Opportunistic Infections in AIDS

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Opportunistic Infections in AIDS
Beata Casanas, D.O. Assistant Professor Division
of Infectious Diseases University of South Florida
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Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
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Complications Based on CD4 Cell Count

• Stage of HIV disease
• Risks differ depending on CD4 count
• Determine prophylaxis for OIs
• Helps assess response to ARV
• Can vary with concurrent illness, vaccination,
  and diurnal
• Can determine AIDS definition (CD4lt200)

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HIV-Related Complications
CD4gt300 CD4lt200 Lymphadenopathy Esophagitis
Pneumonia (Strep) Thrush Candida Vaginitis TB
PCP Cryptococcus
Cryptosporidium KS
Lymphoma CD4lt100 Toxoplasmosis Zoster PML
CMV MAC
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Pneumocystis Carinii (PCP)

• Pneumonia with hypoxemia
• Insidious
• CXR with bilateral disease but can vary
• High morbidity and mortality
• CD4 generally below 200 or lt 14
• Significant alveolar disease (elevated LDH)
• Silver stain of sputum or BAL for diagnosis

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PCP - Interstitial Infiltrates
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Treatment of PCP

• Determine level of hypoxemia and need for
  hospitalization
• TMP-SMX is the most efficacious treatment
• Alternatives exist in those allergic to sulfa
• Steroids indicated if pO2 lt 70
• May get worse before improvement seen
• Usually need to R/O other pathogens

8
Prevention of PCP

• Oral TMP-SMX is prophylaxis of choice
• Alternatives exist (dapsone, pentamidine, etc)
• 10 prophylaxis CD4 lt 200
• 20 prophylaxis with history of prior PCP
• Still being determined is whether prophylaxis can
  be withdrawn after beneficial effects of HAART

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CNS Toxo vs CNS Lymphoma
Toxoplasmosis Lymphoma Toxo IgG Toxo IgG
- Multiple lesions Single lesion No
TMP-SMX TMP-SMX prophy Responds
empirically No response
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Toxoplasmosis
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Treatment / Prevention of Toxo

• Rx Sulfadiazine Pyrimeth. Folinic Acid
• Sulfa allergic Clinda Pyrimeth. Folinic A.
• Repeat MRI to make sure lesions smaller
• Maintenance therapy after induction
• Consider steroids and anticonvulsants
• TMP-SMX is adequate 10 prophylaxis
• dapsone and pentamidine is not protective
• should protect when CD4 lt 100 if IgG

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Cryptococcal Meningitis

• Very subtle presentation at times
• HA, fever, lethargy, nausea
• Imaging studies usually normal
• CSF generally with high opening pressure, mild
  lymphocytic pleocytosis
• CSF with India Ink, crypto Ag, yeast
• Serum crypto Ag can screen HIV cohorts

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Cryptococcus - India Ink Stain
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Treatment of Crypto Meningitis

• Most induce with ampho B /- 5FC
• Can also use high dose fluconazole if unable to
  tolerate Ampho B
• Will need chronic maintenance to control
  infection as cannot be generally cured
• High risk for recurrent elevated ICP which can
  result in hydrocephalous
• May require periodic removal of CSF

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CMV Retinitis

• Results in floaters and decreased vision
• Seen in those with CD4 lt 50-100
• Diagnosis by ophthalmologic exam
• It is a disseminating infection
• Difficult systemic treatment with an induction
  and maintenance treatment
• gancyclovir, foscarnet, cidofovir

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Mycobacterium Avium Complex

• Not uncommon when CD4 lt 75
• Chronic constitutional symptoms such as fever,
  sweats, and weight loss
• Labs may reveal anemia, leukopenia,and elevated
  alk phos
• CT of abdomen may see periaortic or
  retroperitoneal adenopathy and HSM with a
  relative paucity of peripheral adenopathy

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MAC Diagnosis and Treatment

• AFB BC has high yield but takes weeks
• Bone marrow staining and culture
• Treatment requires a minimum of 2 meds
  chronically as it is quite resistant
• macrolide, ethambutol (amikacin, rifabutin,
  cipro)
• 10 Prophylaxis with macrolide in those with CD4
  lt75

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Oropharyngeal Infections

• Candidiasis
• Oral Hairy Leukoplakia (OHL)
• Ulcer Disease
• Periodontal Disease
• Kaposis Sarcoma

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Oral Candidiasis

• gt60 of patients with CD4 lt100 cells/mm3
• Often Asymptomatic or altered taste, burning,
  odynophagia
• Four Forms
• Pseudomembranous
• Erythematous
• Angular Cheilitis
• Hyperkeratotic

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Pseudomembranous Oral Candidiasis
White patches that can be scraped off leaving
erythematous base
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Erythematous Oral Candidiasis
Smooth red patches, found on tongue and cheeks
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Angular Cheilitis
Cracking and fissures at corner of mouth
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Hyperkeratotic Oral Candidiasis
Thickened white patches, do not scrape off
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Oral Candidiasis Diagnosis

• Diagnosis is often clinical, based on typical
  appearance
• KOH preparation of scraping for hyphae,
  pseudohyphae, and budding yeast
• Helpful especially for erythematous and
  hyperkeratotic disease

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Oral Candidiasis Treatment

• Initial topical therapy
• Clotrimazole troches 10mg 5x/day
• Nystatin swish swallow 500,000 units QID
• Refractory to topical treatment
• Fluconazole 100 mg QD
• Itraconazole 100 mg BID

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Oral Candidiasis Treatment

• Fluconazole Refractory Disease
• Higher dose fluconazole (200-800 mg/d)
• Itraconazole 200 mg BID
• Amphotericin B 0.3-0.5 mg/kg/day
• Capsofungin 50mg IV QD
• Duration of Therapy
• 7-14 days or until disease resolution

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Oral Candidiasis Treatment

• Relapsing Disease
• Intermittent therapy vs. chronic suppressive
  treatment
• Decreased azole resistance with chronic
  suppression vs. intermittent therapy if
  recurrences are very frequent.
• Avoid maintenance therapy unless relapses are
  frequent increased azole resistance

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Oral Hairy Leukoplakia

• Caused by Epstein-Barr Virus infection
• Does not scrape off with tongue blade
• NOT a premalignant condition
• Targeted therapy not recommended
• Responds to HAART

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Oral Hairy Leukoplakia
Linear white patches at edge of tongue. Do not
scrape off.
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Oral Ulcer Diseases

• Several Etiologies
• Most Important Differential Diagnoses
• Herpes Simplex Virus
• Cytomegalovirus
• Aphthous Ulcers

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Herpes Simplex Virus

• Multiple vesicular lesions of lips, buccal
  mucosa, soft palate
• Diagnosis often clinical, also may diagnose by
  Tzanck smear, viral culture, immunofluorescence
  assay
• Treatment recommended in patients with HIV

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Herpes Simplex Virus
Multiple ulcers with some confluence of buccal
mucosa
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Herpes Simplex Virus
Tzanck smear with multinucleated giant cells
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Herpes Simplex VirusTreatment

• Oral Therapy
• Acyclovir 400 mg 5x/day 14-21d
• Famciclovir 500 mg BID x 7d
• Valacyclovir 1g PO BID x 7d
• Parenteral Therapy (severe disease)
• Acyclovir 5mg/kg q 8 hours
• Foscarnet or Cidofovir
• for acyclovir resistant disease

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Cytomegalovirus (CMV)

• Visually indistinguishable from HSV oral ulcer
  disease
• Often associated with other systemic
  manifestations of CMV (esophagitis, colitis,
  retinitis)
• Usually diagnosed in HSV refractory to therapy
• Viral Culture/ cytology, IFA, CMV serum antigen
  testing, CMV PCR

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CMV Oral Ulcers
Viral swab demonstrated typical owls eye
intracytoplasmic inclusions. CMV PCR ()
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CMV - Treatment

• Limited oral ulcer disease management unclear,
  but likely a precursor to manifestation at other
  site (esophagitis, colitis, retinitis)
• Induction Therapy
• Ganciclovir 5mg/kg IV Q 12 hours
• Valganciclovir 900 mg BID
• Foscarnet 90 mg IV Q 12 hours
• Cidofovir 5 mg/kg IV q week PLUS
• Probenecid (to decrease renal toxicity)
• Each then followed by suppressive treatment

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Aphthous Ulcers

• Present as crops of ulcers from 1-2 mm to 2-3 cm
• Painful lesions lead to odynophagia, dysphagia,
  secondary weight loss
• Can involve esophagus, other parts of GI tract
• Visually similar to HSV and CMV

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Aphthous Ulcers
1.5 cm ulcer of buccal mucosa
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Aphthous Ulcers

• Diagnosis
• viral studies for HSV, CMV (-)
• Biopsy nonspecific inflammatory changes
• Treatment
• Anesthetic mouth washes
• Topical fluocinonide 0.05
• SEVERE DISEASE
• Prednisone 40 mg/day 4-6 weeks
• Thalidomide 200 mg po QD

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Kaposis Sarcoma

• Can involve any portion of the GI tract.
• Usually symptomatic if oral lesions or intestinal
  obstruction
• Associated with HHV-8 infection

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Oral Kaposis Sarcoma
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Kaposis Sarcoma

• Presentation
• Usually in patients with CD4 lt200 cells/mm3
• Skin most common site of involvement, but GI
  tract involved in 40 of visceral cases
• Diagnosis
• Usually based on pathologic specimen
• Must be distinguished from Bacillary Angiomatosis
  (Bartonella Henselae)

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Kaposis Sarcoma Treatment

• Often improves with HAART
• Localized Disease
• HAART
• Sclerotherapy
• Intralesional Chemotherapy
• Cryotherapy
• Radiation therapy
• Widespread
• Systemic Chemotherapy
• interferon-alfa ,etoposide, vincristine,
  vinblastine and bleomycin

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AIDS Cholangiopathy

• Late manifestation of HIV
• CD4 lt 100 cells/mm3
• May be present with or without papillary stenosis
• Clinical Presentation
• Fever, RUQ pain, nausea, vomiting. Weight loss
• Markedly Elevated Alkaline Phosphatase
• Causes Include
• Cryptosporidium, CMV, microsporidia
• 40 of cases no clear etiology

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AIDS Cholangiopathy

• Diagnosis
• Ultrasound may be normal or show intra- and
  extra-hepatic ductal dilatation
• ERCP allows imaging of biliary ductal system,
  sampling of fluid for culture and cytology
• Treatment
• Sphincterotomy for papillary stenosis, biliary
  stents, targeted therapy at causative agent (if
  identified)

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Diarrhea in HIV/AIDS

• Occurs in 50-60 of AIDS patients
• Evaluation should include travel history, pets,
  medications, foods
• Stool studies
• Stool culture for Shigella, Salmonella, E. Coli,
  campylobacter
• Stool OP, acid fast staining
• C. Difficile Toxin Assay
• If Fever Blood Culture, AFB blood Culture, CMV
  Antigenemia/ PP65

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Salmonella

• Commonly S. typhimurium, S. enteritidis
• 20-100 greater incidence in AIDS
• Bacteremia common
• Recurrent bacteremia AIDS defining
• Diagnosis stool and/or blood cultures
• Treatment ciprofloxacin, ceftriaxone,
  amoxicillin, TMP/SMX
• Suppressive Therapy consider for recurrent
  disease

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Shigella

• S. flexneri, S. dysenteriae
• Presentation bloody diarrhea, fever, abdominal
  pain
• Complications megacolon, perforation, bacteremia
  (50)
• Treatment Same as salmonella
• ciprofloxacin, ceftriaxone, amoxicillin, TMP/SMX

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Clostridium Difficile

• Approximately 8 of AIDS diarrhea
• Diagnosis
• Detection of toxin in stool
• Thickened bowel wall on CT
• Pseudomembrane on colonoscopy
• Treatment
• Metronidazole 250 mg po QID x 10-14 days
• Vancomycin 125 mg po QID x 10-14 days (if failure
  of metronidazole)

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Mycobacterium Avium Complex

• Usually seen with CD4 lt100 cells/mm3
• Presentation fever, abdominal pain, diarrhea,
  weight loss
• Diagnosis
• Culture stool, tissue, blood
• CT scan hepatosplenomegally, abdominal
  lymphadenopathy
• Treatment
• Clarithromycin 500 mg BID OR azithromycin 500 mg
  po QD
• PLUS ethambutol 15-20 mg/kg/day

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Cryptosporidium

• Found in stool of 10-20 of AIDS patients with
  diarrhea
• Acquired via contaminated water or fecal-oral
  route
• May also cause biliary tract disease
• Diagnosed by acid fast stain of stool,
  immunofluorescence

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Cryptosporidium
Acid-fast stain of stool demonstrating oocysts
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Cryptosporidium Treatment

• Mainstay is restoration of immunity with HAART
• Specific Therapy (disappointing efficacy)
• Paromomycin 1500-2000 mg/d x 14-28 days then 500
  mg BID
• Paromomycin 1 g BID PLUS Azithromycin 600 mg QD x
  28 days THEN Paromomycin alone
• Octreotide 50-500 units SQ TID
• Reduces stool volume
• Nitazoxanide 500 mg BID
• Currently under clinical trial

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Isospora Belli

• Acid Fast protozoan
• Symptoms watery diarrhea, weight loss, cramps
• AFB of stool larger than cryptosporidium
  typical elliptical shape
• Treatment TMP/SMX DS po QID x 10 days
• Pyrimethamine (for sulfa allergy)

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Isospora Belli
Oocyte on modified acid-fast stain of stool
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Microsporidia

• 2 species implicated in most diarrheal disease in
  AIDS
• Enterocytozoon bieneusi
• Encephalitazoon intestinalis
• Found in 5-50 of AIDS patients with unexplained
  diarrhea
• Clinical chronic non-bloody diarrhea,
  malabsorption, cholangitis, cholecystitis

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Microsporidia

• Diagnosis
• stool modified trichrome or chemofluorescent
  staining
• Small bowel biopsy
• Treatment
• Albendazole 400-800 mg PO gt21 days for E.
  septata
• E. bieneusi limited efficacy
• Metronidazole, atovaquone

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AIDS Wasting Syndrome

• Unintentional Loss of 10 of body weight
• AIDS defining illness in 15-20 of cases
• Contributing factors
• Medication related anorexia, depression,
  oral/esophageal disease, malabsorption

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AIDS Wasting Syndrome

• Treatment
• Nutritional Supplements
• Oral supplements usually adequate
• TPN for excessive diarrhea from cryptosporidiosis
• Appetite Stimulants
• Megestrol, Dronabinol weight gain mostly fat
• Resistance Exercise

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AIDS Wasting Syndrome

• Anabolic Steroids
• Most weight gain is lean body mass
  (anabolicgtandrogenic effect)
• Nandrolone
• Oxandrolone
• Oxymetholone
• Testosterone
• Indicated for hypogonadism with or without
  wasting
• Improved quality of life, libido, energy, lean
  body mass

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Non TB Mycobacteria

• MAC rarely cause pulmonary disease
• M.kansasii most common
• CD4lt 50
• Interstitial / lobar pneumonia
• Nodules, cavities, adenopathy
• Diagnosis Cx from respiratory specimen
• Treatment RIF/ETB/INH 15-18 mo

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CMV Pneumonias

• Most important AIDS associated viral pulmonary
  pathogen
• Late
• B/L interstitial/alveolar infiltrates
• Diagnosis
• CMV culture( not specific)
• CMV inclusions

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CMV Treatment

• GCV 2.5 mg/kg Q 8h x 20 d or Valgancyclovir 900
  mg BID
• IVIG 500mg/kg QOD x 10 days
• then GCV 5 mg/kg/d x3-5/wk IVIG 500mg/kg
  2x/wk x8 doses
• Foscarnet 90 mg/kg IV Q 12h x 14-21 days
• then 90 mg/kg QD maintenance
• Cidofovir 5 mg/kg IV Q wk w/ probenecid

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Pulmonary Cryptococcosis

• Inhaled pathogen
• lt15 develop pneumonia
• UL lesions, lobar, B/L, miliary pneumonia
• Pleural effusion, cryptococcoma
• Cavity rare
• meningitis primary presentation in HIV

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Pulmonary Cryptococcosis

• Treatment
• Ampho B 0.7-1 mg/kg/d 5-FC 25 mg/kg q 6h x 2
  wks
• Then Fluconazole 400 mg/d x 10wks
• Suppression 200 mg/d until CD4 gt 100
• Surgery for cryptococcoma

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Pulmonary Penicillosis

• Endemic SE Asia, China, Manipur State of India
• Thermally dimorphic fungus
• Infiltrates, nodules, cavities, abscess,
  adenopathy
• Disseminated diseases
• Diagnosis Fungal Culture
• Treatment Ampho B? Itra, 50 relapse

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Rhodococcus equi

• GP coccobacilli
• Synergistic hemolysis
• Antagonism IMP, ß-lactam

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Rhodococcus equi

• TB like syndrome with negative smear
• cavitary/nodular pneumonia
• bacteremia
• ½ extrapulmonary
• 2/3 mortality
• Tx 2-3 drugs
• Vanc, IMP,AMG, cipro, Rifampim, E-mycin

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Non Infectious Pulmonary Diseases

• KS
• Lymphoma
• Nonspecific interstitial pneumonitis
• Lymphocytic interstitial pneumonitis
• BOOP
• PE

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TB Early Clinical Picture

• General complaints
• non-specific
• excessive fatigue
• weight loss
• anorexia
• irritability
• Symptoms of chronic infection
• low-grade fever
• night sweats
• vague digestive disturbances
• recurrent headaches

82
TB Early Clinical Picture

• SPUTUM
• at first dry, and later productive
• purulent sputum
• hemoptysis
• Pleuritic pain from TB pleurisy with effusion,
  may be a presenting symptom in early stages
• Cough rarely associated with pulmonary TB in
  children.

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Severe Pulmonary TB

• Most INFECTIOUS CASES
• Extensive cavities
• Positive smear
• High bacilli output
• gt 10 /HPField or gt500,000/ml
• High mortality
• without treatment (75)
• Very infectious
• 50 of close contacts infected
• RAPID evolution

84
Chest Xrays in TB Control

• DIAGNOSTIC EXAMINATION of a suspected case
• EVALUATION OF A CASE during treatment
• BUT not a substitute to SPUTUM EXAM
• only sputum monitors response of MTB to drugs
• only sputum provides early warning about
  resistance
• BASELINE XRAY at the end of treatment
• Evaluation of a CONTACT or an INFECTED

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Tuberculin Test
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Tuberculosis Screening Skin Tests

• 15mm
• Person from LOW prevalence area
• NO medical risk factors
• NO known exposure to TB
• 10mm
• Person from HIGH prevalence area
• Asia, Africa, Latin America ³1
• MEDICAL RISK factors
• 5mm
• CLOSE CONTACTS to infectious TB
• OLD TB LESIONS
• HIV INFECTION

87
TB Treatment

• Start with 4 drugs in all patients
• INH, RIF, PZA and EMB or SM until sensitivities
  return
• If pan sensitive, D/C EMB or SM
• After 2 months of therapy, D/C PZA
• Continue INH RIF for 4 more months for total of
  6 months
• Must have culture conversion by 2 months
• 6 month regimen good for HIV(-) and ()
• Can use BIW regimen / TIW for HIV ()
• Monitor adherence and toxicity
• DOT, combination pills for self administered
  (exceptions)

88
Resistance

• Primary resistance to any of the 4 major drugs
  (INH, Rif, Emb, Sm) was estimated at 12 in the
  USA in 1995. It ranged in 1994-97 from a low of
  2.0 in the Czech Republic to a high of 41 in the
  Dominican Republic (Global surveillance for
  anti-tb drug resistance. NEJM 1998, 338,23).
• Median prevalences were
• INH 7.3
• Streptomycin 6.5
• Rifampin 1.8
• Ethambutol 1
• All 4 0.2

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Clinical Significance of Resistance

• If pan sensitivegt95 chance of cure
• If resistant to INHgt90 chance of cure
• If resistant to rifampingt70 chance of cure
• If resistant to INH and RIF50 chance of cure
• Before chemotherapy50 chance of cure

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Causes of Resistance

• Irregular Self Administration with Failure to
  closely supervise
• Care of patients by non specialists
• Increased immigration

91
Epidemiology of TB and HIV

• Both have afflicted similar populations
• Both are socially stigmatizing
• Globally, TB is the 2nd leading cause of death
  from an infectious disease (behind HIV)
• TB is the leading cause of death in HIV globally
• Active TB may accelerate HIV replication

92
TB/HIV Epidemiology

• Thirty-six million HIV infected individuals
  worldwide
• One-third of them co-infected with MTB
• 68- Sub Saharan Africa, 22- SEA
• Leading cause of death amongst HIV infected
  individuals worldwide
• Prevalence of HIV in TB patients (India) 20

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Estimated HIV Coinfection in Persons
Reportedwith TB, United States, 19932003
Coinfection
Note Minimum estimates based on reported
HIV-positive status among all TB cases in the
age group.
All case counts and rates for 19932002 have been
revised based on updates received by CDC as of
April 1, 2005.
94
TB/HIV Pathogenesis

• Immunity to MTB partly under control of MHC Class
  II restricted CD4 cells
• Loss of CD4 cells increases risk of
• Reactivation of latent infection
• Primary infection
• Active TB up-regulates HIV replication, leading
  to accelerated progression of HIV

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TB/HIV Pathogenesis

• Life time risk in HIV negative persons 10
• 5 within first two years
• 5 remainder of their lives
• HIV positive persons have 8 risk per year
• HIV incidence 5-16/100 person-years
• Two mechanism
• Reactivation
• Re-infection
• Immune reconstitution TB on HAART

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HIV/TB Treatment

• Do you need to add higher number of drugs?
• Do you need to prolong duration of therapy?
• Can ARV be used concomitantly with ATT
  (anti-Tuberculosis Therapy)?
• Is there increased incidence of AEs?
• Is there increased incidence of MDR-TB?
• Should latent tuberculosis be treated?
  (international)

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REFERENCES
aidsinfo.nih.gov