Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children Fungal Infections

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could become out of date quickly.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
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

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

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

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

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

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

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

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

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 gt90 in
  children with fever and symptoms gt14 days

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

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

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

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

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

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)

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 lt50 kg
  dosage range 0.8-1.6 mg/kg daily gt50 kg, adult
  dosing

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

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)

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

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

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)

24
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

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

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

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 gt 116
  correlate with presence and severity of
  extrapulmonary infection

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

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)

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)

31
CoccidioidomycosisMonitoring, 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

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

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

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

35
Cryptococcosis Prevention

• No proven strategies to prevent exposure
• Believed to be acquired by inhalation of
  aerosolized particles from the environment

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)

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

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

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)

40
CryptococcosisIRIS 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

41
Histoplasmosis Epidemiology

• Pathogen is Histoplasma capsulatum
• Incidence of disseminated histoplasmosis in
  HIV-infected children in the United States is
  lt0.4
• 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

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

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

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

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

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

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

48
HistoplasmosisMonitoring 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

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 lt1 year pre-ART
• CD4 T-cell count not a good indicator of risk in
  infants lt1 year old
• Infection now unusual owing to routine
  prophylaxis with TMP-SMX

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

51
Pneumocystis jiroveci (carinii) Diagnosis

• Hypoxia with low arterial oxygen pressure
  (alveolar-arterial oxygen gradient gt30 mmHg)
• Definitive diagnosis requires demonstrating
  organism
• Induced sputum (difficult lt2 years)
• Bronchoscopy with bronchoalveolar lavage
• Fiberoptic bronchoscopy with biopsy generally
  not recommended

52
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

53
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)

54
Pneumocystis jiroveci (carinii) Prevention (2)

• Chemoprophylaxis with TMP-SMX recommended as
  follows, based on CD4 counts and patient age
• 6 years CD4 count lt200 cells/µL or CD4
  percentage lt15
• 1 to 5 years CD4 count lt500 cells/µL or CD4
  percentage lt15
• All HIV-infected infants lt12 months of age
  regardless of CD4 count or percentage

55
Pneumocystis jiroveci (carinii) Treatment

• TMP-SMX (A I)
• gt2 months 15-20 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

56
Pneumocystis jiroveci (carinii) Treatment (2)

• Adverse reactions
• Rash
• Stevens-Johnson syndrome (rare)
• Neutropenia, thrombocytopenia, megaloblastic or
  aplastic anemia

57
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 60-90
  minutes
• Consider oral atovaquone after 7-10 days(B III)

58
Pneumocystis jiroveci (carinii) Treatment
Alternatives

• Atovaquone (B I)
• Limited data in children
• 30-40 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

59
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

60
Pneumocystis jiroveci (carinii) Treatment
Alternatives (3)

• Clindamycin/primaquine
• Pediatric clindamycin dosing based on other uses
  20-40 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

61
Pneumocystis jiroveci (carinii) Treatment
Alternatives (4)

• Dapsone/TMP
• Use for mild to moderate PCP in adults no data
  in children (C III)
• Dapsone dosage lt13 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

62
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

63
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 11-21
• 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

64
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

65
About This Slide Set

• 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
• http//www.aidsetc.org