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Candidiasis

ETIOLOGIC AGENTS

Candida albicans is the most common cause of mucosal candidiasis and is responsible for about half of all cases of candidemia in hospitalized patients. A small proportion of isolates previously identified as C. albicans have been transferred to a new species, C. dubliniensis. C. tropicalis, C. parapsilosis, C. guilliermondii, C. glabrata (formerly Torulopsis glabrata), C. krusei, and a few other Candida species account for the other half of candidemia cases; all can cause potentially lethal septic shock. The majority of these non-albicans species enter the bloodstream through intravascular catheters. Candida species, taken together, are the fourth or fifth most common cause of nosocomial bloodstream infections in the United States.All Candida species pathogenic for humans are also encountered as commensals of humans, particularly in the mouth, stool, and vagina. These species grow rapidly at 25° to 37°C on simple media as oval, budding cells. In tissue, both yeasts and pseudohyphae are present. The latter are elongated branching structures with constrictions at the septae. Budding yeasts may be seen as separate structures or as projections from pseudohyphae.

C. glabrata differs from other members of the genus in that it forms no true hyphae or pseudohyphae in vitro or in infected tissue. C. albicans and C. dubliniensis can be identified preliminarily by their ability to form germ tubes in serum—a test that requires only a few hours. These two species can be more accurately identified by the formation in special culture medium of thick-walled large spores called chlamydospores. Culture media now available for primary inoculation allow preliminary identification of Candida species by colony color. Accurate identification of Candida species other than C. albicans requires biochemical tests.

PATHOGENESIS

Deeply invasive candidiasis is often preceded by increased colonization of the mouth, vagina, and stool with Candida due to broad-spectrum antibiotic therapy. Additional local and systemic factors favor infection. Oropharyngeal thrush is particularly likely to occur in neonates and in patients with diabetes mellitus, HIV infection, or dentures. Vulvovaginal candidiasis is especially common in the third trimester of pregnancy. Candida from the perineum can enter the urinary tract via an indwelling bladder catheter. Cutaneous candidiasis most often involves macerated skin, such as that in the diapered area of infants, under pendulous breasts, or on hands constantly in water or covered by occlusive gloves. Candida can pass from the colonized surface into deep tissue when the integrity of the mucosa or skin is violated, as, for example, by perforation of the gastrointestinal tract through trauma, surgery, or peptic ulceration or by mucosal damage due to cytotoxic agents used for cancer chemotherapy. Although Candida is not normally a resident of the skin, secretions from the mouth, rectum, or vagina as well as drainage from surgical wounds or tracheostomy sites can contaminate the hub or skin site of a catheter in an umbilical or central vein. Intravenous drug abuse or third-degree burns can also provide a skin portal for Candida that can lead to deep candidiasis. Once Candida has passed the integumentary barrier, very low birth weight (in neonates) and neutropenia or glucocorticoid therapy (in any patient) markedly compromise host defense. Hematogenous seeding is particularly evident in the retina, kidney, spleen, and liver.

CLINICAL MANIFESTATIONS

Mucocutaneous CandidiasisOral thrush presents as discrete and confluent adherent white plaques on the oral and pharyngeal mucosa, particularly in the mouth and on the tongue. These lesions are usually painless, but fissuring at the corners of the mouth can be painful. Unexplained oropharyngeal thrush raises the possibility of HIV infection. Oral thrush is common in acute HIV infection and becomes increasingly common late in disease as the CD4+ cell count falls. At CD4+ counts of <50/µL, esophageal thrush also becomes common. HIV infection appears not to be an independent risk factor for vulvovaginal thrush.Cutaneous candidiasis presents as red macerated intertriginous areas, paronychia, balanitis, or pruritus ani. Candidiasis of the perineal and scrotal skin may be accompanied by discrete pustular lesions on the inner aspects of the thighs. Chronic mucocutaneous candidiasis (CMC) or candidal granuloma typically presents as circumscribed hyperkeratotic skin lesions, crumbling dystrophic nails, partial alopecia in areas of scalp lesions, and both oral and vaginal thrush. Other findings may include chronic ringworm, dental dysplasia, and hypofunction of the parathyroid, adrenal, or thyroid gland. CMC is a major component of the immune polyendocrinopathy syndrome caused by a mutation in the autoimmune regulator gene (AIRE) on chromosome 21q22,3. CMC can begin in childhood as an autosomal dominant or recessive disorder or in association with Job's syndrome and can occur in adults in association with thymoma. Systemic infection is very rare in CMC, but permanent alopecia and disfigurement of the face and hands can be severe. Vulvovaginal thrush causes pruritus, discharge, and sometimes pain on intercourse or urination. Speculum examination reveals an inflamed mucosa and a thin exudate, often with white curds. Excessive colonization of the gastrointestinal tract has been associated with diarrhea and with chronic fatigue syndrome, but the linkage is unconvincing.Esophageal candidiasis is often asymptomatic but can cause substernal pain or a sense of obstruction on swallowing. The pain of esophageal candidiasis may be mistaken for pain of cardiac origin. Most lesions are in the distal third of the esophagus and 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, particularly herpes simplex in patients with hematologic malignancies and cytomegalovirus infection in AIDS patients. Candida esophagitis can cause bleeding and impaired alimentation. Hematogenous dissemination from the esophagus probably occurs in some neutropenic patients but is rarely reported in HIV-infected patients.Deeply Invasive CandidiasisIn the obstructed urinary tract, Candida can cause cystitis, pyelitis, or renal papillary necrosis. When a colonized urinary tract is operated on or instrumented, candidemia may result. However, most patients with Candida cultured from the urine simply have bladder colonization from a Foley catheter or a sizable volume of residual urine. Contamination of a voided midstream specimen by vaginal Candida is also common.Candidemia originating from an intravascular catheter may clear in the immunocompetent patient when the catheter is removed. Focal seeding of the retina can take place even if candidemia clears and the patient becomes afebrile. Unilateral or bilateral small white retinal exudates appear within 2 weeks of the onset of candidemia. Lesions may regress spontaneously or enlarge slowly. The vitreous humor becomes cloudy, and the patient notices blurring, ocular pain, or a scotoma. Retinal detachment, vitreous abscess, and extension to the anterior chamber can occur over the ensuing weeks. These retinal lesions, present in ~10% of nonneutropenic patients with candidemia, are the principal reason that systemic antifungal therapy is recommended for all patients with candidemia. Funduscopy should be performed to ensure that retinal lesions, if present, resolve completely. Most cases with ocular involvement have occurred in nonneutropenic patients. In contrast, so-called hepatosplenic candidiasis is usually recognized in patients with acute leukemia who are recovering from profound neutropenia. This entity, better called chronic disseminated candidiasis, originates from intestinal seeding of the portal and venous circulation. Fever, modestly elevated serum concentrations of alkaline phosphatase, and multiple small abscesses evident on ultrasonography, magnetic resonance imaging, or computed tomography (CT) of the liver, spleen, or kidney suggest the diagnosis. During acute candidemia in neutropenic patients, small erythematous papules may appear anywhere on the skin. If the patient does not expire promptly from disseminated candidiasis, the lesions will develop a necrotic center. Painful muscle lesions may also be found. Punch biopsy of a skin lesion helps distinguish this extremely grave condition from Malassezia folliculitis, a similar-appearing but benign condition that can involve the cape area of the chest or the extremities of a sweaty febrile patient.Hematogenous seeding in the neutropenic patient is occasionally visible radiologically as tiny pulmonary nodules. Candida pneumonia, apart from hematogenous candidiasis, is very rare. Candida endocarditis can be caused by any Candida species and 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 between candidemia and discovery of endocarditis is common. Emboli to large arteries, such as the iliac or femoral artery, are characteristic. Intravenous injection of impure brown heroin has caused a clinical syndrome consisting of Candida endophthalmitis and purulent folliculitis, sometimes accompanied by vertebral osteomyelitis.Candida can cause indolent arthritis, most commonly of the knee, in patients who have received glucocorticoid injections into the joint, in patients who are immunosuppressed, and in low-birth-weight neonates. Prosthetic joints may become infected during implantation. Scanty growth of Candida from joint fluid can cause the laboratory toincorrectly dismiss the organism as a contaminant. Candida can cause subacute peritonitis arising either from a perforated viscus or from a peritoneal dialysis catheter.Hematogenous dissemination can lead to brain abscess or chronic meningitis. Diagnosis of infections of ventriculoperitoneal shunts is difficult because symptoms are indolent and cultures of lumbar fluid are usually sterile.DIAGNOSISDemonstration of pseudohyphae on wet smear with confirmation by culture is the procedure of choice for diagnosing superficial candidiasis. Scrapings for the smear may be obtained from skin, nails, and oral and vaginal mucosa. A culture of urine, sputum, existing abdominal drains, endotracheal aspirates, or the vagina is not diagnostic; however, 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.Deeper lesions due to Candida may be diagnosed by histologic section of biopsies or by culture of cerebrospinal fluid, blood, joint fluid, CT-guided needle aspirates, or surgical specimens. Blood cultures are useful in the diagnosis of Candida endocarditis and intravenous catheter–induced sepsis but are positive less often in other forms of disseminated disease. Serologic tests for antibody or antigen are not useful.

TREATMENT(See also Table 1.)

Cutaneous candidiasis of macerated areas responds to measures that reduce moisture and chafing plus topical application of an antifungal agent in a nonocclusive base. Nystatin powder or a cream containing ciclopirox or an azole is useful. Clotrimazole, miconazole, econazole, ketoconazole, sulconazole, and oxiconazole are available as creams or lotions. Candida vulvovaginitis responds better to an azole than to nystatin suppositories. There is little difference in efficacy among miconazole, clotrimazole, tioconazole, butoconazole, and terconazole vaginal formulations. Systemic treatment of Candida vulvovaginitis with a single 150-mg capsule of fluconazole is more convenient than topical treatment; however, this option is contraindicated in pregnancy, is less effective in patients with multiple relapses, and poses a higher risk of adverse effects. Clotrimazole troches, used five times a day, are more effective in oral candidiasis than nystatin suspension and are approximately as effective as oral fluconazole (100 mg daily). Oral fluconazole (100 to 200 mg once daily) is more convenient and more effective in esophagitis than clotrimazole troches. Esophagitis not responding to fluconazole may warrant repeat endoscopy to exclude other conditions. Itraconazole suspension (100 mg twice daily) alleviates Candida esophagitis in some patients in whom fluconazole treatment fails. Nearly all patients with azole-resistant oropharyngeal or esophageal candidiasis respond to a 2-week course of intravenous amphotericin B (0.3 to 0.5 mg/kg daily) or caspofungin (70 mg for one dose, then 50 mg daily). Relapse is usual.

Management of recurrent oropharyngeal candidiasis in the HIV-infected patient presents special problems. Patients with CD4+ cell counts of <100/µL who have received prolonged fluconazole therapy are at risk of developing azole resistance, requiring an increased dose to mount a response, relapsing early, and eventually failing to respond well to any dose of fluconazole. The increasing azole resistance in this population suggests that HIV-infected patients with oropharyngeal or esophageal candidiasis should be treated for each individual episode and that only when episodes become intolerably frequent or severe should prophylaxis be given.Bladder thrush responds to bladder irrigations with amphotericin B (50 µg/mL for 5 days). If no bladder catheter is in place, oral fluconazole can be used to control candiduria. Most patients with candiduria do not have unrelieved urinary tract obstruction and do not benefit from therapy.Intravenous amphotericin B is the drug of choice for deeply invasive candidiasis in neutropenic or seriously immunosuppressed patients. The deoxycholate formulation is usually given at a dosage of 0.5 to 0.7 mg/kg daily. Open, noncomparative studies of amphotericin B lipid complex and liposomal amphotericin B indicate that either preparation is effective in deeply invasive candidiasis. The usual dose of either formulation is 5 mg/kg daily by the intravenous route.Candida endocarditis on prosthetic or native valves usually relapses unless the valve is replaced. Long-term fluconazole administration has been used to prevent recurrence after valve replacement.In immunocompetent patients with intravenous catheter–acquired C. albicans fungemia, the catheter should be removed in conjunction with the administration of fluconazole (400 mg/d), amphotericin B (0.5 mg/kg daily), or caspofungin (one 70-mg dose followed by 50 mg daily by the intravenous route). Amphotericin B (0.7 to 1.0 mg/kg daily) may be appropriate as initial therapy in severely neutropenic patients. Candidemia from suppurative phlebitis of a peripheral vein may not respond until the infected portion of the vein is excised. Therapy for candidemia is continued for 2 weeks after the patient becomes afebrile. The Candida species involved should be considered in choosing a drug for candidemia. C. krusei and C. inconspicua are rare causes of candidemia but are resistant to fluconazole in vitro. C. glabrata exhibits intermediate susceptibility to fluconazole. Thus either increasing the daily fluconazole dose to 800 mg or using amphotericin B or caspofungin may be appropriate. Caspofungin displays approximately equal activity in vitro against all Candida species, including azole-resistant strains. Strains of C. lusitaniae resistant to amphotericin B but susceptible to azoles or caspofungin have been encountered. Intravenous amphotericin B, with or without flucytosine, is the preferred treatment for Candida endophthalmitis, although cures have been reported with fluconazole. 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.Because amphotericin B and fluconazole penetrate reasonably well into an infected joint, the pleural cavity, and the peritoneum, local injection is not indicated. Removal of prostheses (including prosthetic joints and cardiac valves), peritoneal dialysis catheters, and central venous catheters is usually essential. Debridement, along with antifungal therapy, is beneficial in Candida osteomyelitis. All collections of pus, such as those in the postoperative abdomen, need to be drained surgically or by percutaneous, CT-guided catheterization; an exception relates to the numerous small abscesses in liver, spleen, or kidney in chronic disseminated candidiasis, which cannot be drained effectively and require prolonged antifungal therapy. In general, treatment should continue until the patient with chronic disseminated candidiasis has been afebrile and nonneutropenic for at least 2 weeks. Defects may persist on imaging studies long after cure. Relapse during another episode of neutropenia is common unless the patient is receiving amphotericin B. Repeat cytotoxic therapy or even bone marrow transplantation can be undertaken in patients with prior chronic disseminated candidiasis, but amphotericin B should be given empirically during neutropenia.PROPHYLAXISFluconazole can decrease the incidence of deeply invasive candidiasis in recipients of allogeneic bone marrow transplants when 400 mg is given daily. Some centers continue such prophylaxis for 70 days; others discontinue it after engraftment. Studies of leukemic and other neutropenic patients have found no significant reduction in the incidence of deeply invasive candidiasis associated with prophylactic use of fluconazole or itraconazole oral suspension, although this topic remains controversial. Prophylaxis against recurrent oropharyngeal or esophageal candidiasis in HIV-infected patients is no longer recommended unless recurrences are very frequent or severe. Fluconazole (3 to 6 mg/kg) or itraconazole solution (5 mg/kg) is the recommended daily oral dose. Fluconazole prophylaxis at 400 mg daily may be useful in preventing deeply invasive candidiasis in some high-risk postoperative patients. Definition of groups at sufficient risk to benefit from fluconazole depends on the intensive care unit but likely includes patients undergoing repeat, complicated abdominal surgery and patients who are both heavily colonized with Candida and immunosuppressed at the time of complicated surgery. The presence of intravenous catheters, prolonged stays in the intensive care unit, and renal failure increase the risk of candidemia.

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