INTRODUCTION — The clinical manifestations of infection with Candida species range from local mucous membrane infections to widespread dissemination with multisystem organ failure [1]. Although Candida are considered to be part of the normal microbiota in the gastrointestinal and genitourinary tracts of humans, they have the propensity to invade and cause disease when an imbalance is created in the ecologic niche in which these organisms usually exist. (See "Biology of Candida infections".)
The immune response of the host is an important determinant of the type of infection caused by Candida.
●The most benign infections are characterized by local overgrowth on mucous membranes (oropharyngeal involvement, vaginitis) as a result of changes in the normal microbiota. More extensive persistent mucous membrane infections occur in individuals with deficiencies in cell-mediated immunity, such as acquired immunodeficiency syndrome (AIDS).
●In the neutropenic host or the severely ill patient in the intensive care unit, widespread visceral dissemination occurs when Candida species gain access to the bloodstream.
●Invasive focal infections, such as pyelonephritis, endocarditis, and meningitis, most often occur after hematogenous spread or when anatomic abnormalities or devices (eg, prosthetic heart valves or central nervous system shunts) are present.
There are over 160 species of Candida in nature. However, only about 20 of them actually cause infections in humans. In general, all Candida species are capable of producing all of the clinical syndromes, although infection with Candida albicans is the most common. It is important to identify the infecting organism because some species are more resistant to the azole antifungal agents than others. (See "Management of candidemia and invasive candidiasis in adults".)
This topic will provide a broad overview of the various manifestations of Candida infection. Infection at most of these sites is discussed in detail in other topic reviews and will be only briefly summarized here. The treatment of Candida infections is reviewed separately. (See "Oropharyngeal candidiasis in adults" and "Management of candidemia and invasive candidiasis in adults" and "Candida vulvovaginitis: Clinical manifestations and diagnosis" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)" and "Candida infections of the bladder and kidneys" and "Treatment of endogenous endophthalmitis due to Candida species" and "Treatment of exogenous endophthalmitis due to Candida species" and "Candida osteoarticular infections" and "Candida infections of the central nervous system" and "Candida endocarditis and suppurative thrombophlebitis" and "Candida infections of the abdomen and thorax" and "Candidemia and invasive candidiasis in children: Management" and "Treatment of Candida infection in neonates".)
LOCAL MUCOCUTANEOUS INFECTIONS
Oropharyngeal candidiasis — Oropharyngeal candidiasis, or thrush, is a common local infection seen in infants; older adults who wear dentures; patients treated with antibiotics, chemotherapy, or radiation therapy to the head and neck; and those with cellular immune deficiency states, such as AIDS. Patients with xerostomia and those treated with inhaled glucocorticoids for asthma or rhinitis are also at risk. (See "Esophageal candidiasis in adults".)
The usual symptoms of oropharyngeal candidiasis are a cottony feeling in the mouth, loss of taste, and sometimes pain on eating and swallowing. However, many patients are asymptomatic, whereas patients with denture stomatitis often have pain when they try to wear their dentures. Immunosuppressed patients with thrush often have concomitant Candida esophagitis.
The diagnosis is usually suspected because of the presence of white plaques on the buccal mucosa, palate, tongue, or the oropharynx (picture 1) or under dentures where there is usually erythema without plaques (picture 2). The diagnosis is readily confirmed by scraping the lesions with a tongue depressor and performing a Gram stain or potassium hydroxide (KOH) preparation on the scrapings. Budding yeasts with or without pseudohyphae are seen.
Esophagitis — Esophageal candidiasis is most common in patients with human immunodeficiency virus (HIV), in which it is an AIDS-defining illness, and in patients with hematologic malignancies. Concomitant thrush is usually present but may be absent in approximately 10 percent of cases. (See "Esophageal candidiasis in adults" and "Evaluation of the patient with HIV, odynophagia, and dysphagia".)
The hallmark of Candida esophagitis is odynophagia, or pain on swallowing. Patients usually localize their pain to a discrete retrosternal area. The diagnosis of Candida esophagitis is usually made when white mucosal plaque-like lesions are noted on endoscopy (picture 3). Confirmatory biopsy shows the presence of yeast and pseudohyphae invading mucosal cells, and culture reveals Candida.
Vulvovaginitis — Vulvovaginal candidiasis is the most common form of mucosal candidiasis. It most often occurs in situations associated with increased estrogen levels, such as oral contraceptive use and pregnancy. Antibiotics, glucocorticoids, diabetes mellitus, HIV infection, intrauterine devices, and diaphragm use are also risk factors. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis".)
The clinical manifestations of Candida vulvovaginitis are primarily itching and discharge. Dyspareunia, dysuria, and vaginal irritation also may be present. Physical examination shows vulvar erythema and swelling and vaginal erythema and discharge, which is classically white and curd-like but may be watery. Some patients, primarily those with Candida glabrata infection, have little discharge and often only have erythema on vaginal examination.
The diagnosis of Candida vulvovaginitis is typically made clinically, but confirmation is easily obtained by observing budding yeast, with or without pseudohyphae, on a wet mount or KOH preparation of vaginal secretions (picture 4).
Balanitis — Balanitis can present as white patches on the penis in association with severe burning and itching (picture 5). The infection can also spread to the thighs, gluteal folds, buttocks, and scrotum. (See "Balanitis in adults".)
Chronic mucocutaneous candidiasis — Chronic mucocutaneous candidiasis is a rare syndrome that usually has its onset in childhood. Some patients have autosomal recessive polyglandular autoimmune syndrome type I, which is also referred to as the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1'.)
The clinical manifestations of candidiasis in these patients include severe, recurrent thrush, onychomycosis, vaginitis, and chronic skin lesions. The skin lesions may assume a hyperkeratotic, crusted appearance on the face, scalp, and hands (picture 6). Visceral invasion is rare. (See "Chronic mucocutaneous candidiasis".)
Mastitis — Lactating women with injured nipples are at increased risk for developing skin or breast infections, including candidal infections. The management of such infections is discussed in detail separately. (See "Common problems of breastfeeding and weaning", section on 'Candidal infection'.)
RISK FACTORS FOR INVASIVE INFECTION — Invasive Candida infections are most often associated with candidemia, which primarily occurs in immunocompromised patients and those requiring intensive care. Immunocompromised patients at special risk for candidemia include:
●Those with hematologic malignancies
●Recipients of solid organ or hematopoietic cell transplants
●Those given chemotherapeutic agents for a variety of different diseases
Neutropenia is common in these settings, and most transplant recipients are also receiving glucocorticoids. Other risk factors in these patients include chemotherapeutic agents, especially those associated with extensive gastrointestinal mucosal damage, broad-spectrum antibiotics, and central venous catheters.
Patients in intensive care units (ICUs) account for the greatest number of episodes of candidemia at most hospitals. Surgical units, especially those caring for trauma and burn patients, and neonatal units have the highest rates of Candida infections. Other risk factors commonly associated with candidemia and invasive candidiasis in ICU patients include:
●Central venous catheters
●Total parenteral nutrition
●Broad-spectrum antibiotics
●High APACHE scores
●Acute kidney injury, particularly if requiring hemodialysis
●Prior surgery, particularly abdominal surgery
●Gastrointestinal tract perforations and anastomotic leaks
(See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)
CANDIDEMIA AND INVASIVE CANDIDIASIS — Candidemia refers to the presence of Candida species in the blood. Immunocompromised hosts and patients in intensive care units are at the highest risk of developing candidemia. (See 'Risk factors for invasive infection' above.)
The clinical manifestations vary from minimal symptoms, such as fever, to a full-blown sepsis septic shock syndrome that is indistinguishable from severe sepsis due to bacterial infections. Invasive candidiasis occurs when visceral sites are infected as a result of hematogenous spread.
Clinical clues to the occurrence of hematogenous spread of Candida include characteristic eye lesions, skin lesions, and, less commonly, muscle abscesses. The skin lesions tend to appear suddenly as clusters of painless pustules on an erythematous base and can occur on any area of the body. The lesions vary from tiny pustules that can be easily missed (picture 7) to nodular lesions that can range up to several centimeters in diameter and may occasionally appear necrotic in the center (picture 8). In severely neutropenic patients, the lesions may be macular rather than pustular.
Material obtained by scraping the base of a pustule with a scalpel blade frequently shows yeast on Gram stain (picture 9), and, if enough material is obtained to perform a culture, this will yield Candida species. Alternatively, punch biopsies of skin lesions can be performed and sent for histopathology and culture.
In addition to these typical peripheral sites of involvement, signs of multiorgan system failure may be present. Autopsy studies reveal widespread visceral microabscesses that are especially prominent in the kidneys, heart, liver, spleen, lungs, and brain (picture 10). The clinical manifestations, diagnosis, and treatment of invasive Candida infections are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Management of candidemia and invasive candidiasis in adults".)
HEPATOSPLENIC OR CHRONIC DISSEMINATED CANDIDIASIS — Hepatosplenic candidiasis (also called chronic disseminated candidiasis) is seen almost entirely in patients with hematologic malignancies who have just recovered from an episode of neutropenia. Some patients have a documented prior episode of candidemia; in others, it is assumed that the patient was candidemic during the period of neutropenia. Invasion of Candida species through the portal vasculature originating in the gastrointestinal tract is the likely mechanism by which hepatosplenic candidiasis can occur in the absence of positive blood cultures. (See "Chronic disseminated candidiasis (hepatosplenic candidiasis)".)
The classic presentation of hepatosplenic candidiasis consists of persistent fever, which is frequently high and spiking, in a patient who was recently neutropenic and whose neutrophil count has returned to normal. The fever is often accompanied by right upper quadrant discomfort or pain, nausea, vomiting, and anorexia. Laboratory testing typically reveals an elevated serum alkaline phosphatase concentration. Discrete persistent microabscesses occur in the liver, spleen, and, sometimes, kidneys. The diagnosis can be established by visualizing multiple characteristic lucencies in the liver, spleen, and kidneys on ultrasound, magnetic resonance imaging, or computed tomography scan (image 1).
INVASIVE FOCAL INFECTIONS
Urinary tract infection — Funguria is common finding in hospitalized patients, although it is often difficult to distinguish between colonization and true infection of the urinary tract. Candida infection of the bladder must be distinguished from infection of the kidney, although the two entities can coexist. Invasive infection of the kidney is unusual and is more difficult to treat than infection of the bladder.
Renal infection can be due to either hematogenous seeding of the renal parenchyma or via ascending route from the lower urinary tract. Secondary to hematogenous seeding is typically characterized by multiple microabscesses in the setting of disseminated candidiasis. In contrast, ascending infection develops more insidiously, is frequently unilateral, and can be complicated by the development of an obstructing bezoar or fungus ball. (See "Candida infections of the bladder and kidneys".)
Endophthalmitis — Candida endophthalmitis can develop exogenously following trauma or eye surgery or endogenously through hematogenous seeding of the retina and choroid as a complication of candidemia. Because of the risk of endophthalmitis from hematogenous seeding, a dilated retinal examination by an ophthalmologist should be performed in all candidemic patients. (See "Treatment of exogenous endophthalmitis due to Candida species" and "Treatment of endogenous endophthalmitis due to Candida species" and "Management of candidemia and invasive candidiasis in adults".)
Patients with endophthalmitis may be symptomatic. In symptomatic patients, the primary presentation is diminished visual acuity; pain can sometimes occur. The classic findings of chorioretinal involvement are focal, white, infiltrative, often mound-like lesions on the retina (picture 11). When vitreous extension is present, a vitreal haze is present; sometimes fluffy white balls or "snowballs" in the vitreous are noted (picture 12). The infection can be sight-threatening if it is not treated promptly.
Osteoarticular infections — Candida species infect bones and joints as a result of either hematogenous seeding or direct inoculation during trauma, intra-articular injection, surgical procedures, or injection drug use. Although most infections have been described in native joints, prosthetic joints may also be affected. Among patients with osteomyelitis, the site of involvement varies with age. The vertebrae are most commonly involved in adults, while the long bones of the extremities are more likely to be involved in children. (See "Candida osteoarticular infections".)
Osteoarticular infections often become symptomatic months or as long as a year after an episode of fungemia or a surgical procedure. The manifestations are generally more subtle than those seen with bacterial infections at the same sites. Both of these factors contribute to long delays in diagnosis, especially in patients with vertebral osteomyelitis. The major symptoms of Candida arthritis are pain and decreased range of motion, whereas local pain is the predominant symptom of Candida osteomyelitis.
The diagnosis is established by culture of the infected site. Candida arthritis is more easily confirmed than osteomyelitis because synovial fluid can be readily obtained for culture. Even a single colony of Candida on culture of joint fluid or bone biopsy or aspirate should be viewed as pathogenic.
Meningitis — Candida infections of the central nervous system (CNS) most commonly involve the meninges. Candida meningitis can present as a manifestation of disseminated candidiasis, which most often occurs in premature neonates, as a complication of ventricular drainage devices or as isolated chronic meningitis. In addition to hematogenous spread, Candida can enter the CNS at the time of craniotomy or through a ventriculoperitoneal or ventriculoatrial shunt. (See "Candida infections of the central nervous system".)
The symptoms of Candida meningitis can be the same as in acute bacterial meningitis (eg, fever, stiff neck, altered mental status, headache). However, signs of sepsis and multiorgan failure often predominate in neonates, and fever may be the only manifestation in patients who are neutropenic. In addition, patients with hematogenous seeding may also have other signs of dissemination, such as endophthalmitis, chorioretinitis, endocarditis, and skin or renal involvement. Lumbar puncture to obtain cerebrospinal fluid (CSF) for culture is essential to establish the diagnosis.
The clinical features of chronic Candida meningitis resemble those of meningitis caused by tuberculosis or Cryptococcus species. Headache, fever, and nuchal rigidity are the most common manifestations. The diagnosis is difficult to establish because the organism is present in low numbers, and the yield of standard cultures of CSF is poor. Large-volume lumbar punctures are often required to obtain sufficient CSF for culture. (See "Candida infections of the central nervous system" and "Approach to the patient with chronic meningitis".)
Endocarditis — Candida endocarditis is one of the most serious manifestations of candidiasis and is the most common cause of fungal endocarditis. Candida endocarditis results from candidemia and is usually seen in patients with prosthetic heart valves, people who inject intravenous drugs, and in patients who have indwelling central venous catheters and prolonged fungemia. (See "Candida endocarditis and suppurative thrombophlebitis".)
The clinical manifestations of Candida endocarditis may be similar to those of bacterial endocarditis, including fever, changing or new heart murmurs, and signs and symptoms of heart failure. Peripheral embolization is more likely than with bacterial endocarditis, a probable reflection of larger vegetations. In addition, affected patients can also develop other complications of candidemia, such as visual loss secondary to endophthalmitis. In most patients, blood cultures reveal persistent candidemia, and echocardiography shows large vegetations. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)
Peritonitis and intra-abdominal infections — Candida species frequently contribute to polymicrobial infections that occur following gastrointestinal tract perforation, anastomotic leaks after bowel surgery, or acute necrotizing pancreatitis. Discrete abscesses with or without peritonitis can occur. (See "Candida infections of the abdomen and thorax", section on 'Peritonitis and intra-abdominal infections'.)
Candida peritonitis can also complicate continuous peritoneal dialysis in patients with end-stage kidney disease, which is discussed elsewhere. (See "Fungal peritonitis in peritoneal dialysis".)
Other intra-abdominal manifestations of Candida infection include isolated pancreatic abscess, gangrenous cholecystitis, and obstruction to the common bile duct with a Candida fungus ball. C. albicans has been the predominant species isolated in intra-abdominal infections; however, the frequency of C. glabrata has increased in many centers. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis", section on 'Prevalence of Candida species'.)
The symptoms of Candida peritonitis do not differ from those of bacterial peritonitis, which is usually present concomitantly. Thus, fevers, chills, and abdominal pain are prominent. Complications include bloodstream invasion with associated sepsis and abscess formation requiring surgical drainage.
The diagnosis is best made by aspiration of fluid under computed tomographic or ultrasound guidance, or at the time of intra-abdominal surgery. It should be noted that culture of a Candida species from an indwelling drain is not adequate for the diagnosis of infection because it often reflects only colonization or contamination of the drain.
Pneumonia — Pneumonia due to Candida is extremely rare. Furthermore, Candida pneumonia remains poorly defined as a clinical entity because positive cultures cannot distinguish between true infection and either colonization or contamination of samples with organisms present in the oropharynx. (See "Candida infections of the abdomen and thorax", section on 'Pneumonia'.)
Empyema — Candida empyema occurs most commonly in patients with malignancies or as a complication of a health care-associated infection. Over one-quarter of patients with Candida empyema also have candidemia. (See "Candida infections of the abdomen and thorax", section on 'Empyema'.)
Mediastinitis — Candida mediastinitis almost always occurs after thoracic surgery procedures. In a report of nine cases of Candida mediastinitis, the primary clinical manifestations included chest wall erythema and/or drainage, fever, and sternal instability. These findings are similar to those seen with bacterial causes of postoperative mediastinitis. (See "Postoperative mediastinitis after cardiac surgery".)
Candida mediastinitis is discussed in detail separately. (See "Candida infections of the abdomen and thorax", section on 'Mediastinitis'.)
Pericarditis — Purulent pericarditis due to Candida species is rare but life-threatening. It most often arises as a complication of thoracic surgery or due to a contiguous spread from an adjacent focus, although hematogenous spread can also occur. C. albicans is the most common pathogen, but infection with Candida tropicalis and C. glabrata has also been described. (See "Candida infections of the abdomen and thorax", section on 'Pericarditis'.)
GASTROINTESTINAL TRACT COLONIZATION — Candida species are part of the normal microbiota of the gastrointestinal tract. Isolation of Candida species from stool cultures does not represent infection and therefore does not warrant treatment.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)
SUMMARY AND RECOMMENDATIONS
●Spectrum of clinical disease – The clinical manifestations of infection with Candida species range from local mucous membrane infections to widespread dissemination with multisystem organ failure. Although Candida species are considered to be part of the normal microbiota in the gastrointestinal and genitourinary tracts of humans, they have the propensity to invade and cause disease when an imbalance is created in the ecologic niche in which these organisms usually exist. (See 'Introduction' above.)
●Oral thrush – Oropharyngeal candidiasis, or thrush, is a common local infection seen in infants; older adults who wear dentures; patients treated with antibiotics, chemotherapy, or radiation therapy to the head and neck; and those with cellular immune deficiency states, such as AIDS. Patients with xerostomia and those treated with inhaled glucocorticoids for asthma or rhinitis are also at risk. (See 'Oropharyngeal candidiasis' above.)
●Esophageal candidiasis – Esophageal infection is most common in patients with HIV, in which it is an AIDS-defining illness, and in patients with hematologic malignancies. (See "Esophageal candidiasis in adults" and "Evaluation of the patient with HIV, odynophagia, and dysphagia".)
●Vulvovaginal candidiasis – This is the most common form of mucosal candidiasis. It most often occurs in situations associated with increased estrogen levels, such as oral contraceptive use and pregnancy. Antibiotics, glucocorticoids, diabetes mellitus, HIV infection, intrauterine devices, and diaphragm use are also risk factors. (See 'Vulvovaginitis' above.)
●Chronic mucocutaneous candidiasis – This is a rare syndrome that usually has its onset in childhood. Some patients have autosomal recessive polyglandular autoimmune syndrome type I, which is also referred to as the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. (See 'Chronic mucocutaneous candidiasis' above.)
●Candidemia – Candidemia refers to the presence of Candida species in the blood. Immunocompromised hosts and patients in intensive care units are at the highest risk of candidemia. (See 'Risk factors for invasive infection' above and 'Candidemia and invasive candidiasis' above.)
●Hepatosplenic candidiasis (ie, chronic disseminated candidiasis) – This is seen almost entirely in patients with hematologic malignancies who have just recovered from an episode of neutropenia. Some patients have a documented prior episode of candidemia; in others, it is likely that invasion of Candida species occurred through the portal vasculature. (See 'Hepatosplenic or chronic disseminated candidiasis' above.)
●Other candidal infections – Invasive focal infections include urinary tract infection, endophthalmitis, osteoarticular infections, meningitis, endocarditis, peritonitis and intra-abdominal infections, empyema, mediastinitis, and pericarditis. Pneumonia due to Candida is extremely rare. (See 'Invasive focal infections' above and 'Pneumonia' above.)
