Welcome to I-TECH HIV/AIDS Clinical Seminar Series

8 October, 2009

Opportunistic Infectious

H. Nina Kim, MD, MSc

Adapted from Johns Hopkins AIDS Service

http://www.hopkins-aids.edu/educational/caserounds/caserounds_12.html

Case 1

29 yo woman with advanced AIDS was admitted to the hospital with fever and cough. She had been discharged from the hospital 3 weeks before following treatment for Candidal esophagitis. At that time she had no respiratory complaints and a normal CXR.

One week prior to this admission, she developed a non-productive cough, subjective fevers and dyspnea with exertion. She denied chest pain, diarrhea, nausea or vomiting.

Additional HxPMH• C3 HIV infection – nadir CD4 <20, on HAART last CD4 50• Herpes zoster• Candidal esophagitis• Latent syphilis treated with 3 IM PCN• Bacterial pneumonia x 3

Medications• Combivir (AZT/3TC)• Nevirapine• Bactrim DS• Fluconazole• Methadone

Social Hx

Smokes 1ppd; uses crack cocaine several X qweek. Hx IVDU but none since enrolled in methadone program 3 mo ago.

Physical Exam

T 39.5° C, pulse 112, BP 130/69, RR 22, SaO2 98% RA but 90% on exertion.

General – Chronically ill-appearing woman in no resp distress.

HEENT – oral thrush.Chest – clear to auscultation.Cardiac – regular tachycardic, 2/6 systolic ejection

murmur.ABD – normal bowel tones, no organomegaly, non-

tender.Skin – no rashes.Lymphatic – no adenopathy.NEURO – Alert, oriented x 4. O/W unremarkable.

Labs & Studies

• WBC 6 91% PMNs, 6% lymphs, 3% monos

• Hct 28.8%, MCV 82, platelets 225

• Chemistries: BUN 11, Cr 0.8, ALT 21, AST 17, alk phos 59, T. bili 0.4

• CXR: Bilateral upper lobe nodular infiltrates, L > R.

Differential Dx

• Pneumocystis carinii pneumonia (PCP) • Cryptococcosis • Histoplasmosis • Aspergillosis (invasive) • Tuberculosis • Atypical mycobacteria • Nocardia • Septic emboli from R-sided endocarditis • Lymphoma • Kaposi's sarcoma • Crack cocaine-induced pulmonary edema

Pneumocystis carinii (P. jiroveci) Pneumonia

• Most common OI – pre-HAART ever-risk 80%, relapse 60% without prophylaxis

• Clinical features– Subacute onset, exertional SOB– Fever– Non-productive cough– Chest discomfort

• Radiographic features– Classic: diffuse, bilateral interstitial/alveolar infiltrates– Other: Pneumothorax, blebs/cysts, nodules,

cavitation, normal

Pneumocystis PneumoniaDiagnosis

Non-diagnostic tests• Chest Xray• High-resolution CT• Sputum, expectorated• Blood gas (A:a gradient)• Serum LDH

Diagnostic tests• Induced sputum• Bronchoalveolar

lavage• Transbronchial or

open lung biopsy

A definitive diagnosis for A definitive diagnosis for PneumocystisPneumocystis should be sought. should be sought.

Discontinuation of Pneumocystis Prophylaxis

Recommendations from USPHS/IDSA Guidelines

• Primary Prophylaxis

• Secondary Prophylaxis

CD4 > 200 x ≥ 3 months

CD4 > 200 x ≥ 3 months

MMWR 2001;50 (RR-11):1-52.

Partners Infectious Disease Images

http:// www.idimages.org

Case 2

25 yo HIV-positive man was admitted c/o 1 week of dyspnea, cough productive of yellow, occasionally blood-streaked sputum, fevers and chills, nausea, vomiting and diarrhea.

He had also noted the appearance of unusual skin lesions that initially appeared on his face, then spread to his extremities over a 3-week period.

Additional Hx

PMH– HIV infection of unknown duration – not presently

in care

Medications– None (antiretroviral naïve)

Social Hx– Hx IVDU, active

Physical Exam & Labs

T 38.2° C, pulse 108, BP 134/88, RR 22, SaO2 93% on RA.

General – Thin ill-appearing man able to speak full sentences.

HEENT – whitish plaques oropharynx.Chest – Diffuse rhonchi & wheezes.Cardiac – Normal.ABD – Soft without organomegaly.Skin - …

WBC 7.3, AST 61, ALT 66, alk phos 168, normal bilirubin, LDH 630. CD4 count 15.

Differential?

• Bacillary angiomatosis

• Molluscum contagiosum

• Cryptococcosis

• Histoplasmosis

• Chronic disseminated HSV, VZV

• Kaposi’s sarcoma

Cryptococcosis

• CD4 count < 100

• Meningoencephalitis. AIDS pts have higher likelihood of extraneural disease (skin, lungs).

• Indolent signs/symptoms: fever, malaise, HA

• Pneumonia:– Lungs are portal of entry -- ?underdiagnosed

– Serum CrAg might not be as sensitive here

• ~10% disseminated Cryptococcosis have skin manifestations– Papules, tumors, vesicles, plaques, abscesses, cellulitis, purpura,

draining sinus, ulcers, bullae, or SC swelling

• How would you manage this patient?

• What would you do next?

Cryptococcal meningitis

• Leading cause of meningitis in central/southern Africa - attributable mortality 13-44%

• Poor prognostic features– High organism burden– Abnormal mental status– Poor inflammatory response in CSF (normal parameters 17%)– High opening pressure

• Diagnosis– CSF India ink Sensitivity 75%– CSF CrAg Sensitivity >93%– CSF Culture Sensitivity 90%– Cryptococcus can be isolated from blood, urine, sputum.

Jarvis, AIDS 2007; 21:2119.

Cryptococcal meningitis

HIV webstudy

Managing increased ICP in Cryptococcal meningitis

• Repeated LP

• Drain insertion

• Ventriculoperitoneal shunting

• No proven benefit: Mannitol, acetazolamide, corticosteroids

Case 3

38 yo man with stage 3 HIV and cough.• Dx with HIV 4 months prior when presented for evaluation

of non-healing penile ulcer.

• Baseline CD4 17/3% with VRL > 1 million copies/ml.

• Baseline serologies: Toxo neg, HepB nonimmune, Hep C neg, G6PD normal, STD screen negative

• Started on Bactrim and Azithromycin 3 months PTA (after AFB BCx neg)

• Started on ATV/r, Epzicom 2.5 months PTA

Case courtesy of Dr. Lynn Connolly, Madison Clinical Case ConferenceMarch 2008

Case 3

• 2 mon PTA found to have worsening anemia (Hgb 12.3 to 8.6)

• Anemia work-up:– Peripheral smear: only microcytosis (MCV 77)– Fe 80/ TIBC 256 / Trans Sat 30% / ferritin 656– EPO 11, haptoglobin 503– Retic count 1%– Fecal occult blood negative– Parvovirus B19 PCR negative (IgG post/IgM neg)

• TMP/SMX discontinued

Case 3

• 1 month history of cough productive of scant sputum, SOB with exertion

• Denied F/Ch/NS, weight loss, abdominal pain, diarrhea, fatigue, chest pain, palpitations, lightheadedness, dizziness, headaches

Medications

• Atazanavir

• Ritonavir

• Epzicom (Abacavir + FTC)

• Lisinopril

• Metformin

• Acyclovir

• Inhaled pentamidine

Physical Exam

• GEN: fairly well appearing, in no distress• VS: T=37.4, BP=123/76, HR 132 -> 120 on repeat, RR

16, 100% RA at rest, 98% with exertion, 84 kg• HEENT: pale conjunctiva, no oral lesions• NECK: supple• NODES: no LAD• CHEST: lungs CTAB• COR: tachycardic, II-III/VI systolic murmur LUSB

without radiation• ABD: soft, NTND, no HSM

Labs

• CBC: WBC 5.2 with normal diff, Hgb 8.9, Hct 26%, plts 352

• Chem: notable for Cr 1.8, glucose 140• LFTs: ALT 23, AST 36, alk phos 97, total bili 0.9,

albumin 3.2• LDH 145• ABG: 7.39/37/53 on RA• CD4 171 (19%), HIV RNA 9,260 copies/mL

2 months PTA 3 days PTA

Further work-up

• Induced sputum: Neg PCP, AFB x 2• AFB BCx x 4 NGTD• Fungal BCx x 4 NGTD• Cocci immunodiffusion neg• Urine histo Ag neg• Repeat Toxo serology negative• Bone marrow biopsy: normal trilineage

hematopoeisis. AFB, fungal Cx neg, Parvo B19 PCR neg, flow cytometry normal

• CD4 128/13%, VL 415 copies/ml

Case 3: Bronchoscopy & Mediastinoscopy

• BAL: 2+ AFB• Mediastinal tissue: 1+ AFB• Fungal stains/Cx negative• AMTD on BAL sample:

negative for MTB complex

Induced sputum: 5 colonies MAC

All sputum, mediastinal cultures MAC

Disseminated MAC

• CD4 <50 - AIDS annual frequency 10-20%• Most common bacterial OI in developed world• Non-specific symptoms:

– Fever, night sweats– Fatigue– Wt loss– Diarrhea– Abd pain

• Less commonly:– Hepatosplenomegaly– Lymphadenopathy (esp intra-abd)

Photo Quiz. Clin Infect Dis Nov 2008;47:1320.

Disseminated MAC: DDx ofConstitutional symptoms, pancytopenia,

hepatosplenomegaly

• Disseminated TB

• Disseminated histoplasmosis

• Lymphoma

• Castleman’s disease

Disseminated MAC• Lab abnormalities:

– Anemia (can be severe)– Leukopenia– Elevated alkaline phosphatase– Elevated LDH

• Diagnosis: Mycobacterial blood Cx - sensitivity ~90% with 1, 98% with 2. AFB Cx from sterile sites (bone marrow, lymph node, liver).

• Treatment– Macrolide plus ethambutol +/- rifabutin– HAART– Discontinue therapy when CD4 > 100/mm3 x 6 months AND > 12

months treatment AND asymptomatic

Karakousis, Lancet Infect Dis 2004; 4: 557.

MAC Outcomes

Immune Reconstitution Inflammatory Disease

• Exuberant immune-mediated inflammatory response to antigenic triggers with start of HAART

• Primary disorder = Immune perturbation not infection

• Growing list of associated infections

• Mycobacteria most frequently implicated in IRIS - accounting for ~40% cases since 2002.

Lawn, Lancet Infect Dis 2005; 5: 361.

MAC & Immune Reconstitution Inflammatory Syndrome

• Most without evidence of pre-existing disease

• Commonly presents as fever and LAD:– Peripheral/localized LAD– Intrathoracic LAD/pulmonary disease– Intra-abdominal disease

• Median onset 3-4 weeks from initiation of HAART

Lawn, Lancet Infect Dis 2005; 5:361. Phillips, Clin Infect Dis 2005; 41:1483.

Phillips, Clin Infect Dis 2005; 41:1483.

Case 4

48 yo man with advanced HIV presents with 3 weeks of progressive lower extremity numbness and weakness. Now c/o inability to walk or urinate.

• Last CD4 25, HIV RNA 120,000.

• PMH: Chronic perianal HSV - lost to care

• Meds: None

• Exam: Afebrile, BP 126/89 87 16 97% RA– GEN: Thin frail-appearing man NAD– CHEST, ABD, SKIN unremarkable– NEURO: 3+ out of 5 strength in major muscle groups

LEs. No increased tone.

Case 4

• PEx (cont):– NEURO: Absent DTRs @Achilles, 1+ Patellar

bilaterally. No response to Babinski. Impaired anal sphincter tone. Sensory deficit to LT, cold, vibration from mid-thigh on L, inguinal crease on R.

– No meningismus, alert & fully oriented

• Questions?• What would you do next?

Case 4

• MRI spine: ?possible thickening of cauda equina.

• Labs: – Negative Toxo IgG– Non-reactive RPR– Serum CrAg negative

Adapted from Medscape Neurology & Neurosurgery.Accessed: http://www.medscape.com/viewarticle/439453_1

Case 4

• Lumbar puncture:Opening pressure not reported– 48 WBC (75% PMNs)– 4 RBCs– Protein 83 mg/dl– Glucose 52 mg/dl (serum 114 mg/dl)– Culture no growth

Viral studies: HIV, HSV, EBV negative. CMV positive: 8500 copies/mL.

CMV PolyradiculopathyClinical manifestations

• CD4 <50• Often asymmetrical• Rapidly progressive, ascending course• Sensory loss common (up to 78%) - rare to have

sensory level suggestive of spinal cord involvement• Sacral dysesthesias• Areflexia• Parapesis (flaccid) - lower extremities typical - upper

extremity involvement is late finding• Urinary retention, fecal incontinence or constipation

CMV PolyradiculopathyClinical features

• CSF: mild to moderate neutrophilic pleocytosis, +/- low glucose, high protein is a fairly specific finding - not sensitive (seen in only ~50%)

• Think CMV polyradiculopathy if clinical picture not compatible with bacterial meningitis in patient with advanced HIV -- i.e. sterile CSF

• MRI spine not always revealing - only 25% show gadolinium enhancement of cauda equina

• Mortality 100% if untreated; median survival in pre-ganciclovir, pre-HAART era = 5.4 weeks

CMV PolyradiculopathyDifferential Diagnosis

• Other viral etiologies:– HIV– EBV, HSV, VZV– Echo viruses

• Toxoplasmosis• Syphilis• Tuberculosis• Leptomeningeal lymphoma• Diffuse infiltrative lymphocytosis syndrome• Guillain-Barré syndrome

CMV: Other manifestations?

• Chorioretinitis• Gastrointestinal disease

– Esophagitits– Enterocolititis

• Pneumonititis• Central nervous system

– Polyradiculopathy, myelitis– Encephalititis (subacute)

Case 5

46 yo man with Stage 3 HIV presents with tattoo induration x 4 weeks.

• Last CD4 201, VL <30 on d4T, 3TC, nelfinavir.• Has fever (T >38°C) and a weight loss of 10 kg

in the previous 3 months.• PMH: Hep C, heroin dependence (on

methadone), hx herpes zoster

Lopez-Medrano et. al. Clin Infect Dis 2007;45:220–221.

Lopez-Medrano et. al. Clin Infect Dis 2007;45:220–221.

Lopez-Medrano et. al. Clin Infect Dis 2007;45:220–221.

HIV & Leishmaniasis

• Protozoan spp - tropical temperate regions all over except Australia & Oceania

• Zoonotic disease - transmitted to humans by sandfly bite

• Diagnosis by microscopic or Cx in tissue

• 2nd most common tissue-associated protozoan infection in HIV-infected– High rates of coinfection reported in S. Europe, Brazil

– ?Underreported in Africa, India

• Viscerotropism vs dermatotropism blurred in HIV-infected– HIV increases risk of VL by 100-2000+ fold– HIV increases risk of relapse– VL-HIV - lower cure rate, higher mortality, higher drug toxicity

Thank you!Next session: 15 October, 2009

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Welcome to I-TECH HIV/AIDS Clinical Seminar Series

Next session:15 October, 2009

David Spach, MD & Chris Behrens, MD

HIV Pathogenesis and Antiretroviral Therapy Update