Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children Fungal Infections Recommendations from Centers for Disease Control and Prevention, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics

July These slides were developed using the April 2008 Guidelines. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. Expert opinion should be sought for complex treatment regimens. – AETC NRC About This Presentation

July Aspergillosis: Epidemiology  Aspergillus species are ubiquitous molds found in soil, on plants, and in decomposing organic materials  The most common species causing aspergillosis are A fumigatus and A flavus  Rare but frequently lethal infection  Risk factors include low CD4 count, neutropenia, corticosteroids, concurrent malignancy with chemotherapy, HIV-related phagocytic impairment, previous respiratory infections, broad-spectrum antibiotic exposure

July Aspergillosis: Clinical Manifestations  Pulmonary aspergillosis is the most common presentation  Invasive pulmonary aspergillosis associated with fever, cough, dyspnea, pleuritic pain  Additional manifestations include necrotizing tracheobronchitis, pseudomembranous tracheobronchitis, CNS involvement, cutaneous, sinus, middle ear and mastoid infection

July Aspergillosis: Diagnosis  Usually isolated from the blood but also readily isolated from lung, sinus, brain, and skin biopsy  Definitive diagnosis includes histopathologic demonstration of organisms in biopsy specimens  Presumptive diagnosis of respiratory tract infection can be made if Aspergillus species is recovered from respiratory sample

July Aspergillosis: Diagnosis (2)  Chest radiograph demonstrates either diffuse interstitial pneumonitis or localized wedge-shaped infiltrates  CT of chest may be used to identify a “halo” sign  Cavitation and air crescent formation in chest CDT more frequent in older children and adults

July Aspergillosis: Prevention  Consider excluding plants and flowers from rooms and avoiding food items such as nuts and spices  Erect suitable barriers between patient care and construction sites, clean shower heads routinely as well as hot- water faucets and air-handling systems

July Aspergillosis: Treatment  Voriconazole is recommended for treatment of invasive aspergillosis  Adult data indicate that voriconazole is superior to amphotericin B but data in children are limited  Recommended dosage for children is 6-8 mg/kg IV (or 8 mg/kg orally) Q12H, followed by 7 mg/kg IV or orally twice daily  Treatment is continued for 12 weeks

July Aspergillosis: Adverse Effects and Treatment Failure  Voriconazole side effects include reversible dose-dependent visual disturbances, elevated liver enzymes, and occasional skin rash  Amphotericin toxicity is associated primarily with fever, chills, and nephrotoxicity  Efficacy of antifungal therapy for aspergillosis is poor  Experimental approaches include evaluation of caspofungin

July Candida Infections: Epidemiology  Most common fungal infections in HIV-infected children  Thrush and diaper dermatitis occur in 50-85% of HIV-infected children  In pre-ART era, oropharyngeal candidiasis found in 94% of children with Candida esophagitis  Disseminated candidiasis rare in children except those with CMV or HSV coinfection, and those with central venous catheter

July Candida Infections: Epidemiology (2)  A substantial percentage of children with fungemia receive oral, systemically absorbable azole antifungals (eg, ketoconazole)  Complications include disseminated infection of bone, liver, and kidney; endophthalmitis  Mortality from disseminated candidiasis >90% in children with fever and symptoms >14 days

July Candida Infections: Clinical Manifestations  Thrush and erythematous, hyperplastic, and angular cheilitis  Esophageal candidiasis may present with odynophagia, dysphagia, or retrosternal pain  Children may develop nausea, vomiting, or weight loss and dehydration  New onset of fever in individuals with central venous catheters  Systemic fungemia may lead to endophthalmitis

July Candida Infections: Diagnosis  Culture and KOH preparation with microscopic demonstration of budding yeast cells in wet mounts or biopsy  Blood culture using lysis centrifugation  “Cobblestone” appearance on barium swallow  Perform endoscopy in refractory cases to look for CMV, HSV, MAC coinfections  Research studies or evaluating detection of candidate antigens for early diagnosis

July Candida Infections: Prevention  Routine primary prophylaxis of candidiasis in HIV-infected children is not indicated  Candida organisms are common commensals on mucosal surfaces in healthy individuals and no measures are available to reduce exposure

July Candida Infections: Treatment Treat early uncomplicated oropharyngeal candidiasis (OPC) with topical therapy  Cotrimoxazole: 10 mg troches 4-5 times/day for 2 weeks (B II)  Nystatin suspension: 4-6 mL (400, ,000 units/mL) 4 times/day  Amphotericin B suspension: (100 mg/mL) 1 mL 4 times/day

July Candida Infections: Treatment (2) Oral systemic therapy for OPC  Fluconazole: 3-6 mg/kg orally once daily for 7-14 days (A I)  Itraconazole: 2.5 mg/kg orally BID for 7-14 days (A I)  Ketoconazole: 5-10 mg/kg/day orally divided into 2 doses given for 14 days (D II)  Amphotericin oral suspension or IV for OPC refractory to other treatment

July Candida Infections: Treatment (3) Esophageal disease  Treat both diagnosed esophageal disease and children with OPC and esophageal symptoms (A I)  Initiate treatment with:  Fluconazole 6 mg/kg/day orally or IV on day 1 followed by 3-6 mg/kg for days (A I)  Itraconazole oral solution 2.5 mg/kg/dose given twice daily or 5 mg/kg once daily for days (A I)  Consider low-dose IV amphotericin B minimum of 7 days for refractory disease (B II)

July Candida Infections: Treatment (4) Esophageal disease  Other therapies not fully evaluated in children  Voriconazole: loading dose of 6 mg/kg IV Q12H on day 1, followed by 4 mg/kg Q12H thereafter; after stabilization, change to oral dosing  Caspofungin: available only in IV form; 50 kg, adult dosing

July Candida Infections: Treatment (5) Invasive disease  Remove central venous catheter  Amphotericin B (A I)  mg/kg once daily IV over course of 1-2 hours, administered in 5% dextrose at final concentration of 0.1 mg/mL  For mild to moderate disease, begin at mg/kg and increase as tolerated to 1.5 mg/kg  Once stabilized, administer 1.5 mg/kg every other day (B III)  Treat for 3 weeks after last positive blood culture of symptoms

July Candida Infections: Treatment (6) Invasive disease: alternative therapy  Fluconazole in stable patients with uncomplicated candidemia without previous azole treatment (identification of Candida species essential; C krusei and C glabrata are resistant) (E III)  Amphotericin lipid formulations (limited pediatric experience)  Amphotericin lipid complex (ABLC, Abelcet)  Liposomal amphotericin lipid complex (AmBisome)  Amphotericin B cholesteryl sulfate complex (ABCD)

July Candida Infections: Treatment (7) Treatment under development  Caspofungin, micafungin, and anidulafungin have been studied in battles with HIV infection, neutropenic children at risk of fungal infection in children with documented candidiasis  Data on HIV-infected children are limited

July Candida Infections: Treatment (8) Amphotericin toxicity  Nephrotoxicity: azotemia, hypokalemia  Nephrotoxicity can be minimized by hydration with 0.9% saline intravenously 30 minutes before amphotericin B infusion  Infusion-related chills, fever, and vomiting; pretreat with acetaminophen or diphenhydramine  Rarely: hypotension, arrhythmias, neurotoxicity, hepatic toxicity

July Candida Infections: Treatment (9) Fluconazole, itraconazole, ketoconazole toxicity  Inhibition of CYP450-dependent hepatic enzymes can result in either decreased levels of azole when administered with other drugs with hepatic metabolism or increased levels of other drugs with hepatic metabolism  Nausea, vomiting, rash, pruritus, Stevens-Johnson syndrome (rare), increased liver enzymes, hepatitis, leukopenia, anemia, hemolytic anemia, alopecia (fluconazole)

July Candida Infections: Treatment Failure Oral pharyngeal and esophageal candidiasis  Initial failure should be treated with oral fluconazole, itraconazole, oral amphotericin B, or low-dose IV amphotericin B Invasive disease  Amphotericin B lipid formulations can be used for children who cannot tolerate amphotericin B, have disseminated Candida infection that is resistance to amphotericin B, or are at risk of nephrotoxicity

July Coccidioidomycosis: Epidemiology  Increased risk of infection with Coccidioides immitis and Coccidioides posadasii among HIV-infected children in endemic areas (eg, southwestern United States, northern Mexico, Central and South America)  Primary infection of newborn rare  In utero and perinatal transmission of C immitis reported  Reports of infection in nonendemic areas usually due to reactivation

July Coccidioidomycosis: Clinical Manifestations  Fever and dyspnea most common presentation  Chills, weight loss, lymphadenopathy, chest pain, diffuse reticulonodular pulmonary infiltrates, meningitis  Disseminated disease associated with erythema multiforme; erythema nodosum; erythematous maculopapular rash; arthralgia; bone, joint, and CNS infection

July Coccidioidomycosis: Diagnosis  Direct examination and culture of respiratory secretions and CSF or biopsy of lesions  Blood cultures positive in 15% of cases  Complement fixation assay detects IgG antibody, positive IgM assays suggest active or recent infection, complement fixation titers > 1:16 correlate with presence and severity of extrapulmonary infection

July Coccidioidomycosis: Prevention  Difficult to avoid exposure in endemic areas  Exposure can be reduced by avoiding activities that predispose to inhalation of spores such as disturbing contaminated soil, being outdoors during dust storms

July Coccidioidomycosis: Treatment  Limited data in children; recommendations based on adult data  Treat diffuse pulmonary disease or disseminated disease with amphotericin B dosage of mg/kg/day until clinical improvement occurs (A II)  Follow with chronic suppressive fluconazole or itraconazole therapy (A II)  Alterative therapy: fluconazole 5-6 mg/kg BID or itraconazole 4-10 mg/kg BID for 3 days followed by 2-5 mg/kg BID (B III)

July Coccidioidomycosis: Treatment (2) CNS infection, including meningitis  High-dose fluconazole 5-6 mg/kg BID  If unresponsive to fluconazole, use IV amphotericin B augmented by intrathecal amphotericin B (C I)

July Coccidioidomycosis: Monitoring, Adverse Events and Toxicity  Monitoring of complement fixing IgG antibody is useful  Toxicity of antifungal drugs includes fevers, chills, nausea and vomiting, nephrotoxicity  Interaction of all antifungal agents with ARVs should be investigated; fluconazole and itraconazole appear to be safe in combination with ARVs  Voriconazole should be avoided in patients on PIs or NNRTIs

July Cryptococcosis: Epidemiology  Most infections caused by Cryptococcosis neoformans and Cryptococcosis gattii  Infection occurs primarily in tropical and subtropical areas  Low incidence of infection in children, especially with use of ART  Children usually infected during 6-12 year age range  Usually severely immunosuppressed

July Cryptococcosis: Clinical Manifestations  Meningoencephalitis most common manifestation  Fever, headache, altered mental status evolving over days to weeks  Acute illness with nuchal rigidity, seizures, focal neurologic signs observed in developing countries  Translucent, umbilicated, papules, nodules, ulcers, infiltrated plaques seen in disseminated disease  Pulmonary cryptococcosis unusual in children

July Cryptococcosis: Diagnosis  Microscopic examination of CSF on India ink-stained wet mounts  Detection of cryptococcal antigen in CSF, serum, bronchoalveolar lavage fluid (can be negative in culture-positive meningitis)  Fungal cultures from CSF, sputum, and blood cultures can identify the organism  Antigen levels useful in evaluating response to treatment and relapse  Pulmonary disease diagnosed by bronchoalveolar lavage and direct examination of India ink-stained specimens

July Cryptococcosis: Prevention  No proven strategies to prevent exposure  Believed to be acquired by inhalation of aerosolized particles from the environment

July Cryptococcosis: Treatment Not well studied in children; infection is often fatal in the absence of treatment CNS Disease  Amphotericin B induction ( mg/kg/day IV) combined with 2 weeks of flucytosine (25 mg/kg/dose given 4 times daily) followed by fluconazole for a minimum of 8 weeks  After symptoms are controlled, treat with fluconazole or itraconazole maintenance  Use amphotericin B alone if flucytosine is not tolerated  Fluconazole plus flucytosine is an alternative to amphotericin B (limited data in children)

July Cryptococcosis: Treatment (2) Pulmonary and extrapulmonary cryptococcosis  No clinical trials on the outcome of non-CNS cryptococcosis in HIV-infected patients  Treat with amphotericin B with or without the addition of fluconazole (A III)  Fluconazole or itraconazole should be continued long-term

July Cryptococcosis: Monitoring and Drug Toxicity Amphotericin toxicity  Nephrotoxicity: azotemia, hypokalemia  Nephrotoxicity can be minimized by hydration with 0.9% saline intravenously 30 minutes before amphotericin B infusion  Infusion-related chills, fever, and vomiting; pretreat with acetaminophen or diphenhydramine  Rarely: hypotension, arrhythmias, neurotoxicity, hepatic toxicity

July Cryptococcosis: Monitoring and Drug Toxicity (2) Flucytosine toxicity  Bone marrow: anemia, leukopenia, thrombocytopenia  Liver, GI, and renal toxicity Fluconazole toxicity  Potential interaction with ARV should be evaluated before initiating treatment (A III)

July Cryptococcosis: IRIS and Treatment Failure  IRIS related to cryptococcosis can present within weeks  Optimal treatment of patients experiencing treatment failure has not been defined  Patients failing initial azole treatment should be switched to amphotericin B in combination with flucytosine  Consider use of liposomal amphotericin B  Experience with posaconazole or voriconazole is limited

July Histoplasmosis: Epidemiology  Pathogen is Histoplasma capsulatum  Incidence of disseminated histoplasmosis in HIV-infected children in the United States is <0.4%  Incidence is higher in countries such as Brazil, Argentina, and Mexico (2.7% to 3.8%)  No evidence of dissemination of maternal infection to the fetus or greater severity of infection during pregnancy

July Histoplasmosis: Clinical Manifestations  Prolonged fever is the most common presentation  Malaise, weight loss, and nonproductive cough  Primary pulmonary focus leads to widespread dissemination in children  Pulmonary manifestations common  Physical findings include hepatosplenomegaly, erythematous nodular coetaneous lesions, CNS involvement with meningitis  Anemia, thrombocytopenia, elevated liver transaminases  Progressive disseminated histoplasmosis (PDH) is fatal if untreated

July Histoplasmosis: Diagnosis  Serologic testing using CF and immunodiffusion is insensitive in the presence of HIV infection.  Positive in most patients but not useful for diagnosis of acute infection  For diagnosis of CNS disease, a combination of CSF antibody, antigen, and culture is most sensitive  Skin testing not recommended for diagnosis

July Histoplasmosis: Diagnosis (2)  Culture of Histoplasma from blood or other sources  Detection of H capsulatum polysaccharide antigen in urine, blood, CSF, or bronchoalveolar lavage using EIA  EIA sensitivity greater in disseminated disease or acute pulmonary disease; greater in urine than in serum  Antigen levels decline with treatment and correlate with both response to treatment and relapse

July Histoplasmosis: Prevention  Most infections occur without a recognized history of exposure  Sites and conditions commonly implicated include outbreaks of soil contamination with bird or bat droppings, older urban and rural structures, and decaying vegetation

July Histoplasmosis: Treatment  Limited data for children; recommendations based on adult data  PDH is fatal without treatment and should be treated with either amphotericin B or itraconazole  Fluconazole has been used successfully as an alternative for patients with mild disease and for those who cannot tolerate itraconazole

July Histoplasmosis: Treatment (2)  Amphotericin B for patients with severe disseminated disease requiring hospitalization and for those who are immunocompromised  Amphotericin B induction dosage: 1 mg/kg for 4-6 weeks followed by itraconazole chronic suppressive therapy for 12 months (A I)  After successful treatment of acute disease, use chronic lifelong suppressive therapy with itraconazole  Liposomal amphotericin B alternative in event of amphotericin B intolerance

July Histoplasmosis: Monitoring and Adverse Effects  Antigen levels should be monitored during treatment and for 1 year thereafter  Adverse effects of amphotericin B include nephrotoxicity, infusion related fever, chills, nausea, and vomiting  Azole drugs inhibit CYP450-dependent hepatic enzymes, warranting careful review of drug interactions when using ARVs

July Pneumocystis jiroveci (carinii): Epidemiology  Organisms are found worldwide in the lungs of humans and lower animals  Antibody in 80% of normal children by 4 years  Most common AIDS indicator disease in children  Incidence highest in first year of life, peaking at 3-6 months  Accounted for 57% of AIDS-defining illnesses in infants age <1 year pre-ART  CD4 T-cell count not a good indicator of risk in infants <1 year old  Infection now unusual owing to routine prophylaxis with TMP-SMX

July Pneumocystis jiroveci (carinii): Clinical Manifestations  Fever, tachypnea, cough, dyspnea, poor feeding, weight loss  Abrupt or insidious onset  Bibasilar rales with evidence of hypoxia and respiratory distress  Extrapulmonary locations: spleen, liver, colon, pancreas, ear, eye, GI tract, bone marrow, heart, kidney, lymph nodes, CNS

July Pneumocystis jiroveci (carinii): Diagnosis  Hypoxia with low arterial oxygen pressure (alveolar-arterial oxygen gradient >30 mmHg)  Definitive diagnosis requires demonstrating organism  Induced sputum (difficult <2 years)  Bronchoscopy with bronchoalveolar lavage  Fiberoptic bronchoscopy with biopsy – generally not recommended

July Pneumocystis jiroveci (carinii): Diagnosis (2)  Open lung biopsy most sensitive  Requires thoracotomy, chest tube drainage  Organisms seen on biopsy with:  Gomori methenamine silver stain  Toluidine blue stain  Giemsa or Wright stain  Monoclonal antibody  DNA PCR for Pneumocystis MSG gene in fluids, lavage – sensitive but less specific than histology

July Pneumocystis jiroveci (carinii): Prevention  Need for isolation of hospitalized patients has not been demonstrated, but when prophylaxis cannot be given, may need to isolate patient or susceptible contacts  Infants born to HIV-infected mothers should be considered for prophylaxis at 4-6 weeks of age and continued until 1 year of age (A II)

July Pneumocystis jiroveci (carinii): Prevention (2) Chemoprophylaxis with TMP-SMX recommended as follows, based on CD4 counts and patient age:  6 years: CD4 count <200 cells/µL or CD4 percentage <15%  1 to 5 years: CD4 count <500 cells/µL or CD4 percentage <15%  All HIV-infected infants <12 months of age regardless of CD4 count or percentage

July Pneumocystis jiroveci (carinii): Treatment TMP-SMX (A I)  >2 months mg/kg/day of TMP component IV in 3-4 divided doses  Infuse over course of 1 hour  Administer for 21 days  Can be given orally in children with mild to moderate disease  Lifelong prophylaxis indicated

July Pneumocystis jiroveci (carinii): Treatment (2)  Adverse reactions:  Rash  Stevens-Johnson syndrome (rare)  Neutropenia, thrombocytopenia, megaloblastic or aplastic anemia

July Pneumocystis jiroveci (carinii): Treatment (3) Pentamidine isethionate  Recommended for patients with intolerance to TMP-SMX or clinical failure with TMP-SMX (A I); do not combine use  4 mg/kg/day IV once daily over period of minutes  Consider oral atovaquone after 7-10 days (B III)

July Pneumocystis jiroveci (carinii): Treatment Alternatives Atovaquone (B I)  Limited data in children  mg/kg/day divided into 2 doses, given with fatty foods  Infants 3-24 months may require 45 mg/kg/day divided into 2 doses, given with fatty foods (A II)  Adverse reactions include rash, nausea, diarrhea, increased liver enzymes

July Pneumocystis jiroveci (carinii): Treatment Alternatives (2) Clindamycin/primaquine  Used for mild to moderate PCP in adults; no data in children (C III)  Primaquine contraindicated in G6PD deficiency

July Pneumocystis jiroveci (carinii): Treatment Alternatives (3) Clindamycin/primaquine  Pediatric clindamycin dosing based on other uses: mg/kg/day IV divided into 3 or 4 doses, administered for 21 days  Primaquine dosing based on malaria: 0.3 mg/kg daily of the base, administered orally for 21 days  Adverse reactions include rash, nausea, diarrhea, pseudomembranous colitis

July Pneumocystis jiroveci (carinii): Treatment Alternatives (4) Dapsone/TMP  Use for mild to moderate PCP in adults; no data in children (C III)  Dapsone dosage <13 years 2 mg/kg/day orally once daily (A II) for 21 days  TMP 15/mg/kg/day orally divided into 3 daily doses for 21 days  Adverse reactions include rash, anemia, thrombocytopenia, increased liver enzymes

July Pneumocystis jiroveci (carinii): Treatment Adjunct Corticosteroids  Consider use in moderate to severe PCP  Use within 72 hours of diagnosis  Results in reduced respiratory failure, decreased ventilation requirements, and decreased mortality

July Pneumocystis jiroveci (carinii): Treatment Adjunct (2) Corticosteroids  Dosing recommendations vary  Prednisone: 40 mg BID for 1-5 days; 40 mg once daily days 6-10; 20 mg once daily days  Alternative: prednisone 1 mg/kg BID days 1-5; 0.5 mg/kg BID days 6-10; 0.5 mg/kg once daily days 11-21

July Pneumocystis jiroveci (carinii): Monitoring and Adverse Events  Short courses of corticosteroids have been used in some cases of PCP of moderate to severe intensity starting within 72 hours of diagnosis (A I)  As with other coinfection, IRIS may occur following initiation of ART but has been described infrequently in PCP  Most common adverse reaction to TMP-SMX includes rash and rarely erythema multiforme or Stevens- Johnson syndrome  Pentamidine is associated with renal toxicity, usually occurring 2 weeks after initiation of treatment

July  This presentation was prepared by Arthur Ammann, MD, Clinical Professor of Pediatrics University of California and President of Global Strategies for HIV Prevention for the AETC National Resource Center, in July 2009  See the AETC NRC website for the most current version of this presentation: About This Slide Set