Recommendations from Centers for Disease Control and Prevention,

1. Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected ChildrenFungal 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

2. About This Presentation 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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 www.aidsetc.org

3. 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 www.aidsetc.org

4. 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 www.aidsetc.org

5. 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 www.aidsetc.org

6. 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 www.aidsetc.org

7. 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 www.aidsetc.org

8. 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 www.aidsetc.org

9. Aspergillosis: Adverse Effectsand 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 www.aidsetc.org

10. 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 www.aidsetc.org

11. 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 www.aidsetc.org

12. 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 www.aidsetc.org

13. 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 www.aidsetc.org

14. 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 www.aidsetc.org

15. 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 (400,000-600,000 units/mL) 4 times/day Amphotericin B suspension: (100 mg/mL) 1 mL 4 times/day www.aidsetc.org

16. 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 www.aidsetc.org

17. 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 14-21 days (A I) Itraconazole oral solution 2.5 mg/kg/dose given twice daily or 5 mg/kg once daily for 14-21 days (A I) Consider low-dose IV amphotericin B minimum of 7 days for refractory disease (B II) www.aidsetc.org

18. 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 dosage range 0.8-1.6 mg/kg daily; >50 kg, adult dosing www.aidsetc.org

19. Candida Infections: Treatment (5) Invasive disease Remove central venous catheter Amphotericin B (A I) 0.5-1.5 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 0.25-0.5 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 www.aidsetc.org

20. 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) www.aidsetc.org

21. 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 www.aidsetc.org

22. 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 www.aidsetc.org

23. 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) www.aidsetc.org

24. Candida Infections: TreatmentFailure 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 www.aidsetc.org

25. 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 ofC immitis reported Reports of infection in nonendemic areas usually due to reactivation www.aidsetc.org

26. 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 www.aidsetc.org

27. 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 www.aidsetc.org

28. 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 www.aidsetc.org

29. Coccidioidomycosis: Treatment Limited data in children; recommendations based on adult data Treat diffuse pulmonary disease or disseminated disease with amphotericin B dosage of 0.5-1.5 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) www.aidsetc.org

30. 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) www.aidsetc.org

31. 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 www.aidsetc.org

32. 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 www.aidsetc.org

33. 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 www.aidsetc.org

34. 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 www.aidsetc.org

35. Cryptococcosis: Prevention No proven strategies to prevent exposure Believed to be acquired by inhalation of aerosolized particles from the environment www.aidsetc.org

36. Cryptococcosis: Treatment Not well studied in children; infection is often fatal in the absence of treatment CNS Disease Amphotericin B induction (0.7-1.5 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) www.aidsetc.org

37. 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 www.aidsetc.org

38. 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 www.aidsetc.org

39. 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) www.aidsetc.org

40. 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 www.aidsetc.org

41. 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 www.aidsetc.org

42. 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 www.aidsetc.org

43. 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 www.aidsetc.org

44. 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 www.aidsetc.org

45. 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 www.aidsetc.org

46. 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 www.aidsetc.org

47. 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 www.aidsetc.org

48. 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 www.aidsetc.org

49. 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 www.aidsetc.org

50. 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 www.aidsetc.org