Table 18.1 Nomenclature of bone tumors
Candidiasis
BASIC INFORMATION
DEFINITION
Candidiasis is the most common fungal infection in humans and is predominantly caused by Candida albicans although other species of Candida are increasingly recognized. Candida are small asexual fungi. Most species that are pathogenic to humans are normal oropharyngeal and gastrointestinal commensals. Candidiasis is found world-wide.
Candidiasis is an inflammatory process involving the vulva and/or the vagina and is caused by superficial invasion of epithelial cells by Candida species.
SYNONYMS
Moniliasis
Thrush
Candidosis
EPIDEMIOLOGY & DEMOGRAPHICS
• This is the second most common form of vaginitis in the U.S. It is estimated that up to 78% of women will have at least one episode of vulvovaginal candidiasis (VVC) during their childbearing years and about 48% will have a second attack. A small subpopulation of probably <5% of adult women has recurrent, often intractable episodes. Candida may be isolated in up to 20% of asymptomatic women of childbearing age.
• Factors that predispose to development of symptomatic VVC include pregnancy, antibiotic use, and diabetes. Antibiotic use disturbs normal vaginal flora and allows overgrowth of fungi; pregnancy and diabetes are associated with decrease in cellmediated immunity.
• Factors associated with increased rates of asymptomatic vaginal colonization: pregnancy, high-estrogen oral contraceptives, uncontrolled diabetes mellitus, attendance at STD clinics.
Moniliasis
Thrush
Candidosis
EPIDEMIOLOGY & DEMOGRAPHICS
• This is the second most common form of vaginitis in the U.S. It is estimated that up to 78% of women will have at least one episode of vulvovaginal candidiasis (VVC) during their childbearing years and about 48% will have a second attack. A small subpopulation of probably <5% of adult women has recurrent, often intractable episodes. Candida may be isolated in up to 20% of asymptomatic women of childbearing age.
• Factors that predispose to development of symptomatic VVC include pregnancy, antibiotic use, and diabetes. Antibiotic use disturbs normal vaginal flora and allows overgrowth of fungi; pregnancy and diabetes are associated with decrease in cellmediated immunity.
• Factors associated with increased rates of asymptomatic vaginal colonization: pregnancy, high-estrogen oral contraceptives, uncontrolled diabetes mellitus, attendance at STD clinics.
UNCOMPLICATED VVC:
• Infrequent VVC
• Mild-to-moderate vaginitis and candidia
• Likely to be C. albicans
• Nonimmunocompromised women
COMPLICATED VVC:
• Recurrent VVC
• Severe VVC
• Non-albicans candidiasis
• Women with uncontrolled diabetes, immunosuppression, or those who are pregnant
RX OF COMPLICATED VVC:
• Recurrent VVS: 7 to 14 days of topical therapy
• 150 mg fluconazole PO, repeat in 3 days
• Maintenance regimen
1. Clotrimazole: 500-mg vaginal suppositories once weekly
2. Ketoconazole: 100 mg once daily
3. Fluconazole: 100 to 150 mg PO once weekly
4. Itraconazole 400 mg/mo or 100 mg/day
5. Continue one of the above regimens for 6 mo
COMPROMISED HOST:
• Treat with traditional anlinycotics for at least 7 to 14 days
• Pregnancy: topical azoles recommended for 7 days
• HIV-infected women: fluconazole 200 mg/wk
• Not usually an STD.
PHYSICAL FINDINGS & CLINICAL PRESENTATION
Symptoms of VVC consist of:
• Vulvar pruritus with vaginal discharge that typically resembles cottage cheese
• Erythema and edema of labia and vulvar skin; possible discrete pustulopapular peripheral lesions (satellite lesions)
• Vagina may be erythematous with an adherent, whitish discharge
• Cervix may appear normal.
• Symptoms characteristically exacerbated in the week preceding menses with some relief after onset of menstrual flow.
ETIOLOGY
• Candida are dimorphic fungi (spores and mycelial forms).
• C. albicans is responsible for 85% to 90% of vaginal yeast infections.
• C. glabrata, C. tropicalis (non-albicans species) also cause vaginitis and may be more resistant to conventional therapy.
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
• Bacterial vaginosis
• Trichomoniasis
WORKUP
• Discharge may vary from watery to homogeneously thick. May have complaints of vaginal soreness, dyspareunia, vulvar burning, and irritation. External dysuria may be present.
• Usually normal vaginal pH (<4.5).
• Budding yeast forms or mycelia will appear in as many as 80% of cases. Saline wet prep of vaginal secretions usually is normal; may be increased in inflammatory cells in severe cases.
• Whiff test negative (KOH).
• 10% KCl useful and more sensitive than wet mount for microscopic identification.
• Can make a presumptive diagnosis based on symptomatology in the absence of microscopy-proven fungal elements if the pH and wet prep are normal. Fungal culture is recommended to confirm diagnosis.
• In chronic/recurrent, burning replaces itching as prominent symptom. Confirm diagnosis with direct microscopy and culture. Many may actually have chronic or atrophic dermatitis. Test for HIV.
LABORATORY TESTS
If sending cultures, send on Nickerson’s media or semiquantitative slide-stix cultures. There is no reliable serologic technique for diagnosis.
Clinical Findings & Treatment
A. Mucosal Candidiasis
Esophageal involvement is the most frequent type of invasive mucosal disease. Individuals present with substernal odynophagia, gastroesophageal reflux, or nausea without substernal pain. Oral candidiasis, though often associated, is not invariably present. Diagnosis is best confirmed by endoscopy with biopsy and culture; the condition may be difficult to distinguish from esophagitis caused by infection with cytomegalovirus or herpes simplex virus when barium swallow alone is used for diagnosis. Therapy depends upon the severity of disease. If patients are able to swallow and take adequate amounts of fluid orally, fluconazole, 100 mg/d (or itraconazole solution, 10 mg/mL, 100 mg/d), for 10-14 days will usually suffice. In the individual who is more ill or has developed esophagitis while taking fluconazole, options include oral or intravenous voriconazole 200 mg/twice daily, intravenous amphotericin B, 0.3 mg/kg/d, or intravenous caspofungin, 50 mg/d. Relapse is common with all agents when there is underlying HIV infection without adequate immune reconstitution.
Vulvovaginal candidiasis occurs in an estimated 75% of women during their lifetime. Risk factors include pregnancy, uncontrolled diabetes mellitus, broad-spectrum antimicrobial treatment, corticosteroid use, and HIV infection. In women with HIV infection, vaginal candidiasis is usually the first and most common opportunistic infection. Symptoms include acute vulvar pruritus, burning vaginal discharge, and dyspareunia. Various topical azole preparations (eg, clotrimazole, 100 mg vaginal tablet for 7 days, or miconazole, 200 mg vaginal suppository for 3 days) are effective. One 150 mg oral dose of fluconazole has been shown to have equivalent efficacy with better patient acceptance.
B. Candidal Funguria
Candidal funguria frequently resolves with discontinuance of antibiotics or removal of bladder catheters. Clinical benefit from treatment of asymptomatic candiduria has not been demonstrated, but persistent funguria should raise the suspicion of disseminated infection. When symptomatic funguria persists, oral fluconazole, 200 mg/d for 7-14 days, can be used if renal function is normal. Bladder irrigation with amphotericin B (50-200 mg/mL) is rarely indicated, though it may transiently clear candiduria, especially if colonization is confined to the bladder. However, failure to clear the candiduria in this way suggests the presence of upper urinary tract infection. Rare complications of candidal urinary tract infections are ureteral obstruction and dissemination.
C. Disseminated Candidiasis
The diagnosis of disseminated Candida infection is problematic because Candida species are often isolated from mucosal sites in the absence of invasive disease while blood cultures are positive only 50% of the time in disseminated infection. Serologic tests have not proven useful for distinguishing colonization from invasive disease. Thus, the decision to treat for Candida when organisms are isolated from urine and/or sputum needs to be individualized for each patient. Disseminated candidiasis may represent a benign, self-limited process, but until proven otherwise it should be considered a sign of serious, disseminated disease. If fungemia resolves with removal of intravascular catheters, there are often no further complications, but the incidence of endophthalmitis may be higher than previously recognized.
Important clinical findings in invasive candidiasis are fluffy white retinal infiltrates that extend into the vitreous and raised, erythematous skin lesions that may be painful. Though characteristic, these are seen in less than 50% of cases. Other organ system involvement in invasive disease may include the brain, meninges, and myocardium. Detailed funduscopic examination should be performed on fungemic patients. Antifungal therapy for invasive candidiasis is rapidly evolving with the addition of new agents and the emergence of non-albicans species causing significant disease. Options for treatment include fluconazole, 400-800 mg daily, amphotericin B, 0.3-0.5 mg/kg/d, voriconazole, 200 mg twice a day, or caspofungin, 50 mg/d. Combination therapy with azoles and amphotericin B is an area being explored. Flucytosine, 150 mg/kg/d orally in four divided doses, is added if central nervous system involvement occurs. Therapy for disseminated candidiasis should be continued for 2 weeks after the last positive blood culture and resolution of symptoms and signs of infection. Once patients have become clinically stable, parenteral therapy can be discontinued and oral fluconazole, 200-800 mg orally given as one or two doses daily, used to complete treatment. Removal or exchange of intravascular catheters substantially decreases the duration of candidemia. Mortality of invasive candidiasis approaches 30%.
Another form of invasive disease is hepatosplenic candidiasis. This results from aggressive chemotherapy and prolonged neutropenia in patients with underlying hematologic cancers. Patients typically present with fever and variable abdominal pain weeks after chemotherapy, when neutrophil counts have recovered. Blood cultures are generally negative. Hepatic enzymes reveal an alkaline phosphatase elevation that may be marked. CT scanning of the abdomen shows hepatosplenomegaly, most often with multiple low-density defects in the liver. Diagnosis is established by liver biopsy, histopathology, and culture. Fluconazole, 400 mg daily, or a lipid formulation of amphotericin B is given until clinical and radiographic improvement occurs.
D. Candidal Endocarditis
Candidal endocarditis rarely is a complication of transient fungemia. It usually results from direct inoculation at the time of valvular heart surgery or repeated inoculation with intravenous drug use. Candidal endocarditis occurs with increased frequency on prosthetic valves in the first few months following surgery. Splenomegaly and petechiae are common, and there is a predilection for large-vessel embolization. Non-albicans species such as Candida parapsilosis and Candida tropicalis are more often important etiologic agents in endocarditis than in fungemia, which is most often due to C albicans. The diagnosis is established definitively by culturing Candida from emboli or from vegetations at the time of valve replacement. Valve destruction (usually aortic or mitral) is common, and surgical therapy is necessary in addition to a prolonged course of amphotericin therapy, given in a dosage of 0.5-1 mg/kg/d intravenously, usually to a total dose of 1-1.5 g intravenously.
It is important to note that non-albicans species of Candida now account for over 50% of clinical bloodstream isolates and are often resistant to imidazole antibiotics such as fluconazole. The widespread use of these agents for prophylaxis in immunocompromised patients can lead to the emergence of pathogens such as Candida krusei. Dissemination of this organism has been reported in patients undergoing bone marrow transplantation for leukemia. Imidazole-resistant C albicans has increased in frequency in immunocompromised patients, particularly in patients with late-stage AIDS receiving chronic suppressive fluconazole.
In all forms of invasive candidiasis, an important element of therapy is reversal of the underlying predisposing factor when possible. In high-risk patients undergoing induction chemotherapy or liver transplant recipients, prophylaxis with fluconazole has been shown to be beneficial.
DISPOSITION
Usually relatively limited in duration and occurrence. If chronic or recurrent, may consider screening for diabetes, HIV, or other immune deficiencies.
• Infrequent VVC
• Mild-to-moderate vaginitis and candidia
• Likely to be C. albicans
• Nonimmunocompromised women
COMPLICATED VVC:
• Recurrent VVC
• Severe VVC
• Non-albicans candidiasis
• Women with uncontrolled diabetes, immunosuppression, or those who are pregnant
RX OF COMPLICATED VVC:
• Recurrent VVS: 7 to 14 days of topical therapy
• 150 mg fluconazole PO, repeat in 3 days
• Maintenance regimen
1. Clotrimazole: 500-mg vaginal suppositories once weekly
2. Ketoconazole: 100 mg once daily
3. Fluconazole: 100 to 150 mg PO once weekly
4. Itraconazole 400 mg/mo or 100 mg/day
5. Continue one of the above regimens for 6 mo
COMPROMISED HOST:
• Treat with traditional anlinycotics for at least 7 to 14 days
• Pregnancy: topical azoles recommended for 7 days
• HIV-infected women: fluconazole 200 mg/wk
• Not usually an STD.
PHYSICAL FINDINGS & CLINICAL PRESENTATION
Symptoms of VVC consist of:
• Vulvar pruritus with vaginal discharge that typically resembles cottage cheese
• Erythema and edema of labia and vulvar skin; possible discrete pustulopapular peripheral lesions (satellite lesions)
• Vagina may be erythematous with an adherent, whitish discharge
• Cervix may appear normal.
• Symptoms characteristically exacerbated in the week preceding menses with some relief after onset of menstrual flow.
ETIOLOGY
• Candida are dimorphic fungi (spores and mycelial forms).
• C. albicans is responsible for 85% to 90% of vaginal yeast infections.
• C. glabrata, C. tropicalis (non-albicans species) also cause vaginitis and may be more resistant to conventional therapy.
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
• Bacterial vaginosis
• Trichomoniasis
WORKUP
• Discharge may vary from watery to homogeneously thick. May have complaints of vaginal soreness, dyspareunia, vulvar burning, and irritation. External dysuria may be present.
• Usually normal vaginal pH (<4.5).
• Budding yeast forms or mycelia will appear in as many as 80% of cases. Saline wet prep of vaginal secretions usually is normal; may be increased in inflammatory cells in severe cases.
• Whiff test negative (KOH).
• 10% KCl useful and more sensitive than wet mount for microscopic identification.
• Can make a presumptive diagnosis based on symptomatology in the absence of microscopy-proven fungal elements if the pH and wet prep are normal. Fungal culture is recommended to confirm diagnosis.
• In chronic/recurrent, burning replaces itching as prominent symptom. Confirm diagnosis with direct microscopy and culture. Many may actually have chronic or atrophic dermatitis. Test for HIV.
LABORATORY TESTS
If sending cultures, send on Nickerson’s media or semiquantitative slide-stix cultures. There is no reliable serologic technique for diagnosis.
Clinical Findings & Treatment
A. Mucosal Candidiasis
Esophageal involvement is the most frequent type of invasive mucosal disease. Individuals present with substernal odynophagia, gastroesophageal reflux, or nausea without substernal pain. Oral candidiasis, though often associated, is not invariably present. Diagnosis is best confirmed by endoscopy with biopsy and culture; the condition may be difficult to distinguish from esophagitis caused by infection with cytomegalovirus or herpes simplex virus when barium swallow alone is used for diagnosis. Therapy depends upon the severity of disease. If patients are able to swallow and take adequate amounts of fluid orally, fluconazole, 100 mg/d (or itraconazole solution, 10 mg/mL, 100 mg/d), for 10-14 days will usually suffice. In the individual who is more ill or has developed esophagitis while taking fluconazole, options include oral or intravenous voriconazole 200 mg/twice daily, intravenous amphotericin B, 0.3 mg/kg/d, or intravenous caspofungin, 50 mg/d. Relapse is common with all agents when there is underlying HIV infection without adequate immune reconstitution.
Vulvovaginal candidiasis occurs in an estimated 75% of women during their lifetime. Risk factors include pregnancy, uncontrolled diabetes mellitus, broad-spectrum antimicrobial treatment, corticosteroid use, and HIV infection. In women with HIV infection, vaginal candidiasis is usually the first and most common opportunistic infection. Symptoms include acute vulvar pruritus, burning vaginal discharge, and dyspareunia. Various topical azole preparations (eg, clotrimazole, 100 mg vaginal tablet for 7 days, or miconazole, 200 mg vaginal suppository for 3 days) are effective. One 150 mg oral dose of fluconazole has been shown to have equivalent efficacy with better patient acceptance.
B. Candidal Funguria
Candidal funguria frequently resolves with discontinuance of antibiotics or removal of bladder catheters. Clinical benefit from treatment of asymptomatic candiduria has not been demonstrated, but persistent funguria should raise the suspicion of disseminated infection. When symptomatic funguria persists, oral fluconazole, 200 mg/d for 7-14 days, can be used if renal function is normal. Bladder irrigation with amphotericin B (50-200 mg/mL) is rarely indicated, though it may transiently clear candiduria, especially if colonization is confined to the bladder. However, failure to clear the candiduria in this way suggests the presence of upper urinary tract infection. Rare complications of candidal urinary tract infections are ureteral obstruction and dissemination.
C. Disseminated Candidiasis
The diagnosis of disseminated Candida infection is problematic because Candida species are often isolated from mucosal sites in the absence of invasive disease while blood cultures are positive only 50% of the time in disseminated infection. Serologic tests have not proven useful for distinguishing colonization from invasive disease. Thus, the decision to treat for Candida when organisms are isolated from urine and/or sputum needs to be individualized for each patient. Disseminated candidiasis may represent a benign, self-limited process, but until proven otherwise it should be considered a sign of serious, disseminated disease. If fungemia resolves with removal of intravascular catheters, there are often no further complications, but the incidence of endophthalmitis may be higher than previously recognized.
Important clinical findings in invasive candidiasis are fluffy white retinal infiltrates that extend into the vitreous and raised, erythematous skin lesions that may be painful. Though characteristic, these are seen in less than 50% of cases. Other organ system involvement in invasive disease may include the brain, meninges, and myocardium. Detailed funduscopic examination should be performed on fungemic patients. Antifungal therapy for invasive candidiasis is rapidly evolving with the addition of new agents and the emergence of non-albicans species causing significant disease. Options for treatment include fluconazole, 400-800 mg daily, amphotericin B, 0.3-0.5 mg/kg/d, voriconazole, 200 mg twice a day, or caspofungin, 50 mg/d. Combination therapy with azoles and amphotericin B is an area being explored. Flucytosine, 150 mg/kg/d orally in four divided doses, is added if central nervous system involvement occurs. Therapy for disseminated candidiasis should be continued for 2 weeks after the last positive blood culture and resolution of symptoms and signs of infection. Once patients have become clinically stable, parenteral therapy can be discontinued and oral fluconazole, 200-800 mg orally given as one or two doses daily, used to complete treatment. Removal or exchange of intravascular catheters substantially decreases the duration of candidemia. Mortality of invasive candidiasis approaches 30%.
Another form of invasive disease is hepatosplenic candidiasis. This results from aggressive chemotherapy and prolonged neutropenia in patients with underlying hematologic cancers. Patients typically present with fever and variable abdominal pain weeks after chemotherapy, when neutrophil counts have recovered. Blood cultures are generally negative. Hepatic enzymes reveal an alkaline phosphatase elevation that may be marked. CT scanning of the abdomen shows hepatosplenomegaly, most often with multiple low-density defects in the liver. Diagnosis is established by liver biopsy, histopathology, and culture. Fluconazole, 400 mg daily, or a lipid formulation of amphotericin B is given until clinical and radiographic improvement occurs.
D. Candidal Endocarditis
Candidal endocarditis rarely is a complication of transient fungemia. It usually results from direct inoculation at the time of valvular heart surgery or repeated inoculation with intravenous drug use. Candidal endocarditis occurs with increased frequency on prosthetic valves in the first few months following surgery. Splenomegaly and petechiae are common, and there is a predilection for large-vessel embolization. Non-albicans species such as Candida parapsilosis and Candida tropicalis are more often important etiologic agents in endocarditis than in fungemia, which is most often due to C albicans. The diagnosis is established definitively by culturing Candida from emboli or from vegetations at the time of valve replacement. Valve destruction (usually aortic or mitral) is common, and surgical therapy is necessary in addition to a prolonged course of amphotericin therapy, given in a dosage of 0.5-1 mg/kg/d intravenously, usually to a total dose of 1-1.5 g intravenously.
It is important to note that non-albicans species of Candida now account for over 50% of clinical bloodstream isolates and are often resistant to imidazole antibiotics such as fluconazole. The widespread use of these agents for prophylaxis in immunocompromised patients can lead to the emergence of pathogens such as Candida krusei. Dissemination of this organism has been reported in patients undergoing bone marrow transplantation for leukemia. Imidazole-resistant C albicans has increased in frequency in immunocompromised patients, particularly in patients with late-stage AIDS receiving chronic suppressive fluconazole.
In all forms of invasive candidiasis, an important element of therapy is reversal of the underlying predisposing factor when possible. In high-risk patients undergoing induction chemotherapy or liver transplant recipients, prophylaxis with fluconazole has been shown to be beneficial.
DISPOSITION
Usually relatively limited in duration and occurrence. If chronic or recurrent, may consider screening for diabetes, HIV, or other immune deficiencies.
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