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17 June 2010 Opportunistic Infections H. Nina Kim, MD, MSc

17 June 2010 Opportunistic Infections H. Nina Kim, MD, MSc. Case 1. 43 yo man with HIV c/o bilateral R>L leg swelling and new lesion on his thigh. Has been feeling well, denies any fevers/nightsweats. ROS: Negative for cough/SOB, abd pain or change in stools. PMH: Stage 3 HIV, dx 1999

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17 June 2010 Opportunistic Infections H. Nina Kim, MD, MSc

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  1. 17 June 2010 Opportunistic Infections H. Nina Kim, MD, MSc

  2. Case 1 43 yo man with HIV c/o bilateral R>L leg swelling and new lesion on his thigh. Has been feeling well, denies any fevers/nightsweats. ROS: Negative for cough/SOB, abd pain or change in stools. PMH: Stage 3 HIV, dx 1999 Nadir CD4 45  current 158 cells/mm3 Hx Pneumocystis pneumonia in 1999 Hx oral candidiasis Current Meds: Truvada 1 tab PO qDay Kaletra 2 tabs PO BID TMP-SMX 1 DS tab PO qDay

  3. Physical Exam & Labs T 37.9°C HR 100 BP 130/69, RR 18 General – Fatigue-appearing man, no distress. HEENT – oral thrush. Chest – clear to auscultation. Cardiac – regular tachycardic, 2/6 systolic ejection murmur. ABD – normal bowel tones, no organomegaly, non-tender. Lymphatic – no adenopathy. Neuro – Alert, oriented x 4. O/W unremarkable. SKIN: … LAB: CD4 158. HIV RNA <30. Chemistries WNL including liver function panel.

  4. “Face of AIDS” • In 1981, emergence of KS among young gay men in New York, Los Angeles, San Francisco heralded start of AIDS epidemic • AIDS initially called “Kaposi’s Sarcoma & Opportunistic Infections” (KSOI) • Most common malignancy of AIDS patients • 20,000-fold higher risk to that of general population • 70-fold higher risk to that of other immunosuppressed groups

  5. Kaposi Sarcoma (KS) • Neoplasm • Skin • Mucous membranes • Lymphatic system • Viscera (pulmonary, GI tract) • Four variants • Classic KS (elderly men of E.Europe, Mediterranean descent) • Endemic African KS • Transplantation-related KS • Epidemic HIV-associated KS

  6. Kaposi Sarcoma (KS) • Histopathology • Dilated vessels, vascular slits • Spindle cells • RBCs, hemosiderin deposits • Inflammatory cells • Vascular hyperplasia or true neoplastic growth? • Monoclonal cancer  clonal outgrowth of spindle cells Johns Hopkins Autopsy Resource Image Archive Rabkin et. al. N Engl J Med 1997 Apr; 336:988-93.

  7. Novel herpes viral genome discovered in AIDS-KS tumor specimens in 1994 • Human herpes virus type 8 (HHV-8) or KSHV  targets spindle cell Chang et. al., Science 1994 Dec; 266:1865-9. www.aids-images.ch

  8. HHV-8 • Gamma herpesvirus. • Viral genes homologous to human genes • Tumorigenesis • Kaposi sarcoma • Multicentric Castleman’s disease • Primary effusion (body cavity) lymphoma (also EBV-associated) • Epidemiology (transmission, risk factors) still being worked out • HHV-8 viremia • 0-52% of KS patients viremic at any given time • Portends development of KS in several studies • HHV-8 in PBMC (not plasma) correlates with KS severity Casper, “HHV-8, KS & AIDS-associated Neoplasms.” Accessed www.hivinsite.com

  9. Global distribution of HHV-8 www.aids-images.ch

  10. Global distribution of KS Cancer Research UK www.info.cancerresearchuk.org/cancerstats

  11. Malignancies in Uganda:1982-2000 Kaharuza et. al. Int Conf AIDS 2004 Jul; 15: Abstract C11879.

  12. Clinical Features of KS • Wide spectrum of disease • Skin lesions • Brown, red, violaceous • Macules, papules, plaques, nodules • Differential Dx: • Bacillary angiomatosis • Pyogenic granuloma • Cutaneous manifestation of lymphoma • Angiosarcoma • Visceral involvement • GI tract (asymptomatic, abd pain, diarrhea, bleeding) • Pulmonary (asymptomatic, SOB, cough)  poor prognosis

  13. Courtesy of Dr. Virginia Broudy

  14. Courtesy of Dr. Virginia Broudy

  15. www.hivwebstudy.com www.idimages.org www.hab.hrsa.gov

  16. Staging of KS * >2 weeks of unexplained fever, night sweats, involuntary weight loss >10%, diarrhea AIDS Clinical Trial Group Krown et. al. J Clin Oncol 1997 Sep;15:3085-92.

  17. Survival with KS in HAART era Palmieri, et. al. HIV Medicine 2006 July; 7: 291-3.

  18. Treatment of KS • No universally effective therapy • Palliative. • Main indications are visceral disease, lymphedema & if KS bothers pt (e.g. symptomatic foot disease, facial lesions) • Tailor to individual patient • HAART • Local therapy • Radiation, cryotherapy, topical retinoids, intralesional chemo • Systemic chemotherapy • Liposomal anthracyclines (Doxil) – highest remission rates (60-80%) • Paclitaxel – partial remission seen in up to 60% • IFN-alfa – Response up to 40% Antman, et. al. N Engl J Med 2000 Apr; 342: 1027-38.

  19. Dual ART AZT introduced HAART introduced KS & HAART • Decline in incidence in US and Europe in era of HAART • One case series: 80% early stage lesions responded x 3-6 mo HAART • Madison Clinic data (HAART era): 37% KS improvement with 36 mo follow-up • Certain ARVs more effective vs. KS? Tx slide SEER Stat Database, www.seer.cancer.gov

  20. KS & Immune Reconstitution Inflammatory Syndrome • Immune Reconstitution Inflammatory Syndrome (IRIS) • Exuberant immune-mediated inflammatory response to antigenic triggers with start of HAART • Primary disorder = Immune perturbation not infection • Growing list of associated infectious & rheumatologic diseases • Case series n=9 patients with KS flare • Onset of flare – mean of 5 weeks into HAART (range, 3-7 wks) • Eruption of new lesions, increased edema/prominence of KS • Case of fatal KS-associated IRIS in a patient who presented with respiratory failure (negative BAL, steroid-responsive) Leidner, et. al. AIDS Patient Care STDs 2005 Oct;19: 635-44. Crane, et. al. Int J STD & AIDS 2005 Jan;16: 80-2.

  21. AIDS-associatedKaposi Sarcoma • Incidence high in pre-HAART era, now reduced but still common, esp. among MSM • KS prevalence mirrors prevalence of HHV-8 infection • Chronic disease without a cure, marked by slow often partial remission • Visceral disease, esp pulmonary involvement, associated with poor prognosis • HAART is probably key to KS treatment & should be initiated in all KS pts

  22. Case 2 47 yo journalist with stage 3 HIV with CD4 102 on HAART presents with fever, chills, diffuse abdominal pain, cough, bloody diarrhea. He returned from a recent trip to SE Asia. His exam is notable for HR 123 BP 90/45 RR 25 O2 Sat 93% on 3 L NC, petechial rash on trunk and scattered wheezing in all lung fields. CXR shows bilateral interstitial infiltrates. Bronchoscopy was performed. BAL revealed the following:

  23. What is your diagnosis?

  24. Disseminated Strongyloidiasis • Endemic in tropical or subtropical regions (SE Asia) • Strongyloides cause a systemic dissemination (hyperinfection syndrome) with high mortality in some patients, generally immunosuppressed (HIV+, chemo, steroids) • Intestinal invasion may result in gram negative sepsis • Trivia: what other conditions/meds predispose?

  25. Case 3 35 yo man with stage 3 HIV comes in c/o 3 weeks of HA, sleepiness and double vision. PMH: HIV dx 1990 – last CD4 50 in 2009 Hx depression with psychotic features Chronic hepatitis B Soc Hx: Immigrated from Somalia in 2008.

  26. Case 3 Exam: T 38.0 BP 140/85 HR 65 RR 14 GEN: Drowsy, thin man in no acute distress. Mental status: Opens eyes spontaneously, attends and able to answer questions appropriately, oriented to self, place and year. Obeys commands. NECK: No stiffness. NEURO: Cranial nerves II-XII intact & symmetric. Gait is wide-based. No focal impairment in sensory/motor exam. What would you do next?

  27. Lumbar puncture • Opening pressure 55 cm H2O • CSF WBC 153 (lymphocyte predominant) • CSF glucose 35 • CSF protein 87 CT head with contrast: No focal abnormalities.

  28. Tuberculous vs Cryptococcal Meningitis Cohen, CROI 2009, Abstract #791.

  29. Lumbar puncture • Opening pressure 55 cm H2O • CSF WBC 153 (lymphocyte predominant) • CSF glucose 35 • CSF protein 87 CSF Cryptococcal Antigen 1:512.

  30. Primary Induction Therapy for Cryptococcal Meningitis • Amphoterocin B deoxycholate 0.7-1.0 mg/kg or liposomal AmB 3-4 mg/kg or ABLC 5 mg/kg per day IV plus flucytosine (5-FC) 100 mg/kg/day x 2 weeks minimum OR • AmBd, liposomal AmB, ABLC plus fluconazole 800 mg x 2 wks minimum OR • Fluconazole ≥800 mg/day (1200 mg/day favored) plus 5FC 100 mg/kg/day x 6 weeks OR • Fluconazole 800-2000 mg/day; ≥1200 mg/day favored x 10-12 weeks if used alone Use of itraconazole is discouraged. 2010 Infectious Disease Society of America Guidelines

  31. RCT of Combination High-dose Fluconazole + 5FC vs Fluconazole alone Primary Outcome: Early fungicidal activity Secondary outcomes: 2-week, 10-week Mortality Nussbaum, Clin Infect Dis Feb 2010; 50:338-44.

  32. Nussbaum, Clin Infect Dis Feb 2010; 50:338-44.

  33. Case 3 35 yo man with stage 3 HIV comes in c/o 3 weeks of HA, sleepiness and double vision. PMH: HIV dx 1990 – last CD4 50 in 2009 Hx depression with psychotic features Chronic hepatitis B Soc Hx: Immigrated from Somalia in 2008. Medications: Efavirenz 600 mg PO qHS TDF + FTC 1 tab PO qDay

  34. Cryptococcal Meningitis & IRIS • Incidence 47 cases per 100 person-years • Median interval from HAART initiation to dx IRIS: 63 days (range, 12-129) • Headache is most common symptom; neck stiffness, photophobia, fever, focal neuro deficit less common • Papilledema & decreased LOC may be more common w/ CM-IRIS • OP higher at IRIS c/w first CM dx: median 46 vs 20 cm H2O • % PMN CSF higher in CM-IRIS; CrAg titers lower Sungkanuparph, Clin Infect Dis September 2009; 49:931-4.

  35. How soon can we start HAART in patients with Cryptococcal meningitis? Makadzange, Clin Infect Dis June 2010; 50:1532-38.

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