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Opportunistic Infections

Opportunistic Infections. ID Fellows course 2010 Christian B. Ramers , MD, MPH. Learning Objectives. Develop systematic approach to diagnosis of OI’s in immunocompromised patients Describe preferred initial therapy of select OI’s Review CD4 cell count thresholds/risk of OI’s

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Opportunistic Infections

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  1. Opportunistic Infections ID Fellows course 2010 Christian B. Ramers, MD, MPH

  2. Learning Objectives • Develop systematic approach to diagnosis of OI’s in immunocompromised patients • Describe preferred initial therapy of select OI’s • Review CD4 cell count thresholds/risk of OI’s • Discuss timing of HAART in setting of acute OI

  3. Case #1: HPI • 54 yo Latino male with fever, diarrhea, cough • Presented to Pioneer Square clinic 5/09 with 1 month of fever and diarrhea, 2 months dry cough • HIV Ab and Western Blot positive in clinic • 20 lbs involuntary weight loss • 10+ watery stools/day • Cough mostly dry, some scant whitish mucus • What are you worried about?

  4. Case #1: Additional History • Risk Factor: MSM exclusively, 3 lifetime partners • No prior illnesses/hospitalizations • Rare social EtOH, Denies tobacco, IVDU • Born & raised in Cuernavaca, Mexico • 1986 emigrated to Phoenix, AZ • 1998 moved to Minneapolis, MN • 5/2009 moved to Seattle • Worked odd jobs in AZ, MN, now homeless

  5. Case #1: PEX • Vitals: 38.9, 99, 18, 113/72, SaO2 98% on RA • Gen: thin Latino man, mild distress • Chest: inspiratory crackles B bases • CV: RRR no murmurs • Abd: scaphoid, tympanetic, liver edge palpable at R costal margin, no splenomegaly • Extr: No edema • Skin: No lesions, no rash

  6. Initial Work-up?

  7. CXR 6/1/09

  8. Case #1: Initial Labs • Initial CBC: WBC 4.46, Hct 32, Plt 102 • LFT’s: AST/ALT 97/52; Alb 2.4, LDH 248 • CD4: 21 (3%), HIV VL 580,000; genotype pending What else do you want? AFB sputum smears x 3: NEGATIVE

  9. CT 6/2/09

  10. CT 6/2/09

  11. CT 6/2/09

  12. CT 6/2/09

  13. CT 6/2/09

  14. How would you approach this patient?

  15. Case #1: DDx – undifferentiated fever • TB • MAC • CMV • Bartonella • Lymphoma • Histoplasmosis • Cryptococcus • Leishmania • (Malaria, Penicilliumspp, Amebic liver abscess)

  16. Case #1: DDx – Chronic Watery Diarrhea • Giardia • CMV • MAC • Cryptosporidium • Microsporidium • Cyclospora • Isospora • ‘HIV enteropathy’ • Salmonella • Shigella • Campylobacter • E. coli (EAEC) • C. difficile • E.histolytica

  17. Case #1: DDx – dry cough w/ nodules • TB • KS • Lymphoma • Histoplasmosis • Coccidiomycosis • Legionella • Rhodococcus • Cryptococcus (vargrubii, vargattii) • Nocardia • Toxoplasma • MAC • M. kansasii • Pneumocystis • CMV

  18. Case #1: Follow-up Labs • Stool Studies: • C. difficileA&B toxin NEGATIVE • 6/1 O&P (concentrated/trichrome): NEGATIVE • 6/2 O&P (concentrated/trichrome): NEGATIVE • 6/2 Giardia Ag: NEGATIVE • 6/3 Modified Acid-fast: POSITIVE source: www.hivwebstudy.org

  19. Cryptosporidiosis source: www.hivwebstudy.org

  20. Cryptosporidiosis • Etiology: Cryptosporidium parvum • Presentation: • Self-limited diarrhea in normal hosts • Worse in CD4 < 150: range from foul-smelling bulky to watery ‘cholera-like’. Can also cause biliary, respiratory disease • Pathophysiology: inflammation & villous atrophy  malabsorption, increased permeability, solute flux into the gut lumen; rarely invasive • Diagnosis: Usually missed by traditional ‘O&P’ exam (4-6 mm, similar to yeast); fluorescent or modified Acid-fast stain MMWR April 10,2009; 58 (RR4): 1-206

  21. Cryptosporidiosis - Treatment • Specific therapy usually not necessary • Some data for nitazoxanide for special cases MMWR 2009; 58 (RR4): 1-132

  22. Case #1: Follow-up Labs • Sputum for AFB negative x 3 • TB AMPLIFIED DIRECT TEST - Sputum POST BRONCH AFB POS SMEAR • Last Update: 06/11/09 12:14 Collected: 06/05/09 15:30 • MTB Complex rRNA: POSITIVE • AFB CULTURE W/STAIN - Sputum, Induced mucoid in cup • Last Update: 06/23/09 11:01 Collected: 06/02/09 13:00 • AFB Stain: No acid fast bacilli seen (concentrated smear) by Auramine stain • Culture: Presumptive Mycobacterium tuberculosis complex isolated from broth only : • AFB CULTURE W/STAIN - Sputum POST BRONCH in cup • Last Update: 07/07/09 10:13 Collected: 06/05/09 15:30 • AFB Stain: Rare Acid Fast Bacilli by Auramine stain • Culture: 2+ Mycobacterium tuberculosis : Identification by DNA probe and phenotypic analyses • 2+ MYCOBACTERIUM TUBERCULOSIS - AFB MGIT • Ethambutol (5 mcg/mL) S • Isoniazid (0.1 mcg/mL) S • Rifampin (1 mcg/mL) S • Streptomycin (1 mcg/mL) S

  23. Case #1: Clinical course • Intensive IV fluid, nutrition, electrolytes • Started on RIPE • Developed pancytopenia, transaminitis • Many drug changes • Continuous fever • Who wants to start HAART?

  24. ACTG 5164 – HAART in setting of Acute OI Early ART: within 14 dof OI diagnosis(n = 141) • Entry OI’s: PJP (63%), Crypto (12%), Bacterial Infection (12%), Toxo (5%), Histo (4%), CMV (2%), MAC (2%), [Multiple 33%] Deferred ART: after OItreatment completed(n = 141) 1x Zolopa A, et al PLoS One 2009; 4(5): 5575

  25. ACTG 5164 – HAART in setting of Acute OI • HR 0.53 (95%CI 0.3-0.92) favoring early ART Zolopa A, et al PLoS One 2009; 4(5): 5575

  26. Case #1: Clinical course • Patient had remained relatively stable on RIPE • Discharged with Madison Clinic f/u • HAART deferred due to transaminitis, ongoing fevers, diagnostic uncertainty • Presented to Madison Clinic for initial visit: febrile to 39.0, AST/ALT 150’s • Now what?

  27. Case #1: Follow-up Labs • Serum Histoplasma Ag (6/6/09): POSITIVE 36.0 • AFB CULTURE, BLD CULT BOTTLES - Blood Arm, Right Aerobic and anaerobic bottles • Last Update: 06/29/09 15:36 Collected: 06/03/09 13:23 • Culture: No acid fast bacilli isolated in 26 days. Histoplasmacapsulatum isolated from mycobacterial broth : identification by sequence analysis . • LOWER RESP FUNGAL W/DIR. EXAM - BronchoalveolarLavage No. 2 Lung, Right Middle Lobe Cloudy • Last Update: 07/06/09 11:12 Collected: 06/05/09 14:15 • Stain for Fungus: No fungi seen • Culture: 2+ Presumptive HistoplasmacapsulatumSEE BLOOD CULTURE 6/3/09 FOR CONFIRMATION • AFB CULTURE, BLD CULT BOTTLES - Blood Arm, Left Yellow top tube • Last Update: 08/11/09 11:34 Collected: 06/06/09 07:45 • Culture: Mycobacterium tuberculosis complex isolated from broth only Presumptive identification by colonial morphology. : see sputum of 6/5/09 for susceptibilities Presumptive Histoplasmacapsulatumisolated from mycobacterial broth

  28. Histoplasmosis • Etiology: Histoplasmacapsulatum • Presentation: • Acute: febrile pulmonary infection • Reactivation: fever, chills, wt loss, bone marrow failure, anemia, high LFT’s, may have evidence of old disease on CXR • Pathophysiology: Initially latent disease, with reactivation upon immunosuppresion • Diagnosis: Direct visualization of fungus, culture, Serum or Urine Antigen test • Mortality: low in immune competent; high in immunosuppressed. • Risk Factors: dyspnea, plt < 100K, high LDH

  29. Histoplasma Distribution Edwards LB; Am Rev Repir Dis. 1969; 99(4):Suppl: 1-132

  30. Histoplasma Distribution Mochi A and Edwards PQ; Bull WHO, 1952(5): 252-291

  31. Histoplasmosis - Treatment MMWR 2009; 58 (RR4): 1-132

  32. Case #1: Resolution • Later dx’d with CMV gastritis, Late latent syphilis, H.pylorigastritis (received PCN, Gancyclovir/Val-G, Amox/Clarithro/PPI) • Complicated by ARF, LFT’s, pancytopenia • Started HAART 9/09 (FTC/TDF+ATZ/r) • Developed 3 new liver masses, AST/ALT 200/175 • Liver biopsy: granulomas, no growth (TB/Histo IRIS) • Now doing well on HAART, INH/Ethambutol, Itraconazole, pentamidine (CD4 88, VL < 40)

  33. Case #1: Summary • Cryptosporidium is a common cause of watery diarrhea in immunocompromised. Best diagnosed with Modified Acid-Fast Stain • Immunocompromised patients often have multiple OI’s (sometimes 5!!) • Evidence appears to support early initiation of HAART in the setting of select OI’s (ACTG 5164) but still handled case-by-case • Beware of IRIS

  34. Ockam’s razor Pluralitas non estponenda sine neccesitate • “Plurality is not to be posited without necessity” Frustra fit per plura quod potestfieri per pauciora • “It is futile to do with more things that which can be done with fewer”

  35. Case #2: HPI • 46 yo Caucasian Male 50 lbs wt loss, GI issues • Odynophagia for solids, diarrhea (5-10 loose, foul-smelling BM’s/day) • Out of care x 3 years, previously seen in FL • On Atripla but resistant to ‘two of the three’ • Stopped ARV’s because he felt well • Prescribed Raltegravir + Darunavir/Ritonavir + Etravirine but never picked up

  36. Case #2: Additional History • HIV dx’d 2002, risk: MSM • Previous Nadir CD4 76 • HIV-related hx: thoracic zoster, KS posterior neck, PJP, Oral/Esophageal Candidiasis, HIV wasting, esophageal ulcers, chronic diarrhea • Worked as a flight attendant but lost job • Reports > 30 lifetime partners • Recently moved back to Whidbey Island w/mom

  37. Case #2: PEX • Vitals: 36.5, 76, 20, 110/78, SaO2 98% on RA, 66 kg (6’1”) • Gen: anxious cachectic Caucasian man, no distress • HEENT: temporal wasting, thrush on buccal mucosa, OHL on lateral tongue, angular chelitis • Chest/CV: CTAB, RRR • Abd: scaphoid, no HSM, hyperactive BS • Extr: thin, with atrophy • Skin: scaly erythematous plaques on face concentrated around eyebrows & ears

  38. What can you do on the 1st visit?

  39. Case #2: • Records pending, FL doc gave some via phone • CD4 27 (4%), VL 538,500 • CBC: WBC 2.3, Hct 35, Plt 159 • LFT’s normal, Cr 0.7 • Stool studies: • 6/2/10 O&P (concentrated/trichrome): NEGATIVE • 6/3/10 O&P (concentrated/trichrome): NEGATIVE • 6/2/10 Modified Acid Fast stain: NEGATIVE • 6/2 Giardia Ag: POSITIVE • 6/9/10 O&P (concentrated/trichrome): POSITIVE for G. lamblia cysts and trophozoites

  40. Case #2: Stool Studies Photo courtesy of Carolyn Wallis (HMC Microbiology)

  41. Case #2: Initial Management • TMP/SMX DS – PJP prophylaxis • AzithromycinQweek – MAC prophylaxis • Ketoconazole topical – for Seborrheicderm • (Metronidazole 250 TID x 5 d) • Fluconazole 100 mg PO QD x 3 wks (planned) • Sent Trofile assay, HIV genotype

  42. Candidiasis - Treatment MMWR 2009; 58 (RR4): 1-132

  43. Case #2: • Returns 2 weeks later with improved diarrhea, but worsening odynophagia • EGD scheduled urgently • What’s your pre-EGD Differential Dx?

  44. Case #2: Ddx – Odynophagia • Esophageal Candidiasis • HSV • VZV • CMV • Aphthous ulcers • Gastric/Esophageal KS • Lymphoma • Severe H. pylori gastritis

  45. Case #2: EGD Ulceration – mid-esophagus

  46. Case #2: EGD Patchy erythema – mid-Antrum

  47. Case #2: Esophageal Biopsy Granulation tissue, inflammation, rare inclusions

  48. Case #2: Esophageal Biopsy CMV Inclusions

  49. Cytomegalovirus • Etiology: CMV – β-herpesvirus • Clinical Manifestations: • Seroprevalence 60-70% in US, ~100% in Africa • Mono-like ‘CMV syndrome’, esophagitis, colitis, interstitial pneumonitis, hepatitis, retinitis, meningoencephalitis, myocarditis • Pathophysiology: After acute infection, cycles of latent/reactivated disease • Diagnosis: Serology, Shell vial, serum PCR suggestive, but must demonstrate CMV in tissue to call disease • Mortality: MAJOR cause of mortality in iatrogenicallyimmunosupressed, most common congenital infection

  50. CMV Disease - Treatment MMWR 2009; 58 (RR4): 1-132

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