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The most common fungal infections among HIV-infected children are caused by Candida spp. Oral thrush and diaper dermatitis occur among 50%-85% of HIV-infected children. Candida albicans is the most common cause of mucosal and esophageal candidiasis. Localized disease caused by Candida is characterized by limited tissue invasion to the skin or mucosa. Examples of localized candidiasis include oropharyngeal and esophageal disease, vulvovaginitis, and diaper dermatitis. Once the organism penetrates the mucosal surface and widespread hematogenous dissemination occurs, invasive candidiasis ensues. This can result in candidemia, meningitis, endocarditis, renal disease, endophthalmitis, and hepatosplenic disease.

Oropharyngeal candidiasis (OPC) continues to be one of the most frequent OIs in HIV-infected children during the HAART era (28% of children), with an incidence rate of 0.93 per 100 child-years (3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.). The incidence of esophageal or tracheobronchial candidiasis also has decreased from 1.2 per 100 child-years during the pre-HAART era to 0.08 per 100 child-years during the HAART era (2001-2004) (1Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001;20:40-8.). Candida esophagitis continues to be seen in children who are not responding to antiretroviral therapy (266Chiou CC, Groll AH, Gonzalez CE, et al. Esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors. Pediatr Infect Dis J 2000;19:729-34., 267Walsh TJ, Gonzalez C, Roilides E, et al. Fungemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. Clin Infect Dis 1995;20:900-6.). Children who develop esophageal candidiasis despite HAART may be less likely to have typical symptoms (e.g., odynophagia and retrosternal pain) or have concomitant OPC (268Chiou CC, Groll AH, Mavrogiorgos N, et al. Esophageal candidiasis in human immunodeficiency virus-infected pediatric patients after the introduction of highly active antiretroviral therapy. Pediatr Infect Dis J 2002;21:388-92.); during the pre-HAART era, concomitant OPC occurred in 94% of children with candida esophagitis (266Chiou CC, Groll AH, Gonzalez CE, et al. Esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors. Pediatr Infect Dis J 2000;19:729-34.). Risk factors for esophageal candidiasis include low CD4 count (<100 cells/ mm³), high viral load, and neutropenia (<500 cells/mm³) (1Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001;20:40-8., 3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300., 266Chiou CC, Groll AH, Gonzalez CE, et al. Esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors. Pediatr Infect Dis J 2000;19:729-34., 267Walsh TJ, Gonzalez C, Roilides E, et al. Fungemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. Clin Infect Dis 1995;20:900-6.).

Disseminated candidiasis is infrequent among HIV-infected children, but Candida can disseminate from the esophagus particularly when coinfection with herpes simplex virus (HSV) or CMV is present (228Leibovitz E, Rigaud M, Chandwani S, et al. Disseminated fungal infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1991;10:888-94., 266Chiou CC, Groll AH, Gonzalez CE, et al. Esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors. Pediatr Infect Dis J 2000;19:729-34.). Candidemia occurs in up to 12% of HIV-infected children with chronically indwelling central venous catheters for total parental nutrition or IV antibiotics (267Walsh TJ, Gonzalez C, Roilides E, et al. Fungemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. Clin Infect Dis 1995;20:900-6., 269Gonzalez CE, Venzon D, Lee S, et al. Risk factors for fungemia in children infected with human immunodeficiency virus: a case-control study. Clin Infect Dis 1996;23:515-21.). Approximately 50% of reported cases of Candida bloodstream infections in HIV-infected children are caused by non-albicansCandida spp., including C. tropicalis, C. pseudotropicalis, C. parapsilosis, C. glabrata, C. kruse, and C. dubliniensis. In one study of Cambodian HIV-infected children on HAART who had candidiasis, seven (75%) of nine isolated C. glabrata were resistant to fluconazole, and three (40%) of seven C. parapsilosis isolated were resistant to more than three azole agents (270Krcmery V, Augustinova A, Babelova O, et al. Fungal resistance in Cambodian children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 2006;25:470.). Species-specific epidemiology varies widely by geographic location and hospital. A substantial number of children who develop candidemia have received systemically absorbed oral antifungal azole compounds (e.g., ketoconazole or fluconazole) for control of oral and esophageal candidiasis (267Walsh TJ, Gonzalez C, Roilides E, et al. Fungemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. Clin Infect Dis 1995;20:900-6.). Early detection and treatment of candidemia can decrease mortality. Overall mortality was 90% in one study in children who had >14 days of fever and symptoms before diagnosis of disseminated infection with Candida spp. (228Leibovitz E, Rigaud M, Chandwani S, et al. Disseminated fungal infections in children infected with human immunodeficiency virus. Pediatr Infect Dis J 1991;10:888-94.).

Clinical manifestations of OPC vary and include pseudomembranous (thrush) and erythematous (atrophic), hyperplastic (hypertrophic), and angular cheilitis. Thrush appears as creamy white curdlike patches with inflamed underlying mucosa that is exposed after removal of the exudate. It can be found on the oropharyngeal mucosa, palate, and tonsils. Erythematous OPC is characterized by flat erythematous lesions on the mucosal surface. Hyperplastic candidiasis comprises raised white plaques on the lower surface of the tongue, palate, and buccal mucosa and cannot be removed. Angular cheilitis occurs as red fissured lesions in the corners of the mouth.

Esophageal candidiasis often presents with odynophagia, dysphagia, or retrosternal pain, and unlike adults, a substantial number of children experience nausea and vomiting. Therefore, children with esophageal candidiasis might present with dehydration and weight loss. Evidence of OPC can be absent among children with esophageal candidiasis, particularly those receiving HAART.

New-onset fever in an HIV-infected child with advanced disease and a central venous catheter is the most common clinical manifestation of candidemia. Renal candidiasis presents with candiduria and ultrasonographically demonstrated renal parenchymal lesions, often without symptoms related to renal disease (267Walsh TJ, Gonzalez C, Roilides E, et al. Fungemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. Clin Infect Dis 1995;20:900-6.). Candidemia can lead to endogenous endophthalmitis, and ocular examination by an ophthalmologist is warranted in children with bloodstream Candida infection.

Oral candidiasis can be diagnosed by a potassium hydroxide preparation and culture with microscopic demonstration of budding yeast cells in wet mounts or biopsy specimens. For recurrent or refractory OPC, cultures with in vitro susceptibility testing can be used to guide antifungal treatment (271Muller FM, Groll AH, Walsh TJ. Current approaches to diagnosis and treatment of fungal infections in children infected with human immuno deficiency virus. Eur J Pediatr 1999;158:187-99.).

Esophageal candidiasis has a classic cobblestoning appearance on barium swallow. In refractory symptomatic cases, endoscopy should be performed to rule out other causes of refractory esophagitis (e.g., HSV, CMV, MAC, and azole-resistant Candida spp.). Endoscopy might show few small white raised plaques to elevated confluent plaques with hyperemia and extensive ulceration.

Candidemia is best diagnosed with blood cultures using lysis-centrifugation techniques (267Walsh TJ, Gonzalez C, Roilides E, et al. Fungemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. Clin Infect Dis 1995;20:900-6.) or automated broth-based systems (272Stevens D. Diagnosis of fungal infections: current status. J Antimicrob Chemother 2002;49(Suppl 1):11-9.). When candidemia is present, depending on clinical suspicions, retinal examination for endophthalmitis, abdominal CT or ultrasound for hepatic or renal involvement, and bone scans for osteomyelitis can be considered.

New diagnostic techniques such as the urine D-arabinitol/ L-arabinitol ratio (273Sigmundsdottir G, Larsson L, Wiebe T, et al. Clinical experience of urine D-arabinitol/L-arabinitol ratio in the early diagnosis of invasive candidiasis in paediatric high risk populations. Scand J Infect Dis 2007;39:146-51.), serum D-arabinitol/creatinine ratio (274Yeo SF, Huie S, Sofair AN, et al. Measurement of serum D-arabinitol/ creatinine ratios for initial diagnosis and for predicting outcome in an unselected, population-based sample of patients with Candida fungemia. J Clin Microbiol 2006;44:3894-9.), Candida antigen mannan (277Klingspor L, Jalal S. Molecular detection and identification of Candida and Aspergillus spp. from clinical samples using real-time PCR. Clin Microbiol Infect 2006;12:745-53.), (1Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001;20:40-8., 3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.)-beta-D-gulcan assay (276Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter clinical evaluation of the (1->3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005;41:654-9.), and real time PCR (277Klingspor L, Jalal S. Molecular detection and identification of Candida and Aspergillus spp. from clinical samples using real-time PCR. Clin Microbiol Infect 2006;12:745-53.) are promising diagnostic alternatives under development for early diagnosis of invasive candidiasis in children, but none of these assays have been validated for use in children.

Not applicable.

No adverse effects have been reported with the use of oral nystatin for treatment of oral candidiasis, but bitter taste might contribute to poor adherence.

The azole drugs have relatively low rates of toxicity, but because of their ability to inhibit the CYP450-dependent hepatic enzymes (ketoconazole has the strongest inhibitory effect) they can interact substantially with other drugs undergoing hepatic metabolism. These interactions can result in decreased plasma concentration of the azole because of increased metabolism induced by the coadministered drug or development of unexpected toxicity from the coadministered drug because of increased plasma concentrations secondary to azole-induced alterations in hepatic metabolism. The potential for drug interactions, particularly with antiretroviral drugs such as PIs, should be carefully evaluated before initiation of therapy (AIII).

The most frequent adverse effects of the azole drugs are GI, including nausea and vomiting (10% - 40% of patients). Skin rash and pruritus might occur with all drugs; rare cases of Stevens-Johnson syndrome and alopecia have been reported with fluconazole therapy. All drugs are associated with asymptomatic increases in transaminases (1%-13% of patients) and, less frequently, hepatitis. Hematologic abnormalities have been reported with itraconazole, including thrombocytopenia and leukopenia. Of the azoles, ketoconazole is associated with the highest frequency of side effects. Its use has been associated with endocrinologic abnormalities related to steroid metabolism, including adrenal insufficiency and gynecomastia, hemolytic anemia, and transaminitis. Dose-related, reversible visual changes (e.g., photophobia and blurry vision) have been reported in approximately 30% of patients receiving voriconazole (300Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 2003;36:630-7.). Cardiac arrhythmias and renal abnormalities including nephritis and acute tubular necrosis also have been reported with voriconazole use.

Amphotericin B deoxycolate undergoes renal excretion as inactive drug. Adverse effects of amphotericin B are primarily nephrotoxicity, defined by substantial azotemia from glomerular damage, and can be accompanied by hypokalemia from tubular damage. Nephrotoxicity is exacerbated by use of concomitant nephrotoxic drugs. Permanent nephrotoxicity is related to cumulative dose. Nephrotoxicity can be ameliorated by hydration before amphotericin B infusion. Infusion-related fevers, chills, nausea, and vomiting occur less frequently in children than in adults. Onset occurs usually within 1-3 hours after the infusion is started, typical duration is <1 hour, and the febrile reactions tend to decrease in frequency over time. Pretreatment with acetaminophen or diphenhydramine might alleviate febrile reactions. Idiosyncratic reactions, such as hypotension, arrhythmias, and allergic reactions, including anaphylaxis, occur less frequently. Hepatic toxicity, thrombophlebitis, anemia, and rarely neurotoxicity (manifested as confusion or delirium, hearing loss, blurred vision, or seizures) also can occur.

In approximately 20% of children, lipid formulations of amphotericin B can cause acute, infusion-related reactions, including chest pain; dyspnea; hypoxia; severe pain in the abdomen, flank, or leg; or flushing and urticaria. Compared with infusion reactions with conventional amphotericin B, most (85%) of the reactions to the lipid formulations occur within the first 5 minutes after infusion and rapidly resolve with temporary interruption of the amphotericin B infusion and administration of IV diphenhydramine. Premedication with diphenhydramine can reduce the incidence of these reactions.

Flucytosine has considerable toxicity: adverse effects on the bone marrow (e.g., anemia, leukopenia, thrombocytopenia), liver, GI tract, kidney, and skin warrant monitoring of drug levels and dose adjustment to keep the level at 40-60 µg/mL. Drug levels should be monitored, especially in patients with renal impairment. High levels can result in bone marrow suppression. The drug should be avoided in children who have severe renal impairment (EIII).

The echinocandins have an excellent safety profile. In a retrospective evaluation of 25 immunocompromised children who received caspofungin, the drug was well tolerated, although three patients had adverse events potentially related to the drug (hypokalemia in all three children, elevated bilirubin in two, and decreased hemoglobin and elevated alanine aminotransferase in one) (256Walsh TJ, Adamson PC, Seibel NL, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005;49:4536-45.). In this study, children weighing <50 kg received 0.8-1.6 mg/kg body weight daily, and those weighing >50 kg received the adult dosage. In the pharmacokinetic study of 39 children who received caspofungin at 50 mg/m² body surface area/day, five (13%) patients experienced one or more drug-related clinical adverse events, including one patient each with fever, diarrhea, phlebitis, proteinuria, and transient extremity rash. Two patients reported one or more drug-related laboratory adverse events, including one patient each with hypokalemia and increased serum aspartate transaminase. None of the drug-related adverse events in this study were considered serious or led to discontinuation of caspofungin (256Walsh TJ, Adamson PC, Seibel NL, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005;49:4536-45.).

IRIS associated with Candida infection has not been described in children. However, evidence suggests that candidiasis occurs with increased frequency in adults during the first 2 months after initiation of HAART, except for candidal eosophagitis (301Nacher M, Vantilcke V, Huber F, et al. Increased incidence of mucosal candidiasis after HAART initiation: a benign form of immune reconstitution disease? AIDS 2007;21:2534-6.).

Secondary prophylaxis of recurrent OPC usually is not recommended because 1) the treatment of recurrence is typically effective, 2) the potential exists for the development of resistance and drug interactions, and 3) additional rounds of prophylaxis are costly (DIII). Immune reconstitution with HAART in immunocompromised children should be a priority (AIII). However, if recurrences are severe, data on HIV-infected adults with advanced disease on HAART suggest that suppressive therapy with systemic azoles, either with oral fluconazole (BI) or with itraconazole solution (CI), can be considered (315Goldman M, Cloud GA, Wade KD, et al. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40. Clin Infect Dis 2005;41:1473-80.). Potential azole resistance should be considered when long-term prophylaxis with azoles is considered.

Data on HIV-infected adults suggest that, in children with fluconazole-refractory OPC or esophageal candidiasis who responded to voriconazole or posaconazole therapy or to echinocandins, continuing the effective drug as secondary prophylaxis can be considered because of high relapse rate until HAART produces immune reconstitution (CIII).

In situations where secondary prophylaxis is instituted, no data exist on which to base a recommendation regarding discontinuation. On the basis of experience with HIV-infected adults with other OIs, discontinuation of secondary prophylaxis can be considered when the CD4 count or percentage has risen to CDC Immunologic Category 2 or 1 (CIII) (98CDC. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Official authorized addenda: human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD-9-CM. MMWR 1994;43:1-19.).