December 5, 2007 Opportunistic Infections Robert Harrington, MD

1. December 5, 2007 Opportunistic Infections Robert Harrington, MD

2. HIV-Associated Opportunistic Infections 2007 Robert D. Harrington, M.D. University of Washington

3. 1981 MMWR 1981

4. 1981 MMWR 1981

5. HIV Infection: Pathogenesis Typical Course Sero-conversion Antibody response Anti-HIV T-cell response Intermediate Stage AIDS CD4 Cell Count Plasma RNA Copies Viral set point 1,000 CD4 Cells 500 4-8 Weeks Up to 12 Years 2-3 Years A lot of important stuff happens here

6. CD4 Count and Opportunistic Infections CD4 Cell Count 1,000 Bacterial Pneumonia, TB, HSV, Cryptosporidiosis 500 CD4 Cells Thrush, lymphoma, KS 200 PCP 100 MAC, CMV, PML, PCNSL, Cryptococcus, Microsporidia, Toxo 4-8 Weeks Up to 12 Years 2-3 Years

7. Common OIs PCP MAC Candida Regional Effects Southwest: Coccidiodomycosis Midwest: Histoplasmosis and Blastomycosis South: Blastomycosis and Toxoplasmosis Opportunistic Infections and Geography North America

8. Opportunistic Infections and Geography PCP, TB Candida, MAC Cryptococcus Leishmaniasis The World PCP TB Candida Cryptococcus Penicilliosis Candida PCP MAC TB Bacteria Malaria Cryptococcus PCP TB Cryptococcus Isospora Cryptosporidiosis Microsporidia Holmes, CID, 03 Putong, SEA Trop Med, 02 Margues, Med Mycol, 2000 Amornkul, CID, 03

9. Prophylaxis to Prevent Opportunistic Infections Considerations for Prophylaxis • Infection should be common and/or predictable • Infection should be clinically significant • Treatment (prophylaxis) should be effective, non-toxic and affordable

10. Primary PCP CD4 < 200 MTb PPD > 5mm Toxo IgG+,CD4 < 100 MAC CD4 < 50 VZV Exposure with IgG- or no hstry S. pneumoniae HBV HAV Influenza Secondary PCP Toxo MAC CMV Cryptococcosis Histoplasmosis Coccidioidomycosis Salmonella species bacteremia Recurrent HSV Recurrent Candidiasis Prophylaxis to Prevent Opportunistic Infections in the Developed World

11. Prophylaxis to Prevent Opportunistic Infections in the Developing World Primary prophylaxis: Secondary prophylaxis: for PCP and Cryptococcus WHO Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults. August, 2006

12. TB prevention • WHO recommendation: • Treat tuberculin skin test positive HIV-infected persons without active TB with 6 month regimen isoniazid preventive therapy (IPT) • Difficulties: • Lack of tuberculin skin testing • People not screened • Screen positive do not receive INH • Screen positive started on INH do not complete regimen

13. PCP MAC Cryptosporidiosis Microsporidiosis Bacterial respiratory infections Bacterial enteric infections Bartonellosis Coccidiodomycosis Paracoccidiomycosis Histoplasmosis Cryptococcus Toxoplasmosis Candida TB Aspergillosis CMV HSV VZV PML (JCV) HHV-8 HPV Penicilliosis Leshmaniasis HIV-Associated and Opportunistic Infections

14. HIV ASSOCIATED MALIGNANCIES AIDS Defining Malignancies • Kaposi’s sarcoma • Primary CNS lymphoma (PCNSL) • Non-Hodgkin’s lymphoma (NHL) • Invasive cervical cancer

15. Hodgkin’s disease Anal cancer Multiple myeloma Leukemia Lung cancer Head and neck tumors GI malignancies Genital cancers Hypernephroma Soft tissue tumors HIV ASSOCIATED MALIGNANCIES Increased Rates of Other Cancers in HIV

16. EFFECTS OF HAART ON OPPORTUNISTIC INFECTIONS • Declining incidence • Reduced need for prophylaxis (primary and secondary) • Spontaneous improvements and cure • Immune reconstitution effects

17. EFFECT OF HAART ON INCIDENCE OF OPPORTUNISTIC INFECTIONS J.E. Kaplan et al. CID 2000;30:S5-S14 (Kovacks, NEJM, 2000)

18. Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Primary Prophylaxis PCP When CD4 > 200 for 3 months MAC When CD4 > 100 for 3 months Toxo When CD4 > 200 for 3 months

19. Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Secondary Prophylaxis or Maintenance Therapy PCP When CD4 > 200 for 3 months CMV When CD4 > 100-150 for 6 months MAC When CD4 > 100 for 6 months, no symptoms of MAC and after 12 months of MAC Rx Toxo When CD4 > 200 for 6 months and completed initial Toxo Rx Cryptococcus When CD4 > 100-200 for 6 months and completed initial Crypto Rx

20. Effect of HAART on Opportunistic Infections: Spontaneous Improvement/Cure 1 PML Survival and HAART: ASD 1990-97 0.8 ART with PI 0.6 Survival Proportion 0.4 0.2 ART w/o PI No ART 0 0 6 12 18 24 Months after Diagnosis M.S. Dworkin et al. JID 1999;180:621-625

21. Effect of HAART on Opportunistic Infections: Spontaneous Improvement/Cure Other Infections Cured or Improved with HAART • Microsporidia • Cryptosporidia • Hepatitis B • Molluscum Contagiosum • Kaposi’s Sarcoma

22. Case 1 • A 42 year old man with HIV (CD4 89) presents with fever, headache, fatigue and recurrent molluscum contagiosum. • Blood cultures are taken, his molluscum lesions are treated with liquid nitrogen, he is given Tylenol for his fevers and goes home. • He returns several days later more lethargic with a worsening headache, a temperature of 39 degrees C and more molluscum lesions.

23. Case 1 • What questions do you have regarding his history and physical exam?

24. Case 1 • What questions do you have regarding his history and physical exam? • Does he have any pulmonary symptoms? • What is his TB exposure and testing history? • Where has he lived? • What animal and environmental exposures does he have? • What is his toxoplasmosis serology? • Has he had other infections in the past? • Tell me more about these skin lesions. Can I see them?

25. Case 1 Mandell, Atlas of Infectious Diseases

26. Case 1 • What diagnostic testing do you want?

27. Case 1 • What diagnostic testing do you want? • Brain CT is negative • CSF analysis: opening pressure is 300 mm, WBC 0, protein 60, glucose 30, CRAG is negative, VDRL is negative, PCR for CMV, VZV, HSV and EBV are negative

28. Case 1 • Does he have meningitis? • What is your differential diagnosis?

29. Case 1 • Does he have meningitis? • What is your differential diagnosis? • Cryptococcal meningitis • Bacterial meningitis (S. pneumoniae, H. influenza, N. meningitidis, L. monocytogenes) • Tuberculous meningitis • Other chronic meningitides (histoplamosis, blastomycosis, etc) • Viral meningo-encephalitis (e.g., HSV, enteroviruses, other herpes viruses, rabies

30. Case 1 • What do you want to do next?

31. Case 1 India Ink of CSF Mandell, Atlas of Infectious Diseases

32. Case 1 Silver stain of CSF capsule Narrow base Mandell, Atlas of Infectious Diseases

33. Case 1 • Why was the CSF CRAG negative? • How are you going to treat him?

34. Case 1 • Why was the CSF CRAG negative? • Antigen excess • How are you going to treat him? • Initial therapy; AmphoB (0.7 mg/kg/d) with or without 5-FC for 2 weeks • Followed by fluconazole at 400 mg/day for 10 weeks and then maintenance therapy with fluconazole at 200 mg/day. • Relapse without suppressive therapy (or HAART) is 50 to 60% (Van der Horst, NEJM, 1997) (Saag, CID, 2000)

35. Case 1 • Anything else?

36. Case 1 • Anything else? • High pressure associated with more symptoms (HA, meningismus, cranial nerve deficits) and higher antigen titers. • Pressure > 350 is associated with early (first week) death • Most experts recommend serial large volume spinal taps or spinal drains for patients with elevated CSF pressures (Graybill, CID, 2000)

37. Case 1 • How will you follow him?

38. Case 1 • How will you follow him? • Cryptococcal antigen for monitoring therapy: • Serum; No: no correlation between titer and outcome • CSF; Yes: unchanged or rising titer is associated with failure and relapse. • High dose steroids associated with increased mortality (Powderly, CID, 1994)

39. Case 2 • A 24 year old man with HIV (CD 68) is flown down from Alaska with fever, weight loss and fatigue starting 6 weeks ago but much worse over that last 4 days. He has declined HIV treatment. His PMH is notable only for thrush. • He grew up in Indiana but has lived in Alaska all his adult life. He acquired HIV using IV drugs. He’s a fisherman. • Physical exam reveals a cachectic male with a temperature of 40 degrees C. He has a papular skin rash, a tender oral ulcer and a palpable spleen. WBC is 1.3, Hct 24, plts 66,000. CXR demonstrates diffuse infiltrates and calcified lesions in the hilar region and in the LUQ.

40. Case 2 • What other things would you like to know about his history and exam?

41. Case 2 • What other things would you like to know about his history and exam? • Does he still inject drugs? • What is his TB exposure and testing history? • Where has he lived and traveled besides Alaska and Indiana? • What animal and environmental exposures does he have? • Has he had other infections in the past? • Has he ever had cancer? • Can I see his CXR, skin and oral lesions?

42. Case 2 (Mandell, Atlas of Infectious Disease)s

43. Case 2 (Mandell, Atlas of Infectious Diseases) (www.aids-images.ch)

44. Case 2 • What is your differential diagnosis?

45. Case 2 • What is your differential diagnosis? • Tuberculosis • Cryptococcosis • Syphilis • Histoplasmosis • Blastomycosis • MAC • Leishmaniasis • Parvovirus

46. Case 2 • What diagnostic tests do you want?

47. Case 2 • What diagnostic tests do you want? • PPD • RPR • AFB blood culture • Fungal blood culture • Bacterial blood culture • Skin/ulcer biopsy • CRAG • Buffy coat preparation • Histoplasmosis Ag

48. Case 2 • What diagnostic tests do you want? • PPD negative (anergic) • RPR positive • AFB blood culture done and pending • Fungal blood culture done and pending • Bacterial blood culture done and pending • Skin/ulcer biopsy done • CRAG negative • Buffy coat preparation done • Histoplasmosis Ag done and pending

49. Case 2 Buffy Coat Preparation Intracellular yeast forms (www.accessmedicine.com)

50. Case 2 Yeast phase, liver biopsy Mold phase Macroconidida Yeast forms (Mandell, Atlas of Infectious Diseases)