13 August, 2009 Mystery Cases Shireesha Dhanireddy, MD

1. 13 August, 2009 Mystery Cases Shireesha Dhanireddy, MD

2. Opportunistic Infections • 1981 - Reports of PCP in 5 gay men in Los Angeles

3. HIV: Pathogenesis Typical Course Sero-conversion Antibody response Anti-HIV T-cell response Intermediate Stage AIDS CD4 Cell Count Plasma RNA Copies OIs start here 500 CD4 Cells 4-8 Weeks Up to 12 Years 2-3 Years From Harrington RD

4. Case 1 • 31 year old Mexican MSM presented with gluteal pain. • He also noted intermittent fevers and diarrhea as well. +weight loss 20 lbs over 5 months, + nightsweats, productive cough white sputum x 1 month • Painful penile lesion x 2months

5. Case 1 continued • Social History - moved to US from Mexico 8 months ago; works in a restaurant; MSM h/o unprotected sex 5 months ago; Pets - 6 dogs, many chickens (in Mexico)

6. Case 1 continued • Exam - thin, temporal wasting, +inguinal lymphadenopathy, erythematous ulceration on penis; left buttock indurated, erythematous area c/w abscess; neurologic exam normal

7. Case 1 - continued • Seen by surgery and underwent incision and drainage of buttock abscess and was sent home • He returned a few days later with continued fevers and was admitted for further workup • Buttock abscess had resolved

8. Case 1 - penile lesion

9. Case 1 - continued Based on his following symptoms what tests would you order at this point? Symptoms: Intermittent fevers, diarrhea, weight loss, nightsweats, cough, penile lesion

10. Case 1 - Differential Diagnosis • HIV • TB - sputa x 3 for afb • Diarrhea - stool studies - O&P, enteric pathogens screen, cryptosporidium, isospora • Disseminated MAC - blood culture for afb • Blood cultures - for bacteria and afb

11. Case 1 - Data • Labs - HIV + ; CD4 count 103 (17%); HIV RNA 1 million copies/mL • Sputum afb negative x 3 • Blood culture positive for this organism within 2 days …

12. Case 1 - blood culture

13. Case 1 Which organism is most likely based on blood culture and clinical presentation? • Mycobacterium avium complex • Salmonella nontyphi • Vibrio cholera • Staphylococcus aureus

14. Salmonellosis • Nontyphoid Salmonella bacteremia 20 to 100-fold higher in HIV+ people • From ingestion of contaminated food/water • Possibly from sexual activity • Patients with lower CD4 counts --> increased mortality, increased risk of bacteremia Hung CC et al. Clin Infect Dis 2007;45:e60-7

15. Salmonellosis • Relapses common • Recurrent Salmonella septicemia is an AIDS-defining condition • Treatment of choice - fluoroquinolone ie ciprofloxacin (alternatives TMP/SMX or ceftriaxone) • Length of therapy for CD4 count < 200 is 2-6 weeks • If recurrent disease, consider 6 months + of antibiotics (secondary prophylaxis)

16. Approach to Diarrhea in HIV: US Bacterial enteric pathogens, viruses such as Norwalk, Cryptosporidium, Giardia, E. histolytica CD4 count CMV, MAC, microsporidia, Isospora, KS

17. Approach to Diarrhea in HIV: US • Based on acuity of symptoms and whether bloody workup may include: • Stool culture for bacteria • O&P • Stool for afb & trichrome stain (for Cyclospora, Isospora, Cryptosporidium, microsporidia • C. difficile toxin assay • Giardia stool antigen • Blood cultures for MAC and Salmonella • Colonoscopy for CMV, KS

18. Approach to Diarrhea in HIV: World • Acute diarrhea <14 days - usually bacterial • No bloody in stool - manage symptomatically or metronidazole if severe • Blood in stool - fluoroquinolone x 5 days + metronidazole (for concern of amebic colitis) • Persistent diarrhea >14 days - usually Cryptosporidium, Isospora, microsporidia • WHO recommendations • If no blood in stool --> cotrimoxazole + metronidazole • If no response --> refer or albendazole/mebendazole

19. Case 1 - continued What about his other symptoms and other tests ?

20. Case 1 - additional testing RPR +, VDRL + 1:16 What is your next step? • Treat with PCN IM x 1 for primary or early latent syphilis • Perform lumbar puncture and then treat based on CSF results • Treat with PCN IM x 3 for late latent syphilis • False positive result, do not treat

21. Syphilis & HIV • Can enhance transmission of HIV • Can have negative impact on immune status

22. Syphilis • Primary - painless chancre (ulcer) 2-3 weeks after exposure • Secondary - typically 3-6 weeks after primary; but overlap between 1º and 2º more common with HIV • Tertiary - gumma, cardiovascular changes, neurosyphilis

23. Neurosyphilis • Can occur anytime • Risk factors - low CD4 count (<350), high titer, male gender • CSF evaluation for HIV + patients • with neurologic signs/symptoms • with late latent or syphilis of unknown duration, regardless of symptoms • Abnormal CSF protein or cell count or reactive CSF VDRL can be diagnostic

24. Latent Syphilis Definition - positive test in the absence of symptoms Early latent - acquired within past year (documented negative test within a year Late latent or unknown duration

25. What about the painful penile lesion? Differential diagnosis of genital ulcer disease: HSV, chronic Syphilis H. ducreyi

26. Chronic HSV • AIDS-defining illness • Non-healing lesions (x >1 month) usually in pts with low CD4 counts (< 100) • More commonly acyclovir resistant • Treat until lesions have healed completely

27. HIV & HSV • HSV thought to facilitate transmission / acquisition of HIV • HSV suppressive therapy reduces HIV RNA levels • Use of acyclovir does not reduce HIV incidence • HSV suppression does not reduce HIV acquisition Nagot N et al. NEJM 2007 Watson-Jones D et al. NEJM 2008 Celum C et al. Lancet 2008

29. Case 2 32 year old male presents with rectal bleeding x 2 weeks, more frequent stools HIV - stage 3 (CD4 nadir 43 now 138 on ARVs, diagnosed 2001, intermittently on therapy due to adverse effects and depression MSM

30. Case 2 - Exam Rectal exam - no masses, no hemorrhoids. Anoscopy - clotted blood seen, no masses

31. Case 2 - Next Steps • Stool Tests • C. difficile negative • Giardia negative • Stool enteric pathogen screen negative • O&P negative • Cyclospora, isopora, cryptosporidium negative • What would you do next?

32. Case 2 - Colonoscopy 5 cm rectal mass seen (5cm from anal verge) What is your diagnosis?

33. Anal Cancer • HIV-positive men 60x more likely than HIV-negative men • Overall incidence still low • HPV-associated cancer • Oncogenic HPV types implicated in disease • HPV vaccine not approved in men

34. Anal Cancer: Screening? • Anal Pap smears • 30-60% of HIV-positive persons will have anal cytologic abnormalities • If Pap smear abnormal --> high-resolution anoscopy • Systematic review in 2006 - not enough evidence to recommend routinely • Digital rectal exam recommended for MSM and women who have anal sex Chiao EY et al. Clin Infect Dis 2006;43:223-33

35. Case 2 - pathology

36. Case 2 - pathology Diffuse Large B Cell Lymphoma

38. Case 3 • 34 year old male with low grade fevers, intermittent abdominal pain, and weight loss (20 lb) x 3 months • HIV + • Presents to outside MD, CD4 count 6, VL >1,000,000 • Started on lopinavir/ritonavir/emtricitabine/tenofovir

39. Case 3 - continued • 3 days into therapy -- diarrhea, nausea, vomiting • 4 days later, presents to our hospital with worsening symptoms and altered mental status • Admitted to Neurology • Diagnostic tests?

40. Case 3 - continued LP - normal OP; glu 49; TP 19; WBC 0; RBC 0; PCRs negative, CSF cx negative MRI brain: unremarkable Blood cultures sent CXR: diffuse patchy interstitial opacities Chest CT: ground glass opacities, hilar/mediastinal LAD Sputum culture: 4+ afb

41. Case 3

42. Case 3 - continued Sputum culture: 4+ afb Underwent bronchoscopy: 4+ afb, PCP neg • Blood culture for afb + • He developed hypotension and was transferred to unit briefly • Discharged on treatment for MAC What explains his clinical deterioration? How could it have been avoided?

43. Immune Reconstitution Syndrome Worsening of signs/symptoms due to infections that results from improvement in immune function after the initiation of anti-retroviral therapy

44. Immune Reconstitution Syndrome • Occur in 10 to 40% of patients on HAART • Mycobacterial infections involved in 1/3 of cases • Onset is typically within 8 weeks of HAART (range 1 week to 7 months)

45. IRS - Treatment Options • Interrupt HAART (try to avoid this) • NSAIDs • Steroids - improved symptoms but no effect on survival • IVIG? • Thalidomide? Meintjes, CROI-2009, Montreal, Abst#34

46. Case 3 - back to patient • ARVs stopped for 3 weeks and then restarted • Symptoms improved and then worsened again 10 days after reinitiation of ARVs • Started on prednisone and NSAIDs, ARVs continued • When would you start taper?

47. Case 3 - back to patient • Taper started after 3 weeks • Fevers, abdominal pain recurred 2 weeks into taper • Steroids continued and tapered more slowly over the course of months • Intially improved but then developed worsening abdominal pain - multiple CTs showed mesenteric LAD

48. Case 3 • Then 1 year after his diagnosis -- • Acutely worsening abdominal pain, low blood pressure --> unresponsive --> cardiac arrest • Found to have Gram negative sepsis (GI source) • Imaging showed diffuse bowel edema and necrotic enlarged LN • Made comfort care and died

49. Ideal time to start ARVs Possibly sooner rather than later … Improved survival for OI’s (including TB) Worse possibly for cryptococcal meningitis Zalopa. ACTG 5164, CROI 2008, Boston, Abst# 142 Karim, SAPIT study, CROI 2009, Montreal, Abst# 36a Macadzange, CROI 2009, Montreal, Abst #38cLB