Harrison's Practice: Candidiasis

Harrison's Practice

Candidiasis

Definition

Fungal infections caused by Candida species
Clinical presentations include:
- Mucocutaneous infections
  - Oral thrush
  - Vulvovaginal thrush
  - Cutaneous candidiasis
  - Esophageal candidiasis
- Invasive infections
  - Candidemia
  - Endophthalmitis
  - Peritonitis
  - Pyelonephritis
  - Hepatic, renal, and splenic abscesses
  - Endocarditis
  - Septic arthritis
  - Meningitis
  - Pneumonia

Epidemiology

Candidemia
- ~50% of cases are due to Candida albicans.
- Fourth most common cause of nosocomial bloodstream infections
- 4–8 cases per 100,000 persons in the general population
- 0.5 cases per 1000 patient-days in tertiary care hospitals
- 1 case per 1000 patient-days in surgical intensive care units
Esophageal candidiasis
- Indicator condition for AIDS in 16% of patients with HIV infection

Risk Factors

General
- Conditions causing a compromised host defense
  - Neutropenia
  - Glucocorticoid therapy
  - Malnutrition
Oropharyngeal thrush
- Diabetes mellitus
- HIV infection
  - Common in acute HIV infection
  - Increasingly common late in disease as the CD4+ cell count falls
- Dentures
- Inhaled or oral glucocorticoids
- Neonatal period
- Iron deficiency
Vulvovaginal candidiasis
- Third trimester of pregnancy
- Antibiotic use
Cutaneous candidiasis
- Macerated skin
  - Diapered area of infants
  - Under pendulous breasts or pannus
  - Hands constantly in water
  - Hands covered by occlusive gloves
Esophageal candidiasis
- HIV infection
  - Uncommon until CD4+ counts fall below 50/μL
Invasive candidiasis
- Use of broad-spectrum antibiotic therapy
- Indwelling central venous catheter
- Total parenteral nutrition
- Perforation of the GI tract through trauma, surgery, or peptic ulceration
- Mucosal damage due to cytotoxic agents used for cancer chemotherapy
- Contamination of the hub or skin site of a catheter in an umbilical or central vein with secretions from the mouth, rectum, or vagina or with drainage from surgical wounds or tracheostomy sites
- Intravenous drug abuse
- Third-degree burns
- Very low birth weight (in neonates)
- Neutropenia
- Glucocorticoid therapy

Etiology

Candida species
- Mucosal candidiasis
  - C. albicans most common cause
- Candidemia
  - C. albicans is responsible for about half of all cases in hospitalized patients.
  - Other half are accounted for by:
    - C. dubliniensis (previously identified as C. albicans)
    - C. tropicalis
    - C. parapsilosis
    - C. guilliermondii
    - C. glabrata (formerly Torulopsis glabrata)
    - C. krusei
    - A few other Candida species
Transmission and pathogenesis
- All Candida species pathogenic for humans are also encountered as commensals of humans, particularly in the:
  - Mouth
  - GI tract
  - Vagina
- Invasive candidiasis is often preceded by increased colonization of the mouth, GI tract, and vagina with Candida as a result of broad-spectrum antibiotic therapy.
- Colonizing organisms pass into deep tissues when mucosal or skin integrity is violated.
- Candidemia
  - The majority of non-albicans species enter the bloodstream through intravascular catheters.

Associated Conditions

Oral candidiasis
- HIV infection
- Diabetes mellitus
- Glucocorticoid therapy
Esophageal candidiasis
- HIV infection
Invasive candidiasis
- Neutropenia
Chronic mucocutaneous candidiasis (CMC) (candidal granuloma)
- Major component of the immune polyendocrinopathy syndrome
- Can begin in childhood
  - As an autosomal dominant disorder
  - As an autosomal recessive disorder
  - In association with Job’s syndrome
- Can occur in adults
  - In association with thymoma
- Systemic infection is very rare.
Candida endophthalmitis and purulent folliculitis, sometimes accompanied by vertebral osteomyelitis
- Clinical syndrome caused by injection of impure brown heroin

Symptoms & Signs

Oral thrush
- Discrete and confluent adherent white plaques on the oral and pharyngeal mucosa, particularly in the mouth and on the tongue
- Lesions are usually painless.
- Fissures at the corners of the mouth can be painful.
- Patients may present with a sore red tongue and/or posterior pharynx.
Vulvovaginal thrush
- Pruritus
- Vaginal discharge
- Pain on intercourse
- Pain on urination
- Speculum examination
  - Inflamed mucosa
  - Thin exudate with white curds
Cutaneous candidiasis
- Red macerated intertriginous areas
- Chronic paronychia
- Balanitis
- Pruritus ani
- Candidiasis of the perineal and scrotal skin may be accompanied by discrete pustular lesions on the inner aspects of the thighs.
CMC (candidal granuloma)
- Circumscribed hyperkeratotic skin lesions
- Crumbling dystrophic nails
- Partial alopecia in areas of scalp lesions
- Oral and vaginal thrush
- Other findings
  - Chronic ringworm
  - Dental dysplasia
  - Hypofunction of parathyroid, adrenal, and thyroid glands
Esophageal candidiasis
- Often asymptomatic
- Substernal pain
- Sense of obstruction on swallowing
Urinary tract candidiasis
- Cystitis is often asymptomatic.
- Sepsis syndrome in the setting of urinary tract obstruction and hematogenous dissemination from a colonized urinary tract
Candidemia
- Fever
- Focal seeding of the retina (endophthalmitis)
  - Blurred vision
  - Ocular pain
  - Scotoma
  - Small white retinal exudates
    - Unilateral or bilateral
  - Cloudy vitreous humor
- Chronic disseminated candidiasis (hepatosplenic candidiasis)
  - Fever
  - Microabscesses of liver, spleen, and kidney
- Acute candidemia in neutropenic patients
  - Small erythematous papules anywhere on the skin
    - Develop a necrotic center
  - Painful muscle lesions

Differential Diagnosis

Oral thrush
- Leukoplakia
- Hairy leukoplakia
- Lichen planus
- Secondary syphilis
- Condylomata lata
Vulvovaginal thrush
- Trichomonal vaginitis
- Bacterial vaginosis
- Genital herpes
- Staphylococcal toxic shock syndrome
  - Ulcerative vaginitis
- Desquamative inflammatory vaginitis
- Retained foreign bodies (e.g., tampons)
- Cervical caps
- Vaginal spermicides
- Vaginal antiseptic preparations or douches
- Vaginal epithelial atrophy
  - After menopause
  - During prolonged breast-feeding
- Allergic reactions to latex condoms
- Vaginal aphthae associated with:
  - HIV infection
  - Behçet’s syndrome
- Vestibulitis
Cutaneous candidiasis
- Contact dermatitis
- Radiation dermatitis
- Inverse psoriasis
- Seborrheic dermatitis
- Intertrigo
Esophageal candidiasis
- Herpes simplex esophagitis
- Cytomegalovirus esophagitis
- Reflux esophagitis
- Barrett’s esophagus
- Acute caustic ingestion
Urinary tract candidiasis
- Urinary tract candidal colonization
- Bacterial urinary tract infection
Candidemia
- Bacteremia
- Viremia
- Other fungemia

Diagnostic Approach

Superficial candidiasis
- Demonstration of pseudohyphae on wet smear with confirmation by culture is the procedure of choice.
- Scrapings for the smear may be obtained from skin, nails, and oral and vaginal mucosa.
Invasive infections
- Diagnostic cultures
  - Histologic section of biopsies or
  - Culture of cerebrospinal fluid (CSF), blood, joint fluid, CT-guided needle aspirates, or surgical specimens
  - Blood cultures
    - Useful in diagnosis of Candida endocarditis and IV catheter–associated sepsis
    - Positive less often in other forms of disseminated disease
- Nondiagnostic cultures
  - Urine
  - Sputum
  - Existing abdominal drains
  - Endotracheal aspirates
  - Vagina
  - Recovery of Candida species from multiple superficial sites has been identified as a risk factor for deeply invasive candidiasis in some studies of patients with prolonged neutropenia or complicated abdominal surgery.
- A serum assay for β-D-glucan, a cell-wall component of Candida species and several other fungal species, is being evaluated both as a diagnostic assay and as a tool for monitoring response to therapy.

Laboratory Tests

Wet smear
- Demonstration of pseudohyphae
- Requires culture confirmation
Culture
- Candida grows well on simple media.
- Exclude colonization (as opposed to true infection).
- Positive cultures of samples from multiple sites are associated with invasive candidiasis in at-risk patients.
- Sites for culture diagnosis
  - Blood
  - CSF
  - Joint fluid
  - CT-guided needle aspirates
  - Surgical specimens
Serum antigen test
- β-D-glucan
Histologic section of biopsy samples

Imaging

Echocardiography
- Endocarditis
  - Valve vegetation
Ultrasound; MRI; or CT of liver, spleen, or kidney
- Chronic disseminated candidiasis (hepatosplenic candidiasis)
  - Multiple small abscesses
  - MRI is most sensitive.
Chest x-ray or chest CT scan
- Hematogenous seeding of lung parenchyma
  - Occasionally visible radiologically as tiny pulmonary nodules

Diagnostic Procedures

Blood culture
- Intravenous catheter–related fungemia
- Endocarditis
Urine culture
- A positive result:
  - Most often reflects colonization
  - Is significant if there is associated urinary tract obstruction or pyelonephritis
Endoscopy
- Esophageal candidiasis
  - Most lesions are in the distal third of the esophagus.
  - Lesions appear on endoscopy as areas of redness and edema, focal white patches, or ulcers.
  - Biopsy or brushing is required for diagnosis and for detection of concomitant infections, e.g.:
    - Herpes simplex in patients with hematologic malignancies
    - Cytomegalovirus infection in patients with AIDS
β-D-glucan detection in serum
- Invasive infection
Biopsy for culture and histopathology
- Invasive infection

Treatment Approach

Antifungal agents are the mainstay of treatment.
Removal of foreign bodies is critical.
- Plastic catheters for intravenous fluids
- Peritoneal dialysis shunts
- CSF shunts
- Prosthetic cardiac valves
- Prosthetic joints
All collections of pus need to be drained surgically or by percutaneous, CT-guided catheterization.
- Exceptions: numerous small abscesses in liver, spleen, or kidney in chronic disseminated candidiasis
  - Cannot be drained effectively
  - Require prolonged antifungal therapy
The Candida species involved should be considered in choosing a drug for treatment of candidemia.
- C. glabrata
  - Intermediate susceptibility to fluconazole
    - Increase the daily fluconazole dose to 800 mg or
    - Use amphotericin B or caspofungin
  - Susceptible to caspofungin and amphotericin B
- C. krusei and C. inconspicua
  - Resistant to fluconazole in vitro
  - Susceptible to caspofungin and amphotericin B
- C. lusitaniae strains may be resistant to amphotericin B but are susceptible to azoles or caspofungin.

Specific Treatments

Oropharyngeal candidiasis

Preferred
- Clotrimazole troche (5 times a day for 7–10 days) or
- Fluconazole tablet (100 mg/d for 7–10 days) or
- Itraconazole solution (200 mg/d for 7–10 days)
Alternative
- Nystatin suspension (15 mL, swish and spit, qid for 7–10 days)
- For azole-unresponsive disease
  - Caspofungin IV (50 mg/d until resolved) or
  - Amphotericin B IV (0.3–0.5 mg/kg qd until resolved)

Vulvovaginal candidiasis

Preferred
- Azole cream or suppository (miconazole, clotrimazole, tioconazole, butoconazole, or terconazole vaginal formulations) for 3–7 days
- Single dose of oral fluconazole (150 mg)
  - Contraindicated in pregnancy
  - Less effective in patients with multiple relapses
  - Higher risk of adverse effects
Alternative
- Nystatin suppository

Cutaneous candidiasis

Macerated areas respond to measures that reduce moisture and chafing plus topical application of an antifungal agent in a nonocclusive base.
Preferred
- Topical azole (clotrimazole, miconazole, econazole, ketoconazole, sulconazole, or oxiconazole—available as creams or lotions) for 7–10 days
Alternative
- Topical nystatin

Esophageal candidiasis

Preferred
- Fluconazole tablet (100–200 mg/d for 10 days) or
- Itraconazole solution (200 mg/d for 10 days)
Alternative
- For azole-unresponsive disease
  - 2-week course of:
    - Caspofungin (70 mg once, then 50 mg/d) or
    - Amphotericin B (0.3–0.5 mg/kg qd)

Bladder candidiasis

Most patients with candiduria do not have unrelieved urinary tract obstruction and do not benefit from therapy.
Fluconazole (100 mg PO qd for 5 days)
Single 15-mg dose of IV amphotericin B
Bladder irrigations with amphotericin B (50 μg/mL for 5 days)

Deeply invasive candidiasis (nonneutropenic)

Fluconazole (400 mg/d) or
Caspofungin (70 mg once, then 50 mg/d) or
Amphotericin B (0.5 mg/kg daily)
- Initial doses of 0.7–1.0 mg/kg daily may be appropriate for severely immunosuppressed patients.
- Amphotericin B lipid complex and liposomal amphotericin B are given as 5 mg/kg daily.
Duration: Continue for 2 weeks after the last positive blood culture is obtained and after the patient becomes afebrile.

Deeply invasive candidiasis (neutropenic)

Fluconazole (6 mg/kg daily)
Amphotericin B (0.5 mg/kg daily)
- Initial doses of 0.7–1.0 mg/kg daily may be appropriate for severely immunosuppressed patients.
- Amphotericin B lipid complex and liposomal amphotericin B are given as 5 mg/kg daily.
Duration
- Until recovery from neutropenia
- Resolution of:
  - Symptoms
  - Markers of disease (alkaline phosphatase in hepatosplenic candidiasis)
  - Radiographic abnormalities
- Continue through cycles of chemotherapy.

Candida endocarditis

Valve replacement
- Infections of prosthetic or native valves usually relapse unless the valve is replaced.
- Long-term fluconazole administration is used to prevent recurrence after valve replacement.

Candida endophthalmitis

Preferred
- IV amphotericin B, with or without flucytosine
Alternative
- Fluconazole: cures reported
Pars plana vitrectomy may facilitate diagnosis and cure when a Candida vitreous abscess is present.
Injection of amphotericin B into the vitreous humor can also be helpful.

Candida osteomyelitis

Debridement
Initial therapy with either amphotericin B or fluconazole
- Amphotericin B (0.5 mg/kg daily)
- Fluconazole (6 mg/kg daily)
Maintenance therapy with fluconazole if isolate is susceptible
Treatment duration: 6–12 weeks

Monitoring

General
- Monitor for relapse.
- Monitor for complications of disease.
- Monitor for complications of treatment.
Esophageal candidiasis
- If patient does not respond to fluconazole, conduct:
  - Susceptibility testing to exclude drug resistance
  - Repeat endoscopy to exclude other conditions
Retinal involvement
- Monitor with funduscopy to ensure complete resolution.
Invasive candidiasis
- Serial measurement of ß-1,4-glucan to demonstrate falling levels may be helpful in monitoring the effectiveness of therapy.

Complications

CMC
- Permanent alopecia
- Severe disfigurement of the face and hands
Urinary tract candidemia
- Cystitis
- Pyelitis
- Renal papillary necrosis
Candidemia with hematogenous dissemination
- Retinal seeding with the following complications is documented in 10% of nonneutropenic patients:
  - Retinal detachment
  - Vitreous abscess
  - Extension to the anterior chamber
- Chronic disseminated candidiasis (hepatosplenic candidiasis)
  - Usually occurs in patients with acute leukemia who are recovering from profound neutropenia
  - Originates from intestinal seeding of the portal and venous circulation
  - Clinical findings: fever; modestly elevated serum concentrations of alkaline phosphatase; and multiple small abscesses evident on ultrasonography, MRI, or CT of the liver, spleen, or kidney
- Seeding to the central nervous system with resultant brain abscess or chronic meningitis
  - Diagnosis of infections of ventriculoperitoneal shunts is difficult; symptoms are indolent, and cultures of lumbar fluid are usually sterile.
- Candida pneumonia
  - Rare, apart from hematogenous candidiasis
- Candida endocarditis
  - Favors previously damaged or prosthetic heart valves
  - The source is often an intravascular catheter or contaminated equipment used for illicit intravenous drug injection.
  - An interval of weeks or even months is common between documentation of candidemia and discovery of endocarditis.
  - Emboli to large arteries, such as the iliac or femoral artery, are characteristic.
Indolent arthritis
- Most commonly of the knee
Subacute peritonitis
- Perforated viscus
- Peritoneal dialysis catheter

Prognosis

Prognosis depends on the site of infection and the underlying illness.
Superficial infections
- Most associated with a benign course and full recovery
Cutaneous candidiasis
- Usually treatable
- Occasionally difficult to eradicate
- Recurrences are common.
Disseminated candidiasis
- Mortality: ~44%
- Higher risk of mortality with:
  - Hematologic malignancy
  - Intubation

Prevention

Allogeneic bone marrow transplant recipients
- Fluconazole (400 mg/d) can decrease the incidence of deeply invasive candidiasis.
  - Duration
    - Some centers continue prophylaxis for 70 days.
    - Some discontinue prophylaxis after engraftment.
Leukemic and other neutropenic patients
- Prophylactic use of fluconazole or itraconazole oral suspension remains controversial.
HIV-infected patients
- Prophylaxis against recurrent oropharyngeal or esophageal candidiasis is no longer recommended unless recurrences are very frequent or severe.
- Fluconazole (3–6 mg/kg PO qd) or
- Itraconazole solution (5 mg/kg PO qd)
High-risk postoperative patients
- Patients undergoing repeat, complicated abdominal surgery and patients who are both heavily colonized with Candida and immunosuppressed at the time of complicated surgery
- Presence of intravenous catheters, prolonged stays in the intensive care unit, and renal failure increase the risk of candidemia.
- Fluconazole (400 mg/d)
  - May be useful in preventing deeply invasive candidiasis

ICD-9-CM

112.__ Candidiasis, (specific site of infection specified by fourth and fifth digits)
112.9 Candidiasis of unspecified site