Candidiasis in Emergency Medicine Clinical Presentation

Candidal infection has a wide range of clinical manifestations, from self-limited local mucocutaneous disease to severe sepsis with multiorgan system failure.

Local mucous membrane infections

Oral candidiasis, also referred to as thrush, is characterized by creamy-white curd-like patches on the tongue and oral mucosa. These patches are a pseudomembrane of Candida, desquamated epithelial cells, leukocytes, bacteria, keratin, necrotic tissue, and food debris. Chronic atrophic candidiasis, or denture sore mouth, is a chronic inflammatory reaction with epithelial thinning under dental plates. Saliva usually protects oral mucosa against Candida, while dry mouth increases yeast counts. Dentures also create a reservoir for Candida to incorporate into the biofilm covering the material and increase the risk of invasive candidiasis, especially in immunocompromised persons.

Candidal leukoplakia consists of firm white plaques on the cheeks, lips, and tongue that frequently have a protracted course and can be precancerous. Angular cheilitis is characterized as erythema and fissuring at the corners of the mouth.

Risk factors for oral infection include antibiotic use, immunodeficiency (up to 90% of untreated HIV-positive persons have a symptomatic episode of oropharyngeal candidiasis sometime during progression to AIDS), xerostomia, inhaled corticosteroids, and denture use. Symptoms include dry mouth, loss of taste, and, occasionally, pain with eating.

Candidiasis. White plaques are present on the buccal mucosa and the undersurface of the tongue and represent thrush. When wiped off, the plaques leave red erosive areas. Image courtesy of Matthew C Lambiase, DO.

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Candida epiglottitis is another entity that can develop in immunocompromised persons. It may exist as a co-infection with bacterial organisms or on its own. A KOH preparation and fungal cultures may be helpful in identifying candidal epiglottitis that would not be expected to improve with antibiotics alone. ^[9]

Candida esophagitis is most commonly associated with treatment of hematopoietic or lymphatic malignancies. It is also an AIDS-defining illness, although cases of Candida esophagitis without underlying illness have been reported. Symptoms include dysphagia, sensation of obstruction upon swallowing, retrosternal chest pain, nausea, and vomiting. Definitive diagnosis is made with endoscopic biopsy. On endoscopy, white plaques similar to thrush may be present; ulcerations, pseudomembrane formation, and diverticula may also be seen. Candidal esophagitis can occur concomitantly with herpes simplex virus (HSV) and cytomegalovirus (CMV) infection in severely immunocompromised persons.

Other locations of the gastrointestinal tract are often infected with Candida. Lesions may be found in the stomach and small and large intestines, most commonly in patients with neoplastic disease. Candidal cholecystitis is also a possible location of infection and has been reported in a patient without any history of underlying malignancy. ^[10]

Candidal vaginitis is the most common form of mucosal candidiasis. Vulvovaginal candidiasis is usually secondary to overgrowth of normal flora Candida species in the vagina. Bacteria such as Lactobacillus acidophilus balance Candida and prevent yeast overgrowth and pathogenic infection. Conditions that disrupt the balance of normal vaginal flora include antibiotic use, oral contraceptives, contraceptive devices, high estrogen levels, and immunocompromised states such as in diabetes mellitus and HIV infection. Another risk factor for vulvovaginal candidiasis may be intrauterine contraceptive devices. ^[11]

Of vulvovaginal candidiasis cases, 70%-90% are caused by C albicans, while the remainder of infections are caused by C glabrata and C tropicalis. Symptoms are typically described as pruritus, vaginal irritation, and dysuria. Thick curd-like discharge is often present, but scant discharge may also characterize infection. Vaginal edema and erythema are also often present on examination.

Epidemiologically, vaginal Candida infections are important, as they may increase viral shedding in HIV-infected women.

Cutaneous candidiasis syndromes include the following:

• Generalized cutaneous candidiasis: This infection affects persons of any age and is characterized by widespread eruptions with increased severity in the genitocrural folds, anal region, axillae, and hands and feet.

• Erosio interdigitalis blastomycetica: This is an infection of the web spaces between digits, which is predisposed to maceration.

• Candida folliculitis: This is most frequently seen in immunocompromised hosts and among intravenous drug users.

• Candida balanitis: Rash typically begins as vesicles on the penis that develop into patches similar in appearance to thrush (shown in the image below). Extension may occur to the scrotum and buttocks. Symptoms include burning and pruritus. C glabrata has been implicated as the cause of Fournier gangrene in an immunocompromised patient. ^[12]

  Candidiasis. Dry, red, superficially scaly, pruritic macules and patches on the penis represent candidal balanitis. Image courtesy of Matthew C Lambiase, DO.

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• Mammary candidiasis: This is a condition that can affect breastfeeding women, with both cutaneous and local ductal inflammatory manifestations. ^[13]

• Intertriginous infections: These develop in sites where skin surfaces are close in proximity, such as the axilla or anogenital region. Lesions begin as vesicopustules that enlarge, rupture, and develop maceration and fissuring. Satellite lesions may also be present. A variant form of cutaneous candidiasis in the intertriginous region has a miliary appearance.

• Candidal paronychia: This is associated with frequent hand immersion in water and diabetes mellitus.

• Diaper rash: Skin irritation is exacerbated by wet diapers (shown in the image below).

  Candidiasis. A moist, erosive, pruritic patch of the perianal skin and perineum (with satellite pustule formation) is demonstrated in this woman with extensive candidosis. Image courtesy of Matthew C Lambiase, DO.

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• Perianal candidiasis: Skin maceration and pruritus are common, with frequent extension to the perineum.

• Onychomycosis: Candida species are the most common fungal cause of this nail disease. ^[14] An example of this infection is shown in the image below.

  Candidiasis. A nailfold with candidal infection becomes erythematous, swollen, and tender with an occasional discharge. Image courtesy of Matthew C Lambiase, DO.

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Chronic mucocutaneous candidiasis is a term used to describe a heterogeneous group of Candida infections of the skin, mucous membranes, hair, and nails, which has a protracted course despite typical therapy. It is associated with T-cell lymphocyte dysfunction. A specific subset of individuals with this phenomenon have autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED) syndrome with associated endocrine disorders.

Invasive candidal infections

Invasive candidiasis is a term used to describe severe and invasive disorders that include candidemia, disseminated candidiasis, deep organ involvement, endocarditis, endophthalmitis, and meningitis. Invasive infection is also described as the isolation of Candida from a normally sterile body site, including blood, peritoneal fluid, pleural fluid, intra-articular fluid, or cerebrospinal fluid (CSF).

Risk factors for invasive candidiasis include prolonged ICU stay (incidence peaks around day 10), presence of a central venous catheter, acute renal failure, treatment with broad-spectrum antibiotics, parenteral nutrition, high APACHE II scores, diabetes, immunosuppressive therapy, surgery (especially upper gastrointestinal tract), hemodialysis, pancreatitis, malignancy, transplantation, and organ dysfunction. ^[15]

Skin manifestations of disseminated candidiasis include clusters of painless pustules on an erythematous base on any area of the body. These lesions may be macular or pustular or may have central necrosis.

Acute disseminated candidiasis, or hepatosplenic candidiasis, is most commonly seen in patients with hematologic malignancy who recently had an episode of neutropenia. Symptoms include fever, right upper quadrant pain, and tender hepatosplenomegaly. Multiple organs are frequently involved, and discrete persistent microabscesses occur in the liver, spleen, and kidneys. A palpable erythematous rash may be present, indicating evidence of small-vessel vasculitis. The presumed etiology is a prior episode of candidemia, although invasion through portal vasculature has been theorized.

Central nervous system (CNS) candidiasis usually occurs as a complication of hematogenously disseminated candidiasis. Candida typically forms multiple microabscesses and small macroabscesses scattered throughout the brain. ^[16] Patients with Candida meningitis usually have meningeal irritation and CSF pleocytosis. Untreated, the mortality rate is high. Intraventricular drains increase risk of CNS candidal infection.

Candidal pneumonia occurs rarely as bronchopneumonia originating from endobronchial inoculation, its etiology is more commonly from hematogenous seeding and presents as nodular and diffuse infiltrates. This presentation may be difficult to distinguish from congestive heart failure, acute respiratory distress syndrome (ARDS), or Pneumocystis pneumonia. Diagnosis is also complicated by the inability to confirm that positive cultures are not an oropharyngeal contaminant or colonization. Candida empyema cases have also been documented. ^[17]

Candida can infect both the pericardium and myocardium, and these infections are usually associated with disseminated disease. Candidal pericarditis is rare but fatal without treatment and has been known to cause tamponade. Infective endocarditis with Candida is usually seen in patients with a chronic indwelling intravenous catheter or large-caliber hemodialysis catheter. Other risk factors include congenital cardiac abnormalities, prosthetic valves, and intravenous illicit drug use. Fungal vegetations are often large and more frequently associated with embolic events. The mortality rate is approximately 45% with combined medical and surgical therapy.

Urethral candidiasis can occur in both men and women. In women, it is commonly secondary to an extension of Candida vaginitis. In men, it is usually secondary to sexual contact with women with vaginitis. Invasive infections of the bladder and kidneys can occur, typically in immunocompromised patients secondary to hematogenous spread. This hematogenous spread can also lead to acute renal infarction secondary to the infiltration of the renal parenchyma and occlusion of the hilar vessels. ^[18]

Ocular candidiasis can occur in the form of endophthalmitis. Endophthalmitis may result from exogenous spread, such as trauma or surgery, or endogenous spread due to hematologic seeding.

Untreated candidemia has been associated with retinal lesions in up to 37% of patients. Candida ophthalmitis begins as a choroidal lesion that progresses to an area of retinal necrosis followed by vitreitis and endophthalmitis. Endophthalmitis is characterized by retinal infiltrates and vitreous abnormalities. Chorioretinal involvement appears as focal, white, infiltrative lesions on the retina. Vitreal haze is present with vitreous extension of the infection. Symptoms include pain and decreased visual acuity. Untreated, ophthalmitis will lead to blindness. Typically, involvement is unilateral, but bilateral cases have been reported. C albicans is the most frequent culprit.

Osseous or intra-articular infections may result from either hematogenous spread or exogenous inoculation during trauma or joint injection. Osteomyelitis occurs most commonly in vertebrae in adults and in long bones in children. ^{[19, 20]} Spinal infection can progress to a diskitis. Arthritis can be acute and suppurative, and the knee is most commonly affected. ^[21] Diagnosis of osteoarticular infections may be delayed, as symptoms are frequently more subtle than bacterial infections in the same location and patients often present several weeks to months after an episode of candidemia. Fever is typically absent.

Candidal peritonitis is most frequently secondary to peritoneal dialysis catheter seeding or gastrointestinal surgery.

Mediastinitis secondary to candidal infection may occur after thoracic surgery.

Neonatal invasive candidiasis occurs with an incidence inversely proportional to birth weight. Candida colonization is found in approximately 30% of infants weighing less than 1500 g at birth weight. Sources of invasive infection in one study included blood (70%), urine (15%), CSF (10%), and peritoneal fluid (5%). C albicans and C parapsilosis are the most common species found in neonates.

Candida amnionitis may occur after prolonged rupture of the membranes in mothers given parenteral antibiotics. A neonate's skin may have pustules, vesicles, or diffuse erythema (shown in the image below). Neonates can also develop candidemia even after cesarean delivery due to premature rupture of amniotic membranes. ^[22]

Candidiasis. Discrete superficial pustules developed within hours of birth on the hand of an otherwise healthy newborn. A potassium hydroxide preparation revealed spores and pseudomycelium, and culture demonstrated the presence of Candida albicans. Image courtesy of Matthew C Lambiase, DO.

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See History.

Currently, there are more than 150 known species of Candida; however, only 15 of these species have been isolated from patients as infectious agents. ^[2]

Ninety-five percent candidal infections can be attributed to C albicans, Cglabrata, C parapsilosis, C tropicalis, and Ckrusei, among which C albicans continues to be the most common despite its decreasing share. ^[2]

The isolation rates of non-albicans species vary according to features of the infected hosts (eg, age, comorbid conditions, location and length of hospitalization). Examples are as follows ^[2] :

• C parapsilosis causes 30% of the candidemia cases among newborns; however, it is isolated in only 10%-15% of adults with bloodstream infections.

• C glabrata infection is more common in elderly and neoplastic patients.

• C parapsilosis commonly colonizes the skin and is therefore a common pathogen found in indwelling catheter–related infections.

• C tropicalis is more common in patients with leukemia and those who are neutropenic.

• C krusei is more common is stem cell recipients and in those with leukemia who have received fluconazole prophylaxis.

Denture use, immunosuppressant use, antibiotic therapy, and aging are risk factors for oral colonization with C glabrata. C glabrata exhibits lower oral keratinocyte-adherence capacity but higher denture surface–adherence ability.

New antifungal resistant species:

• Candida auris is a new nosocomial fungal pathogen belonging to the candida genus, first described in Japan in 2009, but has since been reported in 33 countries and over 4000 cases.  Most cases were reported in South African and the United States.  Candidiasis caused by C. auris is concerning because recent systematic reviews and meta-analysis showed an overall crude mortality rate of 39%, and C. auris candidemia (blood stream infection) to have a mortality rate of 45%.  Additionally, C. auris has shown to be highly resistant to certain antifungals, 91% resistant to fluconazole, 12% resistant to amphotericin B, 12.1% resistant to caspofungin, and 0.8% resistant to micafungin. ^[23]