8 October, 2009 Opportunistic Infectious H. Nina Kim, MD, MSc

1. 8 October, 2009 Opportunistic Infectious H. Nina Kim, MD, MSc

2. 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. Adapted from Johns Hopkins AIDS Service http://www.hopkins-aids.edu/educational/caserounds/caserounds_12.html

3. Additional Hx

4. 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.

5. 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.

8. 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

9. 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

10. 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 Pneumocystis PneumoniaDiagnosis A definitive diagnosis for Pneumocystis should be sought.

11. Primary Prophylaxis Secondary Prophylaxis CD4 > 200 x ≥ 3 months CD4 > 200 x ≥ 3 months Discontinuation of Pneumocystis ProphylaxisRecommendations from USPHS/IDSA Guidelines MMWR 2001;50 (RR-11):1-52.

12. 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. Partners Infectious Disease Images http:// www.idimages.org

13. Additional Hx PMH • HIV infection of unknown duration – not presently in care Medications • None (antiretroviral naïve) Social Hx • Hx IVDU, active

14. 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.

17. Differential? • Bacillary angiomatosis • Molluscum contagiosum • Cryptococcosis • Histoplasmosis • Chronic disseminated HSV, VZV • Kaposi’s sarcoma

19. 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

20. How would you manage this patient? • What would you do next?

21. 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.

22. Cryptococcal meningitis HIV webstudy

23. Managing increased ICP in Cryptococcal meningitis • Repeated LP • Drain insertion • Ventriculoperitoneal shunting • No proven benefit: Mannitol, acetazolamide, corticosteroids

24. 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 Conference March 2008

25. 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

26. 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

27. Medications • Atazanavir • Ritonavir • Epzicom (Abacavir + FTC) • Lisinopril • Metformin • Acyclovir • Inhaled pentamidine

28. 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

29. 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

30. 2 months PTA 3 days PTA

32. 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

33. 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

34. 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)

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

36. Disseminated MAC: DDx ofConstitutional symptoms, pancytopenia, hepatosplenomegaly • Disseminated TB • Disseminated histoplasmosis • Lymphoma • Castleman’s disease

37. 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

38. MAC Outcomes Karakousis, Lancet Infect Dis 2004; 4: 557.

39. 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.

40. 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.

41. Phillips, Clin Infect Dis 2005; 41:1483.

42. 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.

43. 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?

44. 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

45. 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.

46. 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

47. 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

48. CMV PolyradiculopathyDifferential Diagnosis • Other viral etiologies: • HIV • EBV, HSV, VZV • Echo viruses • Toxoplasmosis • Syphilis • Tuberculosis • Leptomeningeal lymphoma • Diffuse infiltrative lymphocytosis syndrome • Guillain-Barré syndrome

49. CMV: Other manifestations? • Chorioretinitis • Gastrointestinal disease • Esophagitits • Enterocolititis • Pneumonititis • Central nervous system • Polyradiculopathy, myelitis • Encephalititis (subacute)

50. 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.