Candidiasis

Author: Tarlan Hedayati, MD, Instructor of Clinical Emergency Medicine, Director of Observation Unit, Director of Chest Pain Unit, Department of Emergency Medicine, Los Angeles County/University of Southern California Medical Center

Coauthor(s): Joseph Choi, MD, Resident Physician, Department of Emergency Medicine, LAC+USC Medical Center, Keck School of Medicine, University of Southern California

Introduction

Background

The Candida fungus is both normal flora and an invasive pathogen. The range of infection with Candida species varies from a benign local mucosal membrane infection to disseminated disease. Severe disease is typically associated with an immunocompromised state including those vulnerable to iatrogenic pathogens in the intensive care unit or those with predisposing immunologic conditions such as malignancy, organ dysfunction, or immunosuppressive therapy.

Candidiasis. Image courtesy of Hon Pak, MD.

Candidiasis. Erythema, maceration, and satellite pustules in the axilla, accompanied by soreness and pruritus, result in a form of intertrigo. Image courtesy of Matthew C Lambiase, DO.

Pathophysiology

Candida is a unicellular yeast whose cells reproduce by budding. This organism can flourish in most environments. It frequently colonizes the oropharynx, skin, mucous membranes, lower respiratory, and gastrointestinal and genitourinary tracts. Pathogenesis occurs with increased fungal burden and colonization, such as in the setting of broad-spectrum antimicrobial agents; breakdown of normal mucosal and skin barriers, which can occur with indwelling intravascular devices, recent surgery/trauma or tissue damage secondary to chemotherapy or radiation; or immune dysfunction secondary to disease states or iatrogenic conditions.

Disease manifestation of candidal infection can vary with type of host immunodeficiency. Lymphocytes and cell-mediated immunity are important in the prevention of mucosal candidiasis. Therefore, patients with T-cell deficiency, such as human immunodeficiency virus (HIV), have a propensity to develop recurrent and/or persistent mucocutaneous candidiasis. Patients with neutropenia are at risk for invasive candidiasis and candidemia as functioning monocytes and polymorphonuclear cells are responsible for killing pseudohyphae and blastospores. Complement and immunoglobulins are necessary for intracellular killing of the organisms and patients with deficiencies can have a more prolonged and complicated course of candidal infection.

Frequency

United States

* Candida is the fourth most common cause of nosocomial bloodstream infection in the United States.1

* Three quarters of women experience vaginitis in their lifetime, and 30% of vaginitis is caused by Candida. Vaginitis accounts for 10 million office visits per year.

* Invasive candidiasis is the most common invasive fungal infection in the United States. There is an increasing shift toward infections caused by non-albicans Candida species with 40-60% of the species currently being reported as non-albicans species.

International

* Internationally , Candida epidemiology is similar to that of the United States.

* Non-albicans Candida accounted for 70% of candidemia in a Northern Indian pediatric intensive care unit. Candida species isolated were Candida tropicalis (48.4%), C albicans (29.7%), C guilliermondii (14.1%), C krusei (6.3%), and C glabrata (1.6%).

* Other Candida species that have emerged are C parapsilosis and C dubliniensis.2

* C glabrata and C krusei have been identified as the leading causes of candidemia in patients with malignancy of hematologic origin;3 C parapsilosis has been identified as the leading cause of candidemia secondary to medical instrumentation such as central venous catheters, prosthetic devices, and nosocomial spread.4

* C dubliniensis has been identified in an immunocompromised patient with multifocal osteomyelitis in Germany5 and in a patient with meningitis in Australia6 .

* Fungal keratitis is more prevalent in the tropics; therefore, Candida accounts for proportionately more fungal corneal isolates at temperate latitudes.

Mortality/Morbidity

* Invasive candidiasis has a mortality rate of 40-50%, with an estimated cost of $40,000 per episode.

* Neonates and children have better outcomes with approximately 20% mortality rate for candidemia.

* Risk factors for death or poor prognosis are age, failure to remove central lines, malnutrition, and non-albicans fungemia.

Race

* No racial predilection exists for infection with Candida.

Sex

* Three quarters of all women experience at least one episode of vulvovaginal candidiasis in their lifetime, and about one half of these women experience a recurrence.

Age

* Elderly persons with high Acute Physiology and Chronic Health Evaluation (APACHE) II scores as well as neonates with low gestational age, low APGAR scores, and congenital malformations are at high risk for candidal infection.

Clinical

History

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. Candidal leukoplakia is firm, white plaques affecting the cheeks, lips, and tongue, which 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, 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.

Candida epiglottitis is another entity that can manifest for immunocompromised patients. It may exist as a coinfection with bacterial organisms or on its own. A KOH prep and fungal cultures may be helpful in treating an epiglottitis that is not improving on antibiotics alone.7

Candida esophagitis is most commonly associated with treatment of hematopoietic or lymphatic malignancies. It is also an AIDS-defining illness, though patients with Candida esophagitis and no underlying illness have been reported. Symptoms include dysphagia, sensation of obstruction on swallowing, retrosternal chest pain, nausea, and vomiting. Definitive diagnosis is made by 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 and cytomegalovirus infection in severely immunocompromised patients.

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 was found in a patient without any history of underlying malignancy.8

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 diabetes mellitus and HIV. Another risk factor for vulvovaginal candidiasis may be intrauterine contraceptive devices.9

Of vulvovaginal candidiasis cases, 70-90% are caused by Candida albicans, while the remainder of infections are caused by C glabrata and C tropicalis. Symptoms classically are 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 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 is characterized by widespread eruptions with increased severity in the genitocrural folds, anal region, axillae, and hands and feet that occurs in both children and adults.

* Erosio interdigitalis blastomycetica: This is an intertriginous infection, which is predisposed to maceration.

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

* Candida balanitis: This infection is usually acquired with sexual intercourse with an infected partner. Rash typically begins as vesicles on the penis that develop into patches similar in appearance to thrush. Extension may occur to the scrotum and buttocks. Symptoms include burning and pruritus. C glabrata has been implicated as the cause of Fournier’s gangrene in an immunocompromised patient.

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

* Mammary candidiasis: This is a condition that can affect breastfeeding women.11

* Intertrigo: This develops in sites where skin surfaces are close in proximity. Lesions begin as vesicopustules that enlarge, rupture, and develop maceration and fissuring. Satellite lesions may 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.

* Perianal candidiasis: Skin maceration and pruritus are frequent with frequent extension to the perineum.

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.

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 patients 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.

Risk factors for invasive candidiasis include prolonged intensive care unit (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.

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. Presumed etiology is prior episode of candidemia, although invasion through portal vasculature has been theorized.

Central nervous system candidiasis usually occurs as a complication of hematogenously disseminated candidiasis. Candida typically forms multiple microabscesses and small macroabscesses scattered throughout the brain.12 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 or more commonly a hematogenously seeded, nodular diffuse infiltrate. This presentation may be difficult to distinguish from congestive heart failure or Pneumocystis pneumonia. Diagnosis is also complicated by the inability to confirm that positive cultures are not oropharyngeal contaminant or colonization. Candida empyema cases have been documented.13

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, though it is typically in immunocompromised patients and 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.14

Ocular candidiasis can occur in the form of endophthalmitis. Endophthalmitis may occur secondary to exogenous spread, such as trauma or surgery, or endogenous spread as a result of 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 occur secondary to 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.15,16 Spinal infection can progress to a diskitis. Arthritis can be acute and suppurative, and the knee is most commonly affected.17 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 grams at birth weight. Sources of invasive infection in one study included blood (70%), urine (15%), cerebrospinal fluid (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. Neonates can also develop candidemia even after cesarean delivery due to premature rupture of amniotic membranes

Causes

* C albicans is the most common pathogenic species identified. Other species that are commonly found include C glabrata, C parapsilosis, C tropicalis, and C krusei.

* Non-albicans species have been associated with specific patient populations. C glabrata is seen most commonly in patients with neoplastic disease; C tropicalis in patients with leukemia or neutropenia; C parapsilosis among neonates and those with an indwelling intravenous catheter; and C krusei in stem cell transplant recipients and in patients with leukemia who have received fluconazole prophylaxis.

* Denture use, immunosuppressant, 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.