CHAPTER 13: Human Immunodeficiency Virus Infection

• Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category 2.

• Children with two or more of the following conditions but none of the conditions listed in Categories 3 and 4:

  • Lymphadenopathy (≥0.5 cm at more than two sites; bilateral = one site)

  • Hepatomegaly

  • Splenomegaly

  • Dermatitis

  • Parotitis

  • Recurrent or persistent upper respiratory infection, sinusitis, or otitis media

• Children who have symptomatic conditions, other than those listed for Category 2 or Category 4, that are attributed to HIV infection. Examples of conditions in Clinical Category 3 include, but are not limited to, the following:

  • Anemia (<8 g/dL), neutropenia (<1000 cells/mm³), or thrombocytopenia (<100,000 cells/mm³) persisting ≥30 days

  • Bacterial meningitis, pneumonia, or sepsis (single episode)

  • Candidiasis, oropharyngeal (i.e., thrush) persisting for >2 months in children aged >6 months

  • Cardiomyopathy

  • Cytomegalovirus infection with onset before age 1 month

  • Diarrhea, recurrent or chronic

  • Hepatitis

  • Herpes simplex virus (HSV) stomatitis, recurrent (i.e., more than two episodes within 1 year)

  • HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month

  • Herpes zoster (i.e., shingles) involving at least two distinct episodes or more than one dermatome

  • Leiomyosarcoma

  • Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex

  • Nephropathy

  • Nocardiosis

  • Fever lasting >1 month

  • Toxoplasmosis with onset before age 1 month

  • Varicella, disseminated (i.e., complicated chickenpox)

• Children who have any condition listed in the 1987 surveillance case definition for AIDS (below), with the exception of LIP, which is a Category 3 condition:

  • Serious bacterial infections, multiple or recurrent (i.e., any combination of at least two culture-confirmed infections within a 2-year period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections)

  • Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)

  • Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes)

  • Cryptococcosis, extrapulmonary

  • Cryptosporidiosis or isosporiasis with diarrhea persisting >1 month

  • Cytomegalovirus disease with onset of symptoms at age >1 month (at a site other than liver, spleen, or lymph nodes)

  • Encephalopathy(at least one of the following progressive findings present for at least 2 months in the absence of a concurrent illness other than HIV infection that could explain the findings): (a) failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; (b) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by computerized tomography or magnetic resonance imaging (serial imaging is required for children aged <2 years); (c) acquired symmetric motor deficit manifested by two or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance

  • Herpes simplex virus infection causing a mucocutaneous ulcer that persists for >1 month or bronchitis, pneumonitis, or esophagitis for any duration affecting a child aged >1 month

  • Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes)

  • Kaposi sarcoma

  • Lymphoma, primary, in brain

  • Lymphoma, small, non-cleaved cell (Burkitt), or immunoblastic or large cell lymphoma of B-cell or unknown immunologic phenotype

  • Mycobacterium tuberculosis, disseminated or extrapulmonary

  • Mycobacterium, other species or unidentified species, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)

  • Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)

  • Pneumocystis jiroveci pneumonia

  • Progressive multifocal leukoencephalopathy

  • Salmonella (nontyphoid) septicemia, recurrent

  • Toxoplasmosis of the brain with onset at age >1 month

  • Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings: (a) persistent weight loss >10% of baseline; OR (b) downward crossing of at least two of the following percentile lines on the weight-for-age chart (such as 95th, 75th, 50th, 25th, 5th) in a child ≥1 year of age; OR (c) <5th percentile on weight-for-height chart on two consecutive measurements, ≥30 days apart PLUS (1) chronic diarrhea (i.e., ≥2 loose stools per day for >30 days), OR (2) documented fever (for ≥30 days, intermittent or constant)

Anemia

Thrombocytopenia

Pancreatitis

Hepatotoxicity

Lipoatrophy

Hypersensitivity reaction (abacavir)

Rash

Psychiatric effects (efavirenz)

• Abnormal dreaming

• Insomnia

• Depression

• Anxiety

Hepatotoxicity

Hypersensitivity reaction (nevirapine)

Teratogenic (efavirenz)

Gastrointestinal symptoms (nausea, diarrhea)

Dyslipidemia

Hyperglycemia

Hyperbilirubinemia (atazanavir)

Hepatotoxicity

Nausea, diarrhea, flatulence

Elevations in amylase and liver function tests

Headache

Dizziness, abnormal dreams

Pruritus, rash

Fatigue, muscle pain

Injection site reactions

CD4 count <100 cells/mm³

Elevated antibody titer to organism

Histopathology or PCR

• Pulmonary: Cough, fever, failure to thrive, weight loss

• Extrapulmonary: Most common sites in children are lymph nodes or CNS. However, blood (miliary), cardiac, joint, bone, skin, kidney, eye, and abdomen can be initial sites.

• + Mantoux PPD ≥5 mm

• + Interferon-gamma release assay (IGRA): Caution in those <5 years of age

• Sputum sample with acid fast bacilli (AFB)

• Gastric aspiration (early morning)

• Tissue sampling

• Chest x-ray

• Disseminated disease may progress quickly in infants; prompt initiation of treatment should be considered. Caution with drug–drug interactions with HAART. 4 drug regimen recommended:

  • Ethambutol 20 mg/kg daily dose (max 2.5 g)

  • Isoniazid 10–15 mg/kg daily dose (max 300 mg)

  • Pyrazinamide 30–40 mg/kg daily dose (max 2 g)

  • Rifampin 10–20 mg/kg daily dose (max 600 mg)

• Pulmonary: Less common presentation in children

• Disseminated: More common in children. Rare in first year of life. Symptoms include: fever, night sweats, weight loss, abdominal pain, diarrhea, lymphadenitis

• CD4 counts <50 copies/mm³ or CD4 % ≤15–25% depending on age, with the lower % for younger children

• + Blood culture or culture from site. May use culture of normally sterile site (e.g., bone marrow)

• + AFB stain of blood, sputum, or stool (confirm with culture or PCR testing)

• Perform susceptibility testing to azithromycin and clarithromycin

• Two drug combination therapy for 12 months.

• Preferred regimen:

  • Clarithromycin 7.5–15 mg/kg orally twice daily (max 500 mg per dose) +

  • Ethambutol 15–25 mg/kg once daily (max 2.5 g/day)

  • Severe disease add rifabutin 10–20 mg/kg once daily (max 300 mg daily)

• Alternate regimen:

  • Azithromycin 10–12 mg/kg once daily (max 500 mg daily) may be substituted for clarithromycin

• Secondary prophylaxis is needed after treatment completion.

• Retinitis: Most common presentation; may be unilateral: floaters, central or peripheral visual loss.

• Other sites: GI, liver, kidney, sinuses, or CNS

• Symptoms often nonspecific: Fever, weight loss, odynophagia

• CMV can be isolated in cell culture from blood leukocytes, urine, or tissue

• Positive blood buffy-coat culture

• DNA PCR of blood, fluid, or tissue

• Ophthalmoscopic exam

• Symptomatic congenital infection:

  • Ganciclovir 6 mg/kg IV every 12 hours for 6 weeks

• Disseminated disease and retinitis:

  • Ganciclovir 5–7.5 mg/kg IV every 12 hours for 14–21 days

  • Followed by 5 mg/kg IV per day for 5–7 days per week for chronic suppression

• CNS disease: Also followed by chronic suppression:

  • Ganciclovir 5–7.5 mg/kg IV every 12 hours; PLUS

  • Foscarnet 60 mg/kg IV every 8 hours until symptoms improved

• Usually insidious in onset. May present with focal neurologic deficits, cognitive dysfunction, visual disturbances, paralysis, ataxia, or aphasia.

• PML is generally associated with profound immunosuppression, i.e., CD4% <15.

• MRI of white matter will reveal:

• Deceased signal on T1 images

• Increased signal on T2 and FLAIR sequences

• Presence of JC virus in CNS by PCR in conjunction with MRI findings

• Brain biopsy is gold standard with specificity of 100%, but carries significant risk.

• Poor prognosis in pre-HAART era.

• HAART has increased survival time and is the only treatment that has demonstrated benefit.

• Invasive pulmonary aspergillosis is the most common: Fever, cough, dyspnea, pleuritic pain

• Other sites: Tracheobronchitis, CNS, skin, and sinuses

• Profound immunosuppression (CD4% <15) associated with higher risk

• Blood cultures generally not helpful

• CXR or CT scan for pulmonary involvement

• Biopsy for fungal culture of suspected site

• Invasive pulmonary aspergillosis:

  • Voriconizole 6–8 mg/kg IV every 12 hours for 2 doses followed by 7 mg/kg either IV or orally twice daily for 12 weeks

• Oral thrush and diaper dermatitis occur in a majority of HIV-infected children; primarily caused by C. albicans.

• Esophageal candidiasis presents with odynophagia, retrosternal pain, and children can present with nausea, vomiting, and weight loss.

• Disseminated candidiasis: Blood infections are generally caused by non-albicans species of Candida.

• Oral thrush:

  • Potassium hydroxide preparation of samples will show budding yeast cells.

  • Culture may need to be done in refractory cases or failure of treatment.

• Esophageal thrush:

  • Barium swallow will demonstrate a classic cobblestone appearance

  • Refractory causes may require endoscopy to rule out other causes.

• Disseminated candidiasis:

  • Blood cultures (1–2 days for growth and 1–2 days for speciation)

  • Beta-D-glucan assays (limited validation in children)

  • PCR, but can currently only identify to the Candida species level.

  • Consider ultrasound to identify liver and kidney dissemination

  • Ophthalmology exam to detect eye involvement.

• Oral thrush:

  • Fluconazole 3–6 mg/kg orally once daily (max 400 mg/dose) for 7–14 days.

• Esophageal thrush:

  • Fluconazole 6 mg/kg orally once daily on day 1 followed by 3–6 mg/kg orally once daily (max 400 mg/dose) for 14–21 days.

  • Itraconazole cyclodextrin oral solution 5 mg/kg once daily for 14–21 days.

• Disseminated candidiasis:

  • Amphotericin B 0.5–1.5 mg/kg IV once daily

  • Treat for at least 2–3 weeks after the last positive blood culture.

  • Longer treatment may be needed for some sites (e.g., CNS, lung)

• Pulmonary:

  • Fever, malaise, cough and chest pain.

  • Hemoptysis is less common

• Meningitis:

  • Headache, change in mental status, focal deficits, vomiting often occur. Hydrocephalus is common.

• Disseminated disease:

  • Generalized lymphadenopathy

  • Skin nodules or ulcers

  • Peritonitis

  • Liver involvement

• Tissue histology that shows spherules containing endospores are diagnostic

• Blood cultures and CSF cultures are rarely positive

• Sputum cultures often positive

• Serologic assays, such as complement fixation assays of IgG and IgM may be helpful; however may be falsely negative in severely immunocompromised children.

• Clinical symptoms are nonspecific so consider evaluation in those with travel to endemic areas.

• Pulmonary or disseminated non-meningeal disease:

  • Amphotericin B 0.5–1 mg/kg IV once daily until clinical improvement (min of several weeks).

• Meningeal infection:

  • Fluconazole 5–6 mg/kg IV or orally twice daily (max 800 mg/day).

• Generally occurs in profoundly immunocompromised individuals.

• Meningoencephalitis:

  • Insidious onset

  • Fever, headaches, possibly nuchal rigidity

• Disseminated cryptococcosis:

  • Cutaneous lesions that resemble molluscum contagiosum

  • Nodules

  • Ulcers

• Pulmonary:

  • Rare in children, but may include fever, dry cough, x-ray with focal or diffuse infiltrates.

• Cryptococcal antigen in serum, CSF, or other body fluid is the recommended test.

• CSF analysis:

  • ○ High opening pressure

  • ○ India-ink stained wet mount of CSF (no longer performed in some centers)

• Culture of blood, CSF, and sputum

• CNS disease:

• Acute therapy (2-week induction) is followed by consolidation therapy.

  • Amphotericin B 0.7–1 mg/kg IV daily; PLUS

  • Flucytosine 100 mg/kg orally divided 4 times daily

• Consolidation therapy:

  • Fluconazole 12 mg/kg on day 1, followed by 6-12 mg/kg (max 800 mg daily) either IV or orally for minimum of 8 weeks.

• Localized diseased (not CNS):

  • Fluconazole 12 mg/kg on day 1, followed by 6–12 mg/kg (max 800 mg daily) either IV or orally. Treatment duration varies

• Disseminated disease (no CNS):

  • Amphotericin B 0.7–1 mg/kg IV daily (+/− flucytosine)

• Progressive disseminated histoplasmosis: Most common presentation in HIV-infected children.

  • Prolonged fever

  • Failure to thrive

  • Splenomegaly

  • Cough

  • Lymphadenopathy

  • Ulcerative cutaneous lesions

• Culture is often invasive and slow to grow organism

• EIA probes can detect infection in serum, sputum, and CSF

• CSF can also be tested for histoplasmal antigen.

• Disseminated disease:

  • Itraconazole oral solution. Loading dose of 2–5 mg/kg (max 200 mg) orally for days 1–3, followed by 2–5 mg/kg (max 200 mg) per dose twice daily for 12 months. (Urine antigen should be checked for relapse)

• Pneumonia:

  • Remains a common AIDS defining illness

  • Highest incidence in 1st year of life (3–6 months peak age)

  • Fever

  • Cough (nonproductive)

  • Tachypnea

  • Dyspnea

• CD4 counts are generally <200 cells/mm³ or % <15%.

• Hypoxia is hallmark

• LDH is nonspecific, but often elevated

• Chest x-ray classically shows bilateral diffuse interstitial infiltrates described as “ground glass” in appearance. But, can be normal.

• Stains of sputum (obtained through induced mechanism, bronchoaveolar lavage) include silver stain, toluidine blue, and Wright stain may be used

• Direct fluorescent antibody stains may also be used.

Trimethoprim-Sulfamethoxazole (TMP-SMX) TMP 15–20 mg/kg/day IV or orally divided every 8 hours.

• Duration of treatment is 21 days followed by suppressive therapy.

• In severe disease, corticosteroids may reduce morbidity and mortality

• Cryptosporidiosis:

  • Non-bloody watery diarrhea

  • Abdominal cramping

  • Fever

  • Vomiting

  • Can invade biliary duct causing acalculous cholecystitis or sclerosing cholengitis

• Cryptosporidiosis:

  • EIA is preferred

  • Cannot be cultured

• Microsporidiosis:

  • Trichrome stain

• Cryptosporidiosis:

  • Effective HAART treatment

• Microsporidiosis:

  • Effective HAART treatment

  • Albendazole 7.5 mg/kg (max 400 mg/dose) orally twice daily may be used for disseminated, but not ocular infection for microsporidia other than E. bienuesi.

• Microsporidiosis:

  • Diarrheal illness, non-bloody

  • Hepatitis

  • Peritonitis

  • Myositis

  • Keratoconjunctivitis

  • Cholangitis

• CNS disease:

  • Focal encephalitis

  • Headache

  • Fever

• With progression:

  • Seizures

  • Coma

• Non-CNS presentations are rare in those with HIV/AIDS.

• Congenital toxoplasmosis:

  • Pyrimethamine: Loading dose, 2 mg/kg orally once daily for 2 days, then 1 mg/kg orally once daily for 2–6 months, then 1 mg/kg orally 3 times weekly; PLUS

  • Leucovorin(folinic acid), 10 mg orally or IM with each dose of pyrimethamine; PLUS

  • Sulfadiazine, 50 mg/kg orally twice daily

  • Treatment duration: 12 months

• Acquired toxoplasmosis, acute induction therapy (followed by chronic suppressive therapy):

  • Pyrimethamine: Loading dose, 2 mg/kg (max 50 mg) orally once daily for 3 days, then 1 mg/kg body weight (max 25 mg) orally once daily; PLUS

  • Sulfadiazine, 25–50 mg/kg (max 1.0–1.5 g/dose) orally per dose 4 times daily; PLUS

  • Leucovorin, 10–25 mg orally daily

  • Followed by chronic suppressive therapy

  • Treatment duration (followed by chronic suppressive therapy): ≥6 weeks (longer if clinical or radiologic disease is extensive or response is incomplete at 6 weeks).

• FUO, bacillary angiomatosis, endocarditis, osteomyelitis, splenitis

CD4 count <100 cells/mm³

Elevated antibody titer to organism

Histopathology or PCR

Bacillary angiomatosis, peliosis, bacteremia, and osteomyelitis:

• Doxycycline 100 mg orally per day for 3 months.

Endocarditis:

• Doxycycline 100 mg IV every 12 hours; PLUS

• Gentamycin 1 mg/kg IV every 8 hours for 2 weeks, then

• Doxycycline 100 mg by mouth twice daily for 3 months.

• HIV coinfection can alter the clinical presentation in every stage.

• Primary syphilis: Painless chancre at the site of inoculation.

• Secondary syphilis: Almost any rash, adenopathy, malaise, headache.

• Latent syphilis:

  • ○ Early: Absence of symptoms, but + RPR and treponemal specific confirmatory assay within 12 months of a previously negative RPR

  • ○ Late/Unknown duration: Asymptomatic and + RPR and treponemal specific confirmatory assay over 12 months beyond a previously negative RPR

• Neurosyphilis:

  • ○ Can occur at any stage of syphilis and manifest in varied clinical presentations, such as cranial nerve dysfunction, stroke, meningitis, acute or chronic change in mental status, loss of vibration sense, and auditory or ophthalmic abnormalities. It is important to note that asymptomatic neurosyphilis may be more common in HIV-infected individuals

• Dark-field microscopy, where available, can detect treponemes in primary syphilis.

• Non-treponemal specific screening tests:

  • ○ Venereal Disease Research Laboratory (VDRL)

  • ○ Rapid plasma regain (RPR)

  • ○ Enzyme-linked Assays (EIA)

• RPR allows for the assessment of titer levels

• Treponemal specific confirmatory tests:

• FTA-ABS: Generally remains positive after one episode of syphilis

• Primary, secondary, and early-latent syphilis:

  • Penicillin-G 2.4 million units IM × 1

• Late-latent or syphilis of unknown duration:

  • Penicillin-G 2.4 million units IM weekly × 3 weeks

• Neurosyphilis:

  • Penicillin-G 24 million units IV per day divided every 4 hours for 14 days

• Pulmonary: Cough, fever, night sweats, weight loss

• Extrapulmonary: Blood (miliary), cardiac, joint, bone, skin, kidney, CNS, eye, and abdomen can be initial sites and increasing immunosuppression increases likelihood of extrapulmonary presentation.

• + Mantoux PPD ≥5 mm

• + Interferon-gamma release assay (IGRA)

• Sputum sample with acid fast bacilli (AFB)

• Tissue sampling

• Chest x-ray

• Disseminated disease may progress quickly in infants; prompt initiation of treatment should be considered. Caution with drug–drug interactions with HAART. Four-drug regimen recommended:

  • Ethambutol: Weight-based dosing for 50 kg person, 800 mg daily

  • Isoniazid: 300 mg daily

  • Pyrazinamide: Weight-based dosing for 50 kg person, 1000 mg daily

  • Rifampin: 600 mg daily dose (Note interactions with HAART)

• In patients with AIDS who are not on ART, MAC disease typically is a disseminated, multi-organ infection.

• Early symptoms may be minimal and can precede detectable mycobacteremia by several weeks.

• Symptoms include fever, night sweats, weight loss, fatigue, diarrhea, and abdominal pain.

• CD4 counts <50 copies/mm³

• + Blood culture or culture from site. May use culture of normally sterile site, e.g., bone marrow or lymph node

• + AFB stain of blood, sputum, or stool (confirmation needs to be made with culture or PCR testing)

• Susceptibility testing to azithromycin and clarithromycin is recommended

• Two-drug combination therapy is needed.

• With:

  • Clarithromycin 500 mg orally twice daily+

  • Ethambutol 15 mg/kg orally daily, or

  • Azithromycin 500–600 mg + ethambutol 15 mg/kg orally daily if drug interaction or intolerance precludes the use of clarithromycin

• Duration:

  • At least 12 months of therapy, can discontinue if no signs and symptoms of MAC disease and sustained (>6 months) CD4 count >100 cells/μL in response to ART.

• More common with CD4 count <50 cells/mm³

• Retinitis is the most common manifestation of the disease. Usually unilateral, but can be bilateral: floaters, scotamata, or peripheral visual loss is common.

• Extra-ocular disease: Can affect GI, lung, liver, kidney, sinuses, or CNS

• Symptoms often nonspecific: Fever, weight loss, odynophagia, or profuse bloody diarrhea.

• Pneumonitis is very uncommon

• More common at CD4 <50 cells/mm³

• CMV can be isolated in cell culture from blood leukocytes, urine, or tissue

• Positive blood buffy-coat culture

• DNA PCR of blood, fluid, or tissue

• CMV retinitis:

• Induction therapy: For immediate sight-threatening lesions (adjacent to the optic nerve or fovea):

  • Intravitreal injections of ganciclovir (2 mg) or foscarnet (2.4 mg) for 1–4 doses over a period of 7–10 days to achieve high intraocular concentration faster; PLUS

• Preferred systemic induction therapy:

• Valganciclovir 900 mg orally twice daily for 14–21 days

• For peripheral lesions:

  • Valganciclovir 900 mg orally twice daily for 14–21 days

• Chronic maintenance (secondary prophylaxis):

  • Valganciclovir 900 mg orally daily

• CMV esophagitis or colitis:

  • Ganciclovir 5 mg/kg IV every 12 hours; may switch to valganciclovir 900 mg orally twice daily once the patient can tolerate oral therapy

  • Duration: 21–42 days or until symptoms have resolved

  • Maintenance therapy is usually not necessary, but should be considered after relapses.

• Histologically confirmed CMV pneumonia:

  • Experience for treating CMV pneumonitis in HIV patients is limited.

  • Use of IV ganciclovir or IV foscarnet is reasonable (doses same as for CMV retinitis)

• CMV neurological disease:

• Note: Treatment should be initiated promptly.

  • Ganciclovir 5 mg/kg IV every 12 hours + (foscarnet 90 mg/kg IV every 12 hours or 60 mg/kg IV every 8 hours) to stabilize disease and maximize response, continue until symptomatic improvement and resolution of neurologic symptoms.

• The optimal duration of therapy and the role of oral valganciclovir have not been established for pulmonary or CNS CMV.

• Usually insidious in onset. May present with focal neurologic deficits, cognitive dysfunction, visual disturbances, paralysis, ataxia, or aphasia.

• PML is generally associated with profound immunosuppression, i.e., CD4 count <100–200 cells/mm^3.

• MRI of white matter will reveal:

• Deceased signal on T1 images

• Increased signal on T2 and FLAIR sequences

• Presence of JC virus in CNS by PCR in conjunction with MRI findings

• Brain biopsy is gold standard with specificity of 100%, but carries significant risk.

• Poor prognosis in pre-HAART era.

• HAART has increased survival time and is the only treatment that has demonstrated benefit.

• Invasive pulmonary aspergillosis is the most common presentation: Fever, cough, dyspnea, pleuritic pain, necrotizing pneumonia

• Other presentations include: Tracheobronchitis, CNS disease, skin, sinus disease

• Profound immunosuppression (<100 CD4 cells/mm³) associated with higher risk

• Blood cultures generally not helpful

• CXR or CT scan for pulmonary involvement

• Fungal histology/culture of suspected site

• BAL galactomannan is very specific

• Invasive pulmonary aspergillosis:

  • Voriconizole 6–8 mg/kg IV every 12 hours for 2 doses followed by 7 mg/kg either IV or orally twice daily for 12 weeks

• Oral thrush: Primarily caused by C. albicans. Oral thrush characteristically presents white patches with underlying inflamed mucosa when the patch is removed. Other presentations are possible.

• Oral thrush:

  • May be made clinically

  • Potassium hydroxide preparation of samples will show budding yeast cells.

• Oral thrush:

  • Fluconazole 100 mg orally daily for 7–14 days.

• Esophageal candidiasis presents with odynophagia, retrosternal pain.

• Vulvovaginal candidiasis: Presents similarly to HIV-uninfected women with a white, cottage-cheese-like vaginal discharge and vaginal itching.

• Culture may need to be done in refractory cases or failure of treatment.

• Esophageal thrush:

  • Barium swallow will demonstrate a classic cobblestone appearance

  • Refractory causes may require endoscopy to rule out other causes.

• Vulvovaginal candidiasis:

  • May be made clinically

  • Potassium hydroxide preparation of samples will show budding yeast cells and hyphae.

• Esophageal thrush:

  • Fluconazole 100 mg orally once daily for 14–21 days.

  • Itraconazole oral solution 200 mg once daily for 14–21 days.

• Pulmonary:

  • Fever, malaise, and chest pain.

  • Cough and hemoptysis is a rare presentation

• Meningitis:

  • Headache, change in mental status, focal deficits, vomiting often occur. Hydrocephalus is common

• Disseminated disease:

  • Generalized lymphadenopathy

  • Skin nodules or ulcers

  • Peritonitis

  • Liver involvement

• Tissue histology that shows spherules containing endospores are diagnostic

• Blood cultures and CSF cultures are rarely positive

• Sputum cultures often positive.

• A coccidioidomycosis-specific antigen is available for urine and serum and is useful in making the diagnosis

• Mild disease (e.g., focal pneumonia):

  • Fluconazole 400 mg orally daily

• Severe, non-CNS infection, or disseminated disease:

  • Liposomal amphotericin B 4–6 mg/kg IV daily until clinical improvement and then switch to an azole.

• Meningeal infection:

  • Fluconazole 400–800 mg IV or orally daily.

• Chronic suppressive therapy:

  • Fluconazole 400 mg orally daily

• Generally occurs in profoundly immunocomprised individuals.

• Meningoencephalitis:

  • Insidious onset

  • Fever, headaches, possibly nuchal rigidity

• Disseminated cryptococcosis:

  • Cutaneous lesions that resemble molluscum contagiosum

  • Nodules

  • Ulcers

• Pulmonary:

  • May include fever, dry cough, x-ray with focal or diffuse infiltrates.

  • Mimics PCP

• Cryptococcal antigen in serum, CSF, or other body fluid is effective for rapid diagnosis

• CSF analysis:

  • ○ High opening pressure (≥25 cm H₂O)

  • ○ India-ink stained wet mount of CSF

• Culture of blood, CSF, and sputum

• CNS disease:

• Acute therapy (2-week induction) is followed by consolidation therapy.

  • Liposomal amphotericin B 3–4 mg/kg IV daily; PLUS

  • Flucytosine 100 mg/kg orally divided 4 times daily (renal dosing needed)

• Consolidation therapy: For minimum of 8 weeks followed by maintenance therapy.

  • Fluconazole 400 mg daily either IV or orally

• Maintenance therapy:

  • Fluconazole 200 mg orally daily for at least 12 months.

• Non-CNS, extrapulmonary, and diffuse pulmonary disease:

  • Treat the same as meningitis above.

• Non-CNS with mild to moderate symptoms and focal pulmonary infiltrates:

  • Fluconazole 400 mg orally daily for 12 months.

• Progressive disseminated histoplasmosis:

  • Prolonged fever

  • Hepatosplenomegaly

  • Fatigue

  • Cough

  • Weight Loss

• Histoplasma antigen in blood or urine is sensitive for rapid diagnosis of acute pulmonary disease and disseminated disease

• Culture is often invasive and slow to grow organism

• EIA probes can detect infection in serum, sputum, and CSF

• Moderately severe to severe disseminated disease:

• Induction therapy (for at least 2 weeks or until clinically improved):

  • Liposomal amphotericin B 3 mg/kg IV daily

• Maintenance therapy:

  • Itraconazole 200 mg orally three times daily for 3 days, then 200 mg orally twice daily.

• CNS disease:

  • Fever

  • Headache

  • Focal deficits

• GI disease:

  • Diarrhea

  • Abdominal pain

  • Weight loss

• Pulmonary disease:

  • Cough

  • Fever

  • Pleuritic chest pain

• CSF can also be tested for histoplasmal antigen.

• Less severe disseminated disease:

• Induction and maintenance therapy:

  • Itraconazole 200 mg orally thrice daily for 3 days, then 200 mg orally twice daily for at least 12 months

• Meningitis:

• Induction therapy (4–6 weeks):

  • Liposomal amphotericin B 5 mg/kg/day IV daily

• Maintenance therapy:

• Itraconazole 200 mg orally twice daily for ≥1 year and until resolution of abnormal CSF findings

• Pneumonia:

  • Often subacute onset

  • Fever

  • Cough (nonproductive)

  • Tachypnea

  • Dyspnea

• CD4 counts are generally <200 cells/mm³ or % <14%.

• Hypoxia is hallmark

• LDH is nonspecific, but often elevated

• Chest x-ray classically shows bilateral diffuse interstitial infiltrates described as “ground glass” in appearance. But, can be normal.

• Stains of sputum (obtained through induced mechanism, bronchoaveolar lavage) include silver stain, toluidine blue, and Wright stain may be used

• Direct fluorescent antibody stains may also be used.

• Trimethoprim-Sulfamethoxazole (TMP-SMX) TMP 15–20 mg/kg/day IV or orally divided every 8 hours.

• Duration of treatment is 21 days followed by suppressive therapy.

• In severe disease, corticosteroids reduce morbidity and mortality

• Cryptosporidiosis:

  • Non-bloody watery diarrhea

  • Abdominal cramping

  • Fever

  • Vomiting

  • Can invade biliary duct causing acalculous cholecystitis or sclerosing cholengitis

• Microsporidiosis:

  • Diarrheal illness, non-bloody

  • Hepatitis

  • Peritonitis

  • Myositis

  • Keratoconjunctivitis

  • Cholangitis

• Cryptosporidiosis:

  • EIA is preferred

  • Cannot be cultured

• Microsporidiosis:

  • Trichrome stain

• Cryptosporidiosis:

  • Effective HAART treatment

• Microsporidiosis:

  • Effective HAART treatment

  • Albendazole 7.5 mg/kg (max 400 mg/dose) orally twice daily may be used for disseminated, but not ocular infection for microsporidia other than E. bienuesi.

• CNS disease: The most common clinical presentation.

  • Focal encephalitis

  • Headache

  • Fever

• With progression:

  • Seizures

  • Coma

• Non-CNS presentations are rare in those with HIV/AIDS.

• CT or MRI with contrast will show ring-enhancing lesions in the gray matter of the cortex or basal ganglia. Edema is often present.

• IgG antibodies are uniformly present.

• Stereotactic CT-guided brain biopsy is the only definitive diagnostic tool.

• Detection of Toxoplasma gondii by PCR in CSF is very specific, but has low sensitivity.

• Treatment of acute infection:

  • Pyrimethamine 200 mg orally 1 time, followed by weight-based therapy:

  • If <60 kg, pyrimethamine 50 mg orally once daily + sulfadiazine 1000 mg orally every 6 hours + leucovorin 10–25 mg orally once daily

  • If ≥60 kg, pyrimethamine 75 mg orally once daily + sulfadiazine 1500 mg orally every 6 hours + leucovorin 10–25 mg orally once daily

  • Leucovorin dose can be increased to 50 mg daily or twice daily.

• Duration for acute therapy:

  • At least 6 weeks longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.

• Chronic maintenance therapy:

  • Pyrimethamine 25–50 mg orally daily + sulfadiazine 2000–4000 mg orally daily (in 2–4 divided doses) + leucovorin 10–25 mg orally daily. This should be continued for at least 6 months after CD4 counts have exceeded 200 cells/mm³ before consideration of stopping secondary prophylaxis.