ID Fellows course 2010Christian B. Ramers, MD, MPH

Opportunistic Infections

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

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?

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

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

Initial Work-up?

CXR 6/1/09

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

CT 6/2/09

CT 6/2/09

CT 6/2/09

CT 6/2/09

CT 6/2/09

How would you approach this patient?

Case #1: DDx – undifferentiated fever

• TB• MAC• CMV• Bartonella• Lymphoma• Histoplasmosis• Cryptococcus• Leishmania• (Malaria, Penicillium spp, Amebic liver abscess)

USA Spain India

-- 42% 63%

31% 14% --

11% -- --

8-18% -- --

-- -- --

7% -- 5%

-- -- 10%

-- 14% --

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

Case #1: DDx – dry cough w/ nodules

• TB• KS• Lymphoma• Histoplasmosis• Coccidiomycosis• Legionella• Rhodococcus• Cryptococcus (var grubii, var gattii)

• Nocardia• Toxoplasma• MAC• M. kansasii• Pneumocystis• CMV

Case #1: Follow-up Labs • Stool Studies:

– C. difficile A&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

Cryptosporidiosis

source: www.hivwebstudy.org

Cryptosporidiosis

MMWR April 10,2009; 58 (RR4): 1-206

• 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

Cryptosporidiosis - Treatment

• Specific therapy usually not necessary• Some data for nitazoxanide for special cases

Preferred Alternative Comments

Initiate ART (AII) Nitazoxanide 500-1000 BID (CIII)

Paromomycin not recommended

Aggressive Oral and IV rehydration & electrolyte

replacement (AIII)

Symptomatic treatment of diarrhea (AIII)

Loperamide often helpful

MMWR 2009; 58 (RR4): 1-132

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

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?

ACTG 5164 – HAART in setting of Acute OI

• Entry OI’s: PJP (63%), Crypto (12%), Bacterial Infection (12%), Toxo (5%), Histo (4%), CMV (2%), MAC (2%), [Multiple 33%]

Zolopa A, et al PLoS One 2009; 4(5): 5575

Study Features

Protocol - N = 282 randomized and treated- Age > 13- ARV-naïve- Median CD4 = 29- OI’s presumed or confirmed- TB excluded!!- Composite 48 wk endpoint: Death, AIDS progression, VL < 50

Early ART: within 14 dof OI diagnosis

(n = 141)

Deferred ART: after OItreatment completed

(n = 141)

1x

ACTG 5164 – HAART in setting of Acute OI

• HR 0.53 (95%CI 0.3-0.92) favoring early ARTZolopa A, et al PLoS One 2009; 4(5): 5575

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?

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. Histoplasma capsulatum isolated from mycobacterial

broth : identification by sequence analysis .

• LOWER RESP FUNGAL W/DIR. EXAM - Bronchoalveolar Lavage 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 Histoplasma capsulatum SEE 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 Histoplasma capsulatum isolated from mycobacterial broth

Histoplasmosis• Etiology: Histoplasma capsulatum• 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

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

Histoplasma Distribution

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

Histoplasma Distribution

Histoplasmosis - TreatmentSyndrome Preferred Alternative Comments

Severe Disseminated

Liposomal Ampho B 3 mg/kg x 14 d (AI)

Ampho BABLC

Itraconazole 200 mg TID x 3d BID (AII)

Levels should be optained (AIII)

Less Severe Disseminated

Itraconazole 200 mg TID x 3 d BID (AII) Duration > 12 mos

Meningitis Liposomal Ampho B 5 mg/kg x 4-6 wks

Itraconazole 200 mg BID/TID x > 1 year

Treat until CSF normalizes

Long-term suppression

Itraconazole 200 mg QD

Recommended for CNS disease or any

relapse

MMWR 2009; 58 (RR4): 1-132

Case #1: Resolution• Later dx’d with CMV gastritis, Late latent syphilis,

H.pylori gastritis (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)

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

Ockam’s razor

Pluralitas non est ponenda sine neccesitate• “Plurality is not to be posited without necessity”Frustra fit per plura quod potest fieri per pauciora• “It is futile to do with more things that which can be done with fewer”

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

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

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

What can you do on the 1st visit?

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

Case #2: Stool Studies

Photo courtesy of Carolyn Wallis (HMC Microbiology)

Case #2: Initial Management

• TMP/SMX DS – PJP prophylaxis• Azithromycin Qweek – MAC prophylaxis• Ketoconazole topical – for Seborrheic derm• (Metronidazole 250 TID x 5 d)• Fluconazole 100 mg PO QD x 3 wks (planned)• Sent Trofile assay, HIV genotype

Candidiasis - TreatmentInfection Preferred Alternative Comments

Oral Fluconazole 100 mg QD (AI) x 7-14 d

Itraconazole 200 mg QD (BI)

Chronic Azoles may promote resistance

Clotrimazole 10 mg troche 5X/day

Posaconazole 400 PO BID x 1QD

Higher relapse w/ echinocandins

Nystatin susp 5 mL QID (BII)

Miconazole QD (BII)

Esophageal Fluconazole 100-400 mg QD x 14-21 d (AI)

Echinocandin: Mica-, Caspo-, Anidulafungin (BI)

Suppressive therapy not recommended

Itraconazole 200 mg QD x 14-21 d (AI)

Azole: Vori-, Posaconazole (BI)

Amphotericin B (BI)

MMWR 2009; 58 (RR4): 1-132

Case #2:

• Returns 2 weeks later with improved diarrhea, but worsening odynophagia

• EGD scheduled urgently

• What’s your pre-EGD Differential Dx?

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

Case #2: EGD

Ulceration – mid-esophagus

Case #2: EGD

Patchy erythema – mid-Antrum

Case #2: Esophageal Biopsy

Granulation tissue, inflammation, rare inclusions

Case #2: Esophageal Biopsy

CMV Inclusions

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 iatrogenically immunosupressed, most common congenital infection

CMV Disease - TreatmentInfection Preferred Alternative Comments

RetinitisGCV intraocular

implant + Val-G 900 mg BID x 14-21 d

Foscarnet 60 mg/kg Q8 x 14-21 d

Initial Rx individualized based on lesion

Val-G 900 mg QD Cidofovir 5 mg/kg wk x 14 d

Can D/C maintenance when CD4> 100-150

Esophagitis/ Colitis

GCV or Foscarnet IV x 21-28 d (BII)

Maintenance therapy may not be necessary

Oral Val-G x 21-28 d if symptoms mild

Maintenance should be given for relapses

Pneumonitits GCV or Foscarnet IV CMV-Ig Histologically proven,

no role maintenance

CNS disease GCV AND Foscarnet IV until better

Maintenance Val-G + Foscarnet until

immune recovery

MMWR 2009; 58 (RR4): 1-132

Case #2: Resolution• Received IV Ganciclovir BID x 21 days then

transitioned to Valganciclovir QD• Diarrhea and Odynophagia resolved• Started HAART with FTC/TDF + MVC + RAL• Admitted yesterday with new fevers!

Case #2: Summary• Being ‘out of care’ is bad• MSM have unique risk profile• Lower CD4 counts open the door to a broader

array of pathogens• We still see the ‘old AIDS-defining illnesses’