative and quantitative stability plays a pivotal role in maintaining homeostasis, particularly through its function in colonization resistance. The oral microbiome includes aerobic and facultative anaerobes (e.g., Streptococcus mutans, Streptococcus salivarius, Streptococcus mitis, saprophytic Neisseria, lactobacilli, staphylococci, corynebacteria), obligate anaerobes (e.g., Peptostreptococcus, Bacteroides, Fusobacterium, filamentous bacteria, actinomycetes), and transient flora.

The oral cavity's unique environment—characterized by constant exposure to pathogens and a high risk of chronic infections—emphasizes its crucial role in systemic colonization resistance. Under normal conditions, microbial flora concentrations remain relatively constant, with a defined composition: streptococci (1,000,000–10,000,000 CFU/mL), lactobacilli (1,000 CFU/mL), staphylococci (1,000 CFU/mL), Candida species (100 CFU/mL), and an absence of enterobacteria.

When physiological balance between resistance and aggression factors is disrupted, dysbiosis of the gastrointestinal (GI) tract can arise, often originating in one region and spreading to others. The oropharynx, being highly exposed to external contamination, serves as a key site influencing the downstream microbiota of the GI tract. Conversely, GI disorders associated with dysbiosis often lead to oral dysbiosis, creating a bidirectional relationship.

Oral dysbiosis is defined by qualitative or quantitative shifts in the normal microbiota due to external factors or pathological processes, leading to significant disruptions in systemic balance.

Classification of Candidiasis

Oral candidiasis manifests in various clinical forms: acute (pseudomembranous, erythematous (atrophic)) and chronic (hyperplastic, erosive-ulcerative). 
The ICD-10 (International Classification of Diseases, 10th Revision) and ICD-11 (11th Revision) classifications for oral candidiasis are as follows:

ICD 10

• B37 Candidiasis

           o   B37.0 Candidal stomatitis

                   §  Oral thrush

           o   Candidiasis of other sites

                  §  Candidal:

                           ▪ cheilitis

                            ▪ enteritis

           o   B37.9 Candidiasis, unspecified

                     §  Thrush NOS 

ICD 11

• 01 Certain infectious or parasitic diseases
• Mycoses

            o   1F23 Candidosis

                            ▪ 1F23.0 Candidosis of lips or oral mucous membranes

Pathogenesis of Oral Candidiasis

Oral candidiasis, an opportunistic infection predominantly caused by Candida albicans, is an endogenous infection resulting from the yeast's ability to exploit weakened host defenses. The infection progresses through three stages: adhesion, colonization, and invasion. Candida's pathogenicity hinges on its dimorphic nature, allowing stronger adherence through its pseudohyphal forms, especially under conditions of high moisture, elevated glycogen, and favorable pH.

Despite extensive research, questions remain about why some individuals develop chronic or recurrent infections while others resolve acute episodes with lasting immunity. Key pathogenic factors include impaired immunity (both humoral and cellular), suppression of neutrophil and monocyte activity, and sensitization to Candida allergens.

Factors contributing to Oral Candidiasis in Children

Systemic Factors:

• Prematurity or postmaturity
• Neonatal complications (e.g., aspiration of amniotic fluid)
• Prolonged antibiotic or radiation therapy
• Surgical interventions
• Early cessation or absence of breastfeeding
• GI disorders (malabsorption, acute infections)
• Primary/secondary immunodeficiencies (e.g., HIV, malignancies, transplant patients)
• Salivary gland hypofunction
• Allergies, anemia, or metabolic disorders

Local Factors:

• Maternal Candida infections
• Poor hygiene practices (e.g., contaminated pacifiers or utensils)
• Immature oral mucosa
• Frequent trauma to the mucosa (mechanical or chemical)
• High sugar diets
• Inadequate oral hygiene

Children at Risk Group for Oral Candidiasis:

• Premature infants
• Infants born to mothers with candidiasis
• Children with recurrent upper respiratory infections
• Immunocompromised children (e.g., HIV, malignancies)
• Those with chronic GI or respiratory conditions

Acute Pseudomembranous Candidiasis. Clinical and Morphological Features

Acute pseudomembranous candidiasis typically affects newborns and immunocompromised individuals. It is the most common form in infants, especially newborns and those with weakened immunity due to infections, prematurity, or antibiotic use. This infection may also occur due to steroid inhalers, rinses, gels, and ointments. Salivary gland dysfunction and dry mouth also contribute to this condition. While many cases are asymptomatic, patients using topical steroids for conditions like erosive lichen planus or mucous membrane pemphigoid often experience significant discomfort.

Acute pseudomembranous candidiasis, or thrush, is the most prevalent form in infants, presenting as white or yellow curd-like plaques (patches) on the oral mucosa of the lips, tongue, cheeks, and palate. These patches consist of pseudohyphae, hyphae, and yeast cells of Candida, along with detritus from damaged tissue, fibrin, and blood cells. The severity of the condition can vary depending on the extent of systemic and local changes, ranging from mild to moderate and severe forms.

• Mild Form: Minimal discomfort, removable plaques, and rapid recovery within a week.
• Moderate to Severe Forms: Extensive bleeding lesions after plaque removal on erythematous mucosa, deeper fungal invasion, and systemic symptoms like irritability, poor feeding, and pain.

Without timely treatment, acute pseudomembranous candidiasis may progress to an atrophic form.

Acute Erythematous (Atrophic) Candidiasis. Clinical and Morphological Features

This form is less common in children and can develop independently or as a progression from acute pseudomembranous candidiasis. The primary trigger is a side effect of antibacterial medications or inhaled corticosteroids. Patients often report dryness and a burning sensation in the mouth, difficulty moving the tongue, and heightened sensitivity of the oral mucosa to any irritants. The general condition remains unaffected, though taste perception may be altered.

The mucosa is intensely inflamed, fiery red, dry, and shiny, making it difficult to open the mouth freely. Patients may experience pain during conversation, eating, or dental examination. Examination of the tongue reveals erythematous patches without coating or with deposits in deep folds. The tongue’s dorsal surface, if involved, appears fiery red. The red border of the lips is hyperemic, swollen, and covered with thin gray scales. Occasionally, crusts, cracks, or erosions develop on the lips.

Chronic Hyperplastic Candidiasis. Clinical and Morphological Features

This form is often associated with cytotoxic drug use, antibiotics, tuberculosis, hematological diseases, HIV infection, smoking, or the use of removable dentures. Patients may complain of altered taste, pain when consuming spicy or acidic foods, burning sensations, and dryness in the mouth. Erosions can cause significant discomfort.

The mucosa is inflamed. White plaques of varying sizes with an uneven, "cobblestone" appearance may form on the tongue and cheeks. Over time, these plaques flatten and take on a yellowish hue. In advanced cases, a coarse, whitish-gray coating develops, which is difficult to remove. Underneath the coating, bleeding erosions are often visible. In cases involving the tongue, papillary growth may occur. Plaques typically form on the dorsal surface of the tongue, particularly in the rhomboid area, and may spread to other parts of the oral cavity. Depending on the affected area, associated conditions such as candidal glossitis, cheilitis, angular cheilitis (cracked corners of the mouth), palatinitis, or parotitis may be observed.

Angular Cheilitis. Clinical and Morphological Features

Angular cheilitis, also known as candidal cheilitis, is a fungal infection affecting the tissues at the corners of the mouth – typically the red lip border and adjacent skin, and sometimes the mucosal part of the lips. This form is common in children aged 2–6, particularly those who suck their thumbs, lick their lips excessively, or have nutritional deficiencies (e.g., riboflavin deficiency). Moisture from oral fluids accumulates on the skin of the lips and surrounding areas due to incomplete lip closure, often caused by mouth breathing, weakened tone of the orbicularis oris muscle, or jaw misalignment. This moisture softens the skin, which disrupts the physical barrier, creating an ideal environment for Candida fungi (commonly C. glabrata) to transform into an infectious form. This condition is frequently seen in individuals with ill-fitting dentures, excessive salivation, or nutritional deficiencies (e.g., vitamin B or iron). The area of infection (typically, both corners of the mouth) becomes red and swollen, with a characteristic white coating, often forming a skin fold or, less commonly, a crack. The mucosa in the affected area shows minimal infiltration and has a grayish-white appearance. In the depth of the folds, erosions or cracks with well-defined borders can be observed. The infection may spread to the surrounding skin, leading to infiltration, pinkish-red discoloration, and peeling.

In cases of angular cheilitis, children may experience difficulty opening their mouth and discomfort while eating, although their general condition usually remains unaffected.

Typically, the distinct features of angular candidal cheilitis make the diagnosis quite evident. However, if there is significant exudation and the formation of yellow crusts, this suggests a high bacterial activity at the site. Additionally, if a painless papule forms at the corner of the mouth on a firm base, further testing may be required to rule out or confirm syphilis.

Diagnostics of Oral Candidiasis in Children

The diagnosis of candidiasis in the oral mucosa is established based on a clear clinical symptom complex and confirmed by positive results of mycological testing. Due to the wide range of clinical manifestations in children, diagnosing candidiasis solely from the clinical picture can sometimes be challenging. In such cases, additional diagnostic methods are employed, including:

1. Microscopic examination of pathological material.
2. Quantitative assessment of fungal colonization in affected tissues.
3. Identification of isolated fungal cultures.
4. Intradermal allergy testing with antigens.
5. Serological studies.
6. Radioimmunological and immunoenzymatic assays.
7. Molecular diagnostics, such as chromatography and polymerase chain reaction (PCR).

In dental practice, the first two methods are most commonly used. Microscopic analysis of samples from affected children typically reveals clusters of budding oval or round cells with pseudomycelium threads. Acute candidiasis is dominated by cellular forms, while chronic forms show a predominance of pseudomycelium clusters. These examinations are repeated dynamically over the course of the disease. Different Candida species have distinct microscopic features: Candida albicans forms thick, short pseudomycelium threads, whereas Candida pseudotropicalis exhibits thin, short threads.

Material for testing typically includes scrapings or swabs from affected areas. The presence of "vegetative forms" (budding cells, pseudohyphae, and hyphae) serves as a criterion for positive microscopic diagnosis. However, quantitative mycological tests, assessing colony counts, are essential for confirmation. A diagnostic threshold is generally considered to be over 1,000 CFU (colony-forming units).

Treatment of Oral Candidiasis

Treating oral candidiasis in children involves a comprehensive, individualized approach that includes local and systemic therapies targeting etiological, pathogenetic, and symptomatic aspects. Treatment goals include:

1. Identifying and minimizing risk factors.
2. Antifungal therapy tailored to the sensitivity of the fungus, with precise dosage and duration.
3. Normalizing the oral microbiome.
4. Preventing recurrences through maintenance therapy and immune modulation.
5. Monitoring treatment efficacy via clinical and laboratory evaluations.

Local therapy often involves antifungal solutions, gels, or sprays, used for 2–3 weeks in acute cases and 3–4 weeks for antiseptics. Treatment should continue for one week after symptoms resolve. Systemic therapy is reserved for cases where the infection spreads beyond the oral cavity. For local treatment of children with thrush, antiseptics with a broad spectrum of antimicrobial action, including antifungal properties, are traditionally used. These include chlorhexidine (0.05–0.1–0.2% solution for gargling and applications, lozenges, and tablets), miramistin (0.01% solution), iodine-based preparations (iodinol, povidone-iodine), and water-based aniline dyes (e.g., brilliant green, gentian violet, methylene blue, fucorcin). However, fungi demonstrate rapid adaptation to these agents. The antifungal effect of using 2–5% sodium bicarbonate solution for mouth rinses and the treatment of acrylic dentures or orthodontic appliances is less effective than the use of chlorhexidine and polyene-based preparations.

Etiotropic therapy is a key element in the comprehensive treatment of patients with oral candidiasis. Since the oral cavity may not be the only body area affected by the pathogenic activity of fungi, antifungal medications are prescribed not only in topical forms for application to the mucous membrane of the mouth or the skin around the mouth, but also in forms that ensure systemic antifungal control.

Modern guidelines for treating oral candidiasis in children recommend antifungal agents from the polyene antibiotic, azole, and, less frequently, echinocandin groups.

Polyene antibiotics work by binding to ergosterol in the fungal cell membrane, causing damage and lysis. Depending on the concentration, polyenes can have fungistatic or fungicidal effects (in topical forms) against most Candida species. However, over the years, many strains have developed high resistance to these drugs. Polyene antibiotics do not absorb into the bloodstream when applied to the mucous membranes or gastrointestinal tract, thus not having a systemic effect when taken orally. When administered intravenously, they are highly effective but moderately toxic in modern lipid-associated formulations. Nystatin is available as a suspension for oral cavity treatment, tablets, and skin ointments. Amphotericin B is available as a skin ointment and intravenous formulation. Natamycin is used as a suspension, drops, cream, and tablets.

Azole derivatives, including imidazoles and triazoles, block enzymes in the fungal cell that convert lanosterol into the membrane’s ergosterol. As a result, they have a fungistatic effect when taken systemically, and at high concentrations, they may exhibit a fungicidal effect when applied topically. All azoles are effective against Candida albicans, though sensitivity varies for other species. Imidazole derivatives, particularly first- and second-generation drugs, are used mainly for local treatment, including for the oral cavity. Clotrimazole for oral use comes as a solution for applications and lozenges, with minimal absorption into the bloodstream. Miconazole has notable toxicity, so it is only approved for use in children over 12 years old in gel form (recommended to be held in the mouth until swallowed) and intravenously. Ketoconazole, a third-generation imidazole with proven antifungal activity, is used in children over three years old in tablet form, though it has a cumulative anti-testosterone effect.

Triazole derivatives differ from imidazoles in that they metabolize more slowly and have less impact on sterol synthesis in humans. Fluconazole, a low-toxicity antifungal with high activity against C. albicans, C. guilliermondii, C. pseudotropicalis, C. torulopsis, C. kefir, and C. stellatoidea, is highly bioavailable (its effectiveness when administered intravenously is comparable to oral tablets). Its pharmacokinetics, with concentrations in saliva similar to those in the blood, have made it a first-line treatment for preventing and suppressing Candida activity in oral and systemic candidiasis, including in newborns. It is available in tablet and intravenous solution forms.

Voriconazole is effective against the same species as fluconazole (including strains resistant to polyene antibiotics and other azoles), as well as C. krusei and C. glabrata. It is recommended for surface and deep candidiasis and is available for both oral and parenteral use. It is approved for children over two years old.

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Prevention of Oral Candidiasis

Identifying and minimizing risk factors for the development and progression of candidal infections in the oral cavity is a key task in treating current episodes and preventing recurrences. Controlling modifiable risk factors, such as maintaining proper oral hygiene, treating oral cavity infections, ensuring full lip closure, addressing harmful habits, and assisting with xerostomia, is essential. Dentists should advise the patient's family on rational nutrition. To maintain a balance of normal oral flora, it is important to reduce sugar intake, while regular consumption of probiotic-rich dairy products (e.g., bifidobacteria) can help suppress Candida activity.

Prevention strategies address the epidemiological and pathogenetic aspects of oral candidiasis:

• Maintain proper oral hygiene.
• Manage and treat underlying conditions, including ENT pathologies.
• Use antibiotics, corticosteroids, and cytostatics judiciously, pairing them with prophylactic antifungal agents when necessary.
• Promote immune resilience in vulnerable children.
• Encourage a healthy lifestyle and clean environmental conditions.

For expecting mothers, prenatal screening and treatment of urogenital and oral candidiasis are essential, along with sanitizing the birth canal. Stringent hygiene practices in maternity wards, hospitals, and childcare facilities are critical to control the disease's spread. Rational use of antibiotics and appropriate probiotic supplementation after antimicrobial therapy can also help prevent candidiasis.

Lastly, public education plays a vital role in discouraging the misuse of broad-spectrum antibiotics, which can lead to dysbiosis and candidiasis.

Oral candidiasis and dysbiosis serve as significant clinical markers of broader systemic imbalances, highlighting the intricate connection between local and systemic health. Effective prevention and management require addressing both systemic vulnerabilities and local risk factors.

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