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School of Molecular & Biomedical Science
The University of Adelaide
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Dr David Ellis
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Candidiasis

Description:

Candidiasis is a primary or secondary mycotic infection caused by members of the genus Candida. The clinical manifestations may be acute, subacute or chronic to episodic. Involvement may be localized to the mouth, throat, skin, scalp, vagina, fingers, nails, bronchi, lungs, or the gastrointestinal tract, or become systemic as in septicemia, endocarditis and meningitis. In healthy individuals, Candida infections are usually due to impaired epithelial barrier functions and occur in all age groups, but are most common in the newborn and the elderly. They usually remain superficial and respond readily to treatment. Systemic candidiasis is usually seen in patients with cell-mediated immune deficiency, and those receiving aggressive cancer treatment, immunosuppression, or transplantation therapy.

Clinical manifestations:

1. Oropharyngeal candidiasis: including thrush, glossitis, stomatitis and angular cheilitis (perleche).

Oral candidiasis in a new bornOral candidiasis in an immunosuppressed patient
Oral candidiasis in a new born (left) and in an immunosuppressed patient (right).

Acute oral candidiasis is rarely seen in healthy adults but may occur in up to 5% of newborn infants and 10% of the elderly. However, it is often associated with severe immunological impairment due to diabetes mellitus, leukemia, lymphoma, malignancy, neutropenia and HIV infection where it presents as a predictor of clinical progression to AIDS. The use of broad-spectrum antibiotics, corticosteroids, cytotoxic drugs, and radiation therapy are also predisposing factors. Clinically, white plaques that resemble milk curd form on the buccal mucosa and less commonly on the tongue, gums, the palate or the pharynx. Symptoms may be absent or include burning or dryness of the mouth, loss of taste, and pain on swallowing.

2. Cutaneous candidiasis: including intertrigo, diaper candidiasis, paronychia and onychomycosis.

Interdigital candidiasis.
Interdigital candidiasis.

Candidiasis between the toes
Candidiasis between the toes mimicking tinea.

Candidiasis in the groin
Candidiasis in the groin mimicking tinea.

Intertriginous candidiasis is most commonly seen in the axillae, groin, inter- and sub-mammary folds, intergluteal folds, interdigital spaces, and umbilicus. Moisture, heat, friction and maceration of the skin are the principle predisposing factors in the normal patient, however obesity, diabetes mellitus, warm water immersion or occlusion of the skin and the use of broad-spectrum antibiotics are additional factors. Lesions consist of a moist, macular erythematous rash with typical satellite lesions present on the surrounding healthy skin.


"Nappy rash" candidiasis in an infant which spread to the mouth area.

Diaper candidiasis is common in infants under unhygienic conditions of chronic moisture and local skin maceration associated with ammonitic irritation due to irregularly changed unclean diapers. Once again characteristic erythematous lesions with erosions and satellite pustules are produced, with prominent involvement of the skin folds and creases.

Paronychia of the finger nails may develop in persons whose hands are subject to continuous wetting, especially with sugar solutions or contact with flour, that macerates the nail folds and cuticle. Lesions are characterized by the development of a painful, erythematous swelling about the affected nails. In chronic cases the infection may progress to cause onychomycosis with total detachment of the cuticle from the nail plate.

Candida onychomycosis
Candida onychomycosis in an immunosuppressed patient.

Chronic Candida onychomycosis often causes complete destruction of nail tissue and is seen in patients with chronic mucocutaneous candidiasis or other underlying factors that affect either the hormonal or immunologic status of the host. These include diabetes mellitus, hypoparathyroidism, Addison's disease, dysfunction of the thyroid, malnutrition, malabsorption and various malignancies. The use of steroids, antibiotics and antimitotics may also be contributing factors.

3. Vulvovaginal candidiasis and balanitis:

Vulvovaginal candidiasis is a common condition in women, often associated with the use of broad-spectrum antibiotics, the third trimester of pregnancy, low vaginal pH and diabetes mellitus. Sexual activity and oral contraception may also be contributing factors and infections may extend to include the perineum, the vulva and the entire inguinal area. Chronic refractory vaginal candidiasis, associated with oral candidiasis, may also be a presentation of HIV infection or AIDS. Symptoms include intense vulval pruritus, burning, erythema and dyspareunia associated with a creamy white, curd-like discharge.

In cases of balanitis, diabetes mellitus should be excluded and the sexual partner should be investigated for vulvovaginitis. The symptoms include erythema, pruritus and vesiculopustules on the glan penis or prepuce. Infections are more commonly seen in uncircumcised men and poor hygiene may also be a contributing factor.

4. Chronic mucocutaneous candidiasis:

Chronic mucocutaneous candidiasis is a form of persistent candidiasis, usually caused by C. albicans, of the skin, nails and mucous membranes that occurs in patients with various metabolic disturbances to cell-mediated immunity. These include defects in leukocyte function or endocrine disorders such as hypoparathyroidism, Addison's disease, hypothyroidism, diabetes, dysfunction of the thyroid and polyglandular autoimmune disease. The patients are usually children. Candida granuloma is a severe localized form which may occur with or without endocinopathy characterized by marked hyperkeratic granulomatous lesions.

5. Neonatal and congenital candidiasis:

Low birthweight and age, prolonged intravascular catheterization and the use of antibiotic drugs are the principle predisposing conditions for systemic candidiasis in neonates. Blood cultures are often positive and there is also a high incidence of meningitis. Renal complications due to fungus ball formation in the ureters or renal pelvis may also occur. Congenital candidiasis acquired in utero is usually confined to the skin in the form of a generalized erythematous vesicular rash, however intrauterine candidiasis may also result in abortion.

6. Oesophageal candidiasis:

Oesophageal candidiasis is frequently associated with AIDS and severe immunosuppression following treatment for leukemia or solid tumors. Concomitant oral candidiasis is often present. Oesophagitis may also lead to septicemia and disseminated candidiasis. Symptoms include burning pain in the substernal area, dysphagia, nausea and vomiting. The clinical diagnosis relies on radiological and endoscopic findings, which usually shows white mucosal plaques with erythema resembling those seen in oral candidiasis. Herpes simplex or cytomegalovirus (CMV) infection may also be present and the clinical diagnosis may need to be confirmed by histopathology and culture.

7. Gastrointestinal candidiasis:

Patients with acute leukemia or other hematological malignancies may have numerous ulcerations of the stomach and less commonly the duodenum and intestine. Perforation can lead to peritonitis and hematogenous spread to the liver, spleen and other organs. Colonization and invasion of the stomach or intestinal mucosa is often accompanied by the excretion of large numbers of yeasts which may be detected in stools.

8. Pulmonary candidiasis:

Pulmonary candidiasis can be acquired by either hematogenous dissemination causing a diffuse pneumonia or by bronchial extension in patients with oropharyngeal candidiasis. Aspiration of yeasts from the oral cavity has also been reported in infants. Pulmonary candidiasis is difficult to diagnose due to non-specific radiological and culture findings and most patients, especially those with granulocytopenia, present at autopsy. The presence of yeasts in alveolar lavage or sputum specimens is not specific and blood cultures may also be negative. Unfortunately, only histopathology can provide a definitive diagnosis and this is not always possible in patients with coagulation problems.

9. Peritonitis:

Candida peritonitis can result from colonization of indwelling catheters used for peritoneal dialysis (CAPD) or gastrointestinal perforation due to ulcers, diverticular colitis, surgery or intra-abdominal neoplasm. Symptoms include fever, abdominal pain, tenderness and a cloudy peritoneal dialysate containing greater than 100 leukocytes/mm3. Candida peritonitis usually remains localized to the abdominal cavity unless patients are severely immunosuppressed.

10. Urinary tract candidiasis:

Transient asymptomatic candiduria may occur during antibiotic or corticosteroid treatment which promotes the growth of Candida, throughout the gastrointestinal and genital tracts, and most lower urinary tract infections result from local spread of yeasts from these sites. This condition is most common in women. Candida cystitis or bladder colonization may be caused by prolonged catheterization with concomitant antibiotic treatment, diabetes and glycosuria, anatomical uropathy, previous bladder endoscopy or surgery, diabetic neurogenic bladder, chronic outlet obstruction from prostatic hypertrophy, or pelvic irradiation for cervical cancer.

Renal candidiasis (pyelonephritis) is usually the result of either an ascending infection or more frequently, hematogenous dissemination from another organ focus. Symptoms include fever, rigors, lumbar pain and abdominal pain. The development of a fungus ball in the renal pelvis, although rare may complicate the infection. Predisposing factors for this include constriction of the urinary tract, localized papillary necrosis, urethral or bladder catheters and diabetes. Even though, up to 80% of patients with disseminated candidiasis also have renal infection and associated candiduria, urine cultures alone are not a reliable method for diagnosis of disseminated infection.

The practical problem in a patient with candiduria is to distinguish between colonization and/or contamination and infection. Therefore, it is important to determine whether renal function is present or whether infection is confined to the bladder. Mycological findings are usually inconclusive which makes the clinical parameters important. The following criteria are suggestive of renal infection; the isolation of yeasts in urine specimens obtained by suprapubic aspiration, positive blood cultures and a positive immunodiffusion precipitin test result or serological conversion in a patient with iatrogenic predisposing factors and/or an underlying illness.

It should be noted that many clinicians do not recommend suprapubic aspirates as they are invasive and require additional expertise, especially in immunocompromised patients. Laboratories are also advised on the need to report the isolation of any yeasts from urine specimens obtained from high risk immunosuppressed patients.

11. Meningitis:

Candida meningitis is a rare entity, predominantly seen in low birthweight neonates with septicemia and in patients with hematological malignancies, complicated neurosurgery or intracerebral prosthetic devices such as ventriculoperitoneal shunts. Symptoms include a feverish meningeal irritation. Diagnosis in the neonate requires a high index of suspicion by the clinician to the possibility of meningitis as a sequel to septicemia. The detection of Candida cells in smears and its isolation from CSF is often difficult.

12. Hepatic and hepatosplenic candidiasis:

Hepatosplenic candidiasis occurs in patients with severe neutropenia, usually acute leukemia. Symptoms include fever, hepatosplenomegaly and increased blood concentrations of alkaline phosphatases. Histopathology shows diffuse hepatic and/or splenic necrotic lesions or abscesses containing small numbers of pseudohyphae. However, blood and biopsy cultures are usually culture negative. A definitive diagnosis is often difficult due to the inability to adequately biopsy these patients.

13. Endocarditis, myocarditis and pericarditis:

Endocarditis is the most common form of cardiac candidiasis. Pre-existing valvular disease with concomitant intravenous catheterization and antibiotic treatment, intravenous drug abuse, heart surgery and valve prosthesis are the most common predisposing factors. Clinical symptoms include fever, murmur, congestive heart failure, anemia and splenomegaly. Blood cultures are often positive and echocardiology and serology for the detection of Candida antibodies (immunodiffusion precipitin tests) are other useful diagnostic procedures. Myocardial abscesses, arterial emboli and purulent pericarditis are additional rare complications of Candida septicemia or surgery.

14. Candidemia (Candida septicemia) and disseminated candidiasis:

Candidemia has been defined as the presence of yeasts in the blood with or without visceral involvement. Hematogenous dissemination may then occur to one or more other organ systems with the formation of numerous microabscesses. Candida species have been reported to cause up to 15% of cases of septicemia seen in hospital patients.

Predisposing factors include intravenous catheters, use of antibacterial drugs, urinary catheters, surgical procedures, corticosteroid therapy, neutropenia, severe burns, parental nutrition, and chemotherapy induced impairment of oropharyngeal or gastrointestinal mucosa. A characteristic presentation is antibiotic resistant fevers in the neutropenic patient with tachycardia and dyspnea. Hypotension is also common and skin lesions may also occur.

When yeasts are isolated from blood or from tissue biopsies a diagnosis is straightforward, however this is not often the case. Blood cultures often remain negative even in patients dying from proven disseminated candidiasis, especially in the granulocytopenic patient. If at all possible, suspected foci should be aspirated, including articular, peritoneal, CSF, or even vitreal specimens; and liver and/or lung biopsies should also be performed. However histopathology is more often not a viable option because biopsies are contraindicated due to the patients underlying illness. Finally, the detection of yeasts from more accessible no-sterile sites, like urine, is too common to be of diagnostic value. In this situation, of clinically suspected unproven disseminated candidiasis, only cutaneous and/or ocular lesions can rapidly confirm the diagnosis. Specific, reliable serological tests are still not generally available. Empiric antifungal treatment is usually initiated in these cases.

15. Ocular candidiasis:

Ocular candidiasis
Endophthalmitis due to Candida.

Candida endophthalmitis is often associated with candidemia, indwelling catheters or drug abuse, however it is rare in patients with severe neutropenia. Lesions are often localized near the macula and patients complain of cloudy vision. Exogenous Candida endophthalmitis is rare, but cases have been reported following ocular trauma or surgery. Similarly, conjunctival and corneal infections have also been recorded following trauma.

16. Osteoarticular candidiasis:

Arthritis may be a late sequel of candidemia in neonates or neutropenic patients. Prosthetic or rheumatoid joints are also prone to infection by Candida either by hematogenous spread or direct inoculation during surgery or intra-articular corticosteroid injection. The knee is the main site involved with pain on weight bearing or on full extension. The diagnosis depends on the isolation of yeasts from joint fluid obtained by needle aspiration or from synovial biopsies.

17. Other forms of candidiasis:

As candidiasis is an iatrogenic, nosocomial infection which is usually endogenous in origin many other clinical manifestations may occur, especially in the debilitated patient. For example, the reported cutaneous, ocular and arthritic manifestations reported in heroin addicts; fever, rash and myalgia associated with leukemia patients; Candida cholecystitis; Candida prostatitis; pancreatic abscesses; epiglottitis and osteomyelitis, to name a few.

Summary of clinical groups and/or predisposing factors for invasive candidiasis.

Neutropenia (especially >7 days).
Hematological malignancy.
Solid tumor malignancy.
Postsurgical intensive care patients.
Prolonged intravenous catheterization.
Broad-spectrum or multiple antibiotic therapy.
Diabetes mellitis.
Parental nutrition.
Severe burns.
Neonates.
Corticosteroid therapy.
Intravenous drug abuse.

Laboratory diagnosis:

1. Clinical Material: Skin and nail scrapings; urine, sputum and bronchial washings; cerebrospinal fluid, pleural fluid and blood; tissue biopsies from various visceral organs and indwelling catheter tips.

2. Direct Microscopy: (a) Skin and nails should be examined using 10% KOH and Parker ink or calcofluor white mounts; (b) Exudates and body fluids should be centrifuged and the sediment examined using either 10% KOH and Parker ink or calcofluor white mounts and/or gram stained smears; (c) Tissue sections should be stained using PAS digest, Grocott's methenamine silver (GMS) or Gram stain. Note Candida may be missed in H&E stained sections. Examine specimens for the presence of small, round to oval, thin-walled, clusters of budding yeast cells (blastoconidia) and branching pseudohyphae. Candida pseudohyphae may be difficult to distinguish from Aspergillus hyphae when blastoconidia are not observed as often happens in liver biopsies.

KOH mount from a skin scraping
10% KOH mount showing the presence of budding yeast cells and pseudohyphae in a skin scraping.

PAS stained smear
PAS stained smear showing the presence of budding yeast cells and pseudohyphae in a urine specimen.

Interpretation: As a rule, a positive direct microscopy from a sterile site, especially a tissue biopsy, should be considered significant, even if the laboratory is unable to culture the yeast. Further, the demonstration of pseudohyphae in scrapings or smears from cutaneous, oral, esophageal and vaginal lesions should be considered significant, provided the clinical manifestations support the diagnosis. However, the finding of just budding yeast cells in such material is of little diagnostic importance. Note, pseudohyphae will not be observed in smears when C. glabrata is involved and the diagnosis will require additional supporting evidence. Direct microscopy of sterile body fluids, such as CSF, vitreous humor, joint fluid and peritoneal fluid is relatively insensitive and positive culture will usually be required to make a diagnosis.

3. Culture: Colonies are typically white to cream colored with a smooth, glabrous to waxy surface.

Typical moist colonies of Candida
Typical moist colonies of Candida.

Interpretation: A positive culture from blood, or other sterile body fluid, or tissue biopsy should be considered significant. Lysis centrifugation is currently the most sensitive method for the isolation of Candida from blood. However, positive culture from non-sterile specimens such as sputum, bronchial lavage, esophageal brushings, urine, stool, and surgical drains are of little diagnostic value. Similarly, culture of skin or mucous membrane lesions without supporting evidence from direct microscopy is not diagnostic. Candida species are commonly isolated from the mouth, vagina, anus, and less often, moist skin surfaces of normal individuals who do not have candidiasis.

4. Serology: Various serological procedures have been devised to detect the presence of Candida antibodies, ranging from immunodiffusion to more sensitive tests such as counter immunoelectrophoresis (CIE), enzyme-linked immunosorbent assay (ELISA), and radioimmunoassay (RIA). However, these are often negative in the immunocompromised patient, especially at the beginning of an infection. The production of four or more precipitin lines in CIE tests has been reported to be diagnostic of candidiasis in the predisposed patient .

Tests for circulating antigen by immunological or non-immunological means have also been developed. Of the non-immunological techniques, use of gas liquid chromography (GLC) to detect mannose derivatives of the cell wall or a metabolic by-product, D-arabinitol, have proved the most useful. The detection of antigen by immunological methods such as ELISA or RIA have been used, however for the small laboratory latex agglutination tests for glycoprotien antigen have proved to be the most useful, although variable results have been reported.

It must be stressed that the interpretation of serological tests for Candida, especially in the neutropenic patient, is often difficult and must be correlated with other diagnostic methods. False-negatives and false-positive results do occur. Hopwood and Evans (1991) provide an excellent review of the current serological methods available.

5. Identification: The genus Candida is characterized by globose to elongate yeast-like cells or blastoconidia that reproduce by multilateral budding. Most Candida species are also characterized by the presence of well developed pseudohyphae, however this characteristic may be absent, especially in those species formally included in the genus Torulopsis. Arthroconidia, ballistoconidia and colony pigmentation are always absent. Within the genus Candida, fermentation, nitrate assimilation and inositol assimilation may be present or absent, however, all inositol positive strains produce pseudohyphae.

Causative agents:

Candida albicans, Candida dubliniensis, Candida famata, Candida glabrata, Candida guilliermondii, Candida haemulonii, Candida kefyr, Candida krusei, Candida lusitaniae, Candida norvegensis, Candida parapsilosis, Candida tropicalis, Candida viswanathii

Management:

Candidiasis in immunocompetent patients.

The first step in the management of candidiasis should be to correct the underlying conditions that allow Candida to colonise the skin or mucosa ie to restore the normal epithelial barrier function. For cutaneous candidiasis control of excessive moisture, heat and friction which cause local skin maceration and treatment with a topical imidazole compound is usually effective. Sometimes this is also given in combination with a topical steroid such as hydrocortisone. For oral candidiasis in infants, Nystatin suspension [100, 000 units/ml] dropped into the mouth at 4-6 hour intervals or after each feed is usually used. In older children and adults Clotrimazole troches [10 mg 5 times/day] or miconazole oral gel [5-10 ml of 250 mg miconazole at 6 hour intervals] are recommended. Nystatin may also be used, however it has a bitter taste and patient compliance is usually poor. For vaginal candidiasis, azole suppositories and creams are often used with good results, however many patients prefer to use a single dose treatment with fluconazole [150 mg] which has proven efficacious in up to 95% of cases. Women with recurrent vaginal candidiasis may also require intermittent prophylactic treatment to prevent symptomatic episodes.

Candidiasis in immunosuppressed patients.

As it is often not possible to correct the underlying predisposing conditions that would prevent candidiasis in these patients, infections are usually more severe and generally do not respond well to topical imidazole treatment. Oral Fluconazole [100-400 mg/day for 1-2 weeks] is currently the drug of choice for controlling oropharangeal candidiasis in AIDS patients. However, indefinite maintenance treatment with Fluconazole [150-300 mg/week] is required, and intermittent dosing depending on symptoms has now been advocated to prevent the emergence of Fluconazole resistant strains of C. albicans.

Neutropenic patients with invasive candidiasis require high dose Amphotericin B treatment [1.0 mg/kg/day] often given in combination with 5- Flucytosine [150 mg/kg/day]. With the use of 5-Flucytosine blood levels should be monitored and antifungal susceptibility tests performed. These patients present a major diagnostic problem for the clinician, primarily due to the inadequacies of current diagnostic methods. Thus empiric treatment with Amphotericin B is usually initiated in patients with persistent antibacterial resistant fever for greater than 72-96 hours duration. High dose Fluconazole [400-800 mg/day] and Liposomal Amphotericin B [3-5 mg/kg/day] have also been used with success, especially in cases of hepatosplenic candidiasis. More recently, the combined use of Fluconazole with 5-Flucytosine and Fluconazole with Amphotericin B have been used to treat some patients with systemic candidiasis. In addition, haematopoietic growth factors such as G-CSF, GM-CSF and M-CSF have been used to stimulate neutrophil and/or monocyte-macrophage production in order to boost the host immune system.

Candiduria

A practical problem in patients with candiduria is to distinguish between lower urinary tract colonisation and renal infection. The treatment for cystitis or bladder colonisation in patients without indwelling catheters would be similar to that for oral candidiasis in the AIDS patient in that the drug of choice would be oral Fluconazole [200-400 mg/day for 2-4 weeks]. However, in patients with indwelling urethral catheters continuous bladder irrigation with Amphotericin B [50 mg/L/day for 5-7 days] is often successful. For renal candidiasis systemic antifungal therapy with either Amphotericin B [0.3-1.0 mg/kg/day], with or without Flucytosine [150 mg/kg/day] or Fluconazole [200-400 mg/day] has been used, often in combination with local irrigation of the renal pelvis and surgical removal of obstructions.

Prophylactic treatment in AIDS patients or patients undergoing immunosuppressive therapies.

As already mentioned, AIDS patients with a history of oropharangeal candidiasis usually require intermittent prophylaxis with Fluconazole. For some, the use of prophylaxis in the neutropenic patient still remains a controversial issue, however with the increasing number of life threatening fungal infections, especially due to Candida, it is clearly warranted in patients undergoing bone marrow transplantation, patients with acute leukemia undergoing remission induction chemotherapy and patients receiving intensive cancer chemotherapy. Fluconazole [400 mg/day] has been successful with the prevention of candidiasis, and is recommended for primary prophylaxis against Candida. However, its role in preventing aspergillosis is limited. The incidence of aspergillosis varies between institutions and one of the first preventative measurers would be the installation of high efficiency particulate air [HEPA] filters to provide a protected environment. At present, Aspergillus prophylaxis usually consists of either low dose intravenous Amphotericin B [0.1/kg/day] or intranasal aerosol administration of Amphotericin B. Itraconazole is an alternative antifungal which appears to suppress bronchopulmonary colonisation, however its absorption is often erratic and requires monitoring. High dose immunoglobulin and haematopoietic growth factors have also been used in conjunction with an antifungal in prophylactic therapy.

Further reading:

Ajello L and R.J. Hay. 1997. Medical Mycology Vol 4 Topley & Wilson's Microbiology and Infectious Infections. 9th Edition, Arnold London.

Barnett et al. 1990. Yeasts characteristics and identification. Cambridge University Press, New York. Computerised identification key also available.

Chandler FW., W. Kaplan and L. Ajello. 1980. A colour atlas and textbook of the histopathology of mycotic diseases. Wolfe Medical Publications Ltd. London.

Elewski BE. 1992. Cutaneous fungal infections. Topics in dermatology. Igaku-Shoin, New York and Tokyo.

Ellis, D.H., D, Marriott and T. Sorrell. Candidial and Cryptococcal infections. An interactive CD-ROM, Pfizer Australia.

Kreger-van Rij. 1996. [4th edition due out any time] The yeasts a taxonomic study. Elsevier Science Publishes B.V. Amsterdam.

Kwon-Chung KJ and JE Bennett 1992. Medical Mycology Lea & Febiger.

Odds, F.C. 1988. Candida and candidosis. 2nd Ed. Bailliere Tindall, London.

Richardson MD and DW Warnock. 1993. Fungal Infection: Diagnosis and Management. Blackwell Scientific Publications, London.

Rippon JW. 1988. Medical Mycology WB Saunders Co.

Warnock DW and MD Richardson. 1991. Fungal infection in the compromised patient. 2nd edition. John Wiley & Sons