Candidiasis: causes, symptoms, diagnosis, and treatment

Candidiasis, also known as candidosis, is a local or systemic infectious disease caused by various pathogenic Candida, more common in patients with immunodeficiency, and can invade local skin, mucous membranes, and various tissues and organs, with various clinical manifestations and varying degrees of severity. In recent years, with the increase of risk factors such as tumor chemotherapy, organ transplantation, and extensive use of glucocorticoids, immunosuppressants, and broad-spectrum antibacterials, the incidence of invasive candidiasis has increased significantly. Candidemia is the most common manifestation of invasive candidiasis and is usually with a poor prognosis. Early diagnosis and prompt treatment can significantly improve the prognosis of patients with invasive candidiasis.


Causes

Candida are unicellular fungi. It is believed that 25% - 50% of healthy persons may have Candida in their oral cavity, digestive tract, and vagina. After the defense function of hosts is reduced, non-pathogenic Candida is pathogenic. Therefore, Candida are conditioned pathogens. Infections caused by Candida are also called opportunistic infections.

There are currently 81 species of Candida, but only 7 are pathogenic, including Candida albicans, Candida stellatoidea, Candida tropicalis, Candida krusei, Candida parapsilosis, Candida guilliermondii, and Candida pseudotropicalis. Candida albicans and Candida tropicalis are most pathogenic and are the most common pathogens of candidiasis.


Signs and Symptoms

Candidemia

Candidemia is a common bloodstream infection. Mild early systemic symptoms, nonspecific clinical symptoms and signs, and slow progression are present, so that the illness may be concealed by primary underlying diseases and secondary infections. In severe cases, multiple organ dysfunction or failure and even septic shock may occur. The pathogens are easily disseminated to various organs in high-risk patients, resulting in infective endocarditis, endogenous endophthalmitis, osteomyelitis, and hepatic and splenic abscesses.

Disseminated candidiasis

Candida invade the blood circulation, grow and replicate in the blood, and then are disseminated to 2 or more nonadjacent organs, causing infection of the organs, which is termed disseminated candidiasis. According to different clinical manifestations, the illness is divided into acute and chronic disseminated candidiasis.

Acute disseminated candidiasis is characterized by acute onset, multiple hepatic and splenic abscesses, and cutaneous or subcutaneous abscesses in the acute stage of candidemia, and can be also manifested by infective endocarditis, osteomyelitis, endophthalmitis, and pneumonia. The clinical presentations are rigors, high fever, continuous positive blood culture, multiple abscesses in organs and tissues, apathia, lethargy, and multiple organ dysfunction or failure, and septic shock, with poor prognosis.

Chronic disseminated candidiasis is a unique manifestation of invasive candidiasis, mainly involving the liver and spleen, occasionally involving other organs such as kidney, so the disease is also known as hepatosplenic candidiasis (HSC), and mostly occurs in the recovery stage of agranulocytosis in patients with acute leukemia or stem cell transplantation. After agranulocytosis is healing, if fever continues, the disease should be considered. Imaging examination can indicate multiple focal infections in the liver, spleen, and even kidneys.

Candidal endocarditis

Candidal endocarditis includes infections of natural heart valves, artificial valves, and electronic heart devices, with high mortality and recurrence rate. The most common pathogens are Candida albicans and Candida parapsilosis. The clinical manifestations are cardiac involvement, such as fever, anemia, heart murmurs, and splenomegaly, resembling other infective endocarditis. However, valve neoplasms are usually large and brittle, and the embolus is easy to fall off to cause embolism. Arterial embolization is more common than in bacterial endocarditis, with poor prognosis. Therefore, after prompt antifungal treatment in patients with candidemia, if persistent positive blood cultures, cardiac murmurs, heart failure, and embolism are present, candidal endocarditis should be suspected.

Intra-abdominal candidiasis

Intra-abdominal candidiasis is one of the common invasive candidiasis, mainly including peritonitis and abdominal abscesses. The clinical manifestations are nonspecific, resembling diffuse or focal peritonitis. The illness is often accompanied by bacterial infections, with a mortality rate of 20% - 70%.

Candida endophthalmitis

Candida endophthalmitis can be an exogenous infection caused by surgery or trauma, but can also be an endogenous infection due to Candida entering the eye through blood circulation. Subacute onset usually occurs several days to several weeks after candidemia. The disease is initially choroiditis or chorioretinitis, progressing into endophthalmitis after pathogens go through the retina and enter the vitreous body. Initial symptoms are mild eye pain or eye floaters. If untreated, hypopsia may occur, and visual loss may occur days to weeks after candidemia.

Bronchopulmonary candidiasis

Bronchopulmonary candidiasis mainly includes candida tracheobronchitis and candida pneumonia.

Lower respiratory tract infections caused by Candida, especially candida tracheobronchitis, are not uncommon. Mucosal leukoplakia, congestion, and edema in the airway lumen can be seen in bronchoscopy. In severe cases, erosion, ulcers, hemorrhage, and even airway obstruction can occur. Mucositis, hyphae, and multiple abscesses distributed along the airway can be seen in histopathology, but there is no obvious vascular invasion.

Primary candida pneumonia is relatively rare in clinical practices, but pneumonia secondary to blood dissemination is common. Clinical manifestations can be chills and fever. In addition to pneumonia changes and hyphae, vascular invasion is common in histopathology.

Central nervous system candidiasis

The central nervous system is involved in half of patients who died from invasive candidiasis. Clinical manifestations often include fever, headache, and various degrees of consciousness disturbance such as delirium and coma. Meningeal irritation, hydrocephalus, slightly increased white cell count in the cerebrospinal fluid, normal or lowered sugar content, and obviously increased protein content are present.

Candida osteomyelitis

Subacute or chronic onset is usually present. Nearly 70% of patients are caused by blood dissemination, followed by direct inoculation or infection of adjacent tissues. Candida albicans infections are the most common, and mixed bacterial infections also often occur. Specifically, staphylococcus aureus infections are not uncommon. Adult vertebrae, especially the lumbar vertebrae, are mostly involved, and multiple sites are often invaded. Therefore, when a site is infected, probable infections on other sites should be examined. In addition, when pain of local lesions cannot be relieved, especially in patients with immunocompromise, the disease should be suspected. ESR and CRP are slightly elevated, and Contrast-enhanced magnetic resonance imaging (MRI) can help to find infected lesions.

Candidal arthritis

Candidal arthritis is less common, is usually part of disseminated candidiasis, and can also be an infection associated with the implant of joint. Local pain, tenderness, and edema of the affected joints are common clinical manifestations, and fever is relatively rare. When patients with invasive candidiasis, especially candidemia, have joint swelling or pain, or antibacterial therapy is ineffective after joint infection, the disease should be suspected.

Mucosal candidiasis

Oropharyngeal candidiasis

Oropharyngeal candidiasis includes acute pseudomembranous candidiasis (thrush), candida angular cheilitis, acute and chronic atrophic stomatitis, and chronic hyperplastic candidiasis. Patients with immunodeficiency caused by long-term broad-spectrum antibacterials or glucocorticoids, AIDS, and malignant tumor are susceptible to this disease.

Thrush is the most common manifestation of Candida albicans infection. Due to the low oral pH in neonates, it is conducive to the growth of Candida albicans, which causes the tongue and soft palate to be covered with a creamy, white to gray pseudomembrane that can be dispersed, fused, or adhered to the mucous membrane. After removal of the pseudomembrane, red exudative base can be seen. In severe cases, mucosal ulcers and necrosis can occur. The pseudomembrane is often more extensive and can involve the trachea, esophagus, and corners of the mouth, and can affect swallowing or breathing due to tissue swelling. The clinical manifestations of thrush in adults are similar to those in children.

Figure 1 thrush

Candidal esophagitis

The most common symptoms are odynophagia, dysphagia, and substernal pain or burning sensation when swallowing food, as well as thrush, nausea, vomiting, anorexia, and weight loss, with mild systemic symptoms. Local mucosal congestion, edema, pseudoleukoplakia, or superficial ulcers of the lower esophageal wall may be seen in endoscopy. Candidal esophagitis is one of the main causes of esophageal ulcers, and can cause necrotizing esophagitis if untreated.

Intestinal candidiasis

Initial mild diarrhea manifested by frothy or mucoid stools and occasionally bloody stools is followed by bloody purulent stools and dark red, mushy, mucoid stools in late stage. Most patients have abdominal distension, and the involvement of rectum and anus can cause perianal discomfort. Large amounts of hyphae and spores can be seen in the stools in microscopy.

Vulvovaginal candidiasis

The disease is more common, especially in pregnant women. Genital redness, swelling, severe pruritus, and burning sensation are obvious. Congestion and edema of the vaginal wall, gray pseudomembrane on the vaginal mucosa, and thick, yellow, creamy vaginal discharge, sometimes with cottage cheese discharge, without odor, are present.

Urinary candidiasis

Patients often have frequent urination, urgent urination, dysuria, and even hematuria. A small number of patients can also have asymptomatic bacteriuria, often secondary to long-term indwelling catheter, diabetes, multiple renal calculi, and urethrostenosis. In addition, disseminated candidiasis can spread through the bloodstream and invade the kidneys. The involvement of renal cortex and medulla results in abscesses and necrosis, leading to renal dysfunction. The clinical manifestations are fever, rigors, low back pain, and abdominal pain.

Cutaneous candidiasis

Cutaneous candidiasis is more common in skin folds, such as armpits, groin, skin under breasts, perianal area, perineum, fingers, and toes, mainly including candidal intertrigo, papular cutaneous candidiasis, candidal paronychia, and chronic mucocutaneous candidiasis.

Candidal intertrigo can be primary or secondary to other lesions, more common in the armpits, groin, skin under breasts, perianal area, and umbilicus. On the basis of typical erythema, erosion and exudation with flabellate edges occur and are surrounded by satellite vesicles, pustules, or bullae, forming erosion with irregular edges after rupture. Sometimes the skin lesions can be dry and desquamating. The disease is common in individuals with diabetes, obesity, or chronic alcoholism, or poor peripheral blood supply.

Figure 2 candidal intertrigo

Candidal paronychia is characterized by hard, thickened, brown nail plates, with streaks or grooves.

Figure 3 candidal paronychia

Diaper dermatitis is often secondary to anal and oral candidiasis in infants, and can also be seen in infants who are unhygienic and do not change diapers regularly. The symptoms can be primary irritant dermatitis, which can invade the dermis. In severe cases, the axilla, face, conjunctiva can be involved.

Figure 4 diaper dermatitis

Lichen planus-like cutaneous candidiasis is characterized by initial red maculopapular rash and papulovesicles, more common in infants and children, mostly on the shoulders and neck, with mild pruritus. Sometimes desquamative papular lesions are present, resembling lichen planus, resembling dermatitis and eczema after scratches, so the illness is often misdiagnosed. Candida can be found in Gram stain.

Candidal granuloma is manifested by primary papules covered by thick, sticky, yellowish brown crusts, mostly on the face, but also on the scalp, nails, torso, legs, and pharynx. Sometimes, the skin lesions are protruding up to 2 cm, resembling cutaneous horns. Immunodeficiency and lymphopenia are present. Sometimes patients die from underlying illness.

Candidide is similar to dermatophytid in clinical presentations, morphology, and distribution, and is characterized by aseptic clustered vesicles in the interdigital space and other areas of the body. After treatment of Candida infections in other areas, candidide can subside accordingly.


Diagnosis

Since Candida are symbiotic fungi in humans, cultures of Candida from sputum, mouth, vagina, urine, feces, or skin do not necessarily indicate the presence of progressive invasive Candida infection. Diagnosis must be based on the characteristic clinical lesions, pathological evidences of fungal invasion, such as yeast, pseudohyphae, and hyphae in tissue specimens, and exclusion of other pathogen infections. Positive culture results of specimens derived from sterile sites, such as blood, cerebrospinal fluid, and pericardial effusion, can provide a reliable basis for systemic antifungal treatment.

Serum β-glucan is often positive in patients with invasive candidiasis, and on the contrary, a negative result indicates a low possibility of systemic infection.

It is recommended that all patients with candidemia undergo ophthalmologic examination to rule out intraocular candidiasis.

Mucosal and cutaneous candidiasis can be diagnosed based on the clinical findings and spores and pseudohyphae found in KOH microscopic examination.

Figure 5 hyphae found in microscopy


Treatment

Predisposing factors, such as neutropenia, immunosuppression, use of broad-spectrum antibiotics, overnutrition, and indwelling catheters, should be reversed or controlled. In patients with neutropenia, venous catheter should be removed.

If patients are in critical condition or with suspected infection caused by Candida glabrata or Candida krusei, caspofungin, micafungin, and anidulafungin can be selected.

If patients are stable or with suspected infection caused by Candida albicans or Candida parapsilosis, fluconazole can be administered.

Esophageal candidiasis can be treated by fluconazole or itraconazole. Patients who have failed this treatment regimen or those with severe infections can be treated with voriconazole or posaconazole. Echinocandins can also be considered.

The course of treatment lasts until 14 days after the last negative blood culture.

Candidal intertrigo can be treated with desiccants and topical antifungals such as miconazole powder. Generalized candidal intertrigo can be treated with oral fluconazole.

The treatment of diaper dermatitis includes regular diaper changes, the use of disposable absorbent diapers, and topical imidazole cream. Children with oropharyngeal candidiasis can take buccal fungicidin.

Candidal paronychia is treated with topical or oral antifungals.

Oral candidiasis can be treated with clotrimazole and lozenges, oral nystatin suspension, or systemic antifungals such as oral fluconazole.

Chronic mucosal and cutaneous candidiasis requires long-term oral antifungals such as fluconazole.