Infectious Disease CPC Scott & White Internal Medicine Peter Yau, M.D. Faculty advisor John Carpenter, M.D.

Case 28 y.o. white male transferred from Metroplex with hypotension, O2 sat 80% on RA. PMHx: HIV Meds: None SHx: lives in Houston, recently moved in with mother. Non-compliant with meds.

Case PE: T: 99 BP116/89 after IVF, P100, 90%6L HEENT: oral thrush CV: no murmur, rubs or gallops Resp: b/l upper lobe crackles Abd: benign Neuro: non focal, AxOx3 Skin: diffuse blue-black macular papular rash sparing the palms and soles

Case Labs: ANC 100 Hematocrit 12.2 Platelet 5000 AST 512 ALT 42 Cr 1.1 Electrolytes: mild AG CXR with bilateral upper lobe infiltrates

Hospital Course -Placed on Bactrim, steroids & broad antibiotics -Airborne isolation -Pan cultured -Blood transfused -Bone marrow obtained -MRI head -GI consulted -Derm consulted

Problem list

Pulmonary infiltrates Severe sepsis Pancytopenia HIV hx Abnormal LFT GI Bleed Skin Lesions Oral thrush Renal failure Metabolic acidosis Altered mental status

Immunocompromised Patients & Pulmonary Infiltrates Infectious „

Bacteria (37%), fungi (14%), viruses (15%), Pnemoncystis jiroveci (8%), nocardia (7%), TB (1%), mixed infections (20%)

Non-infectious „

P.E., malignancy, radiation pneumonitis, atelectasis, drug allergy/ toxicity, pulmonary hemorrhage

Immunocompromised Patients & Pulmonary Infiltrates Travel and employment Prolonged duration of neutropenia Hx of frequent antimicrobial exposure Potential or hx of aspiration Hx of presence of pulmonary pathogens/molds Cardiac abnormalities, catheters, lines Hx of metastases DM with sinopulmonary infection

HIV Patients with Pulmonary Symptoms Bacterial infections Mycobacterial infections (TB, MAC) Fungal infections (Pneumocystis jiroveci, aspergillus, histoplasmosis, cryptococcus, mucormycosis) Viral infections (CMV, herpes, RSV) Parasitic infections (strongyloides, toxoplasmosis) Non infectious (PE, lymphoma, Kaposi’s)

Our Patient Pulmonary infiltrates Severe sepsis Pancytopenia HIV hx Abnormal LFT GI Bleed Metabolic acidosis Oral thrush Skin Lesions Renal failure Altered mental status

Systemic Diseases Infectious: TB, MAC, disseminated histoplasmosis, CMV, bacteria, Pneumocystis jiroveci, toxoplasmosis Non-infectious: Kaposi’s sarcoma, lymphoma Mixed diseases

CMV Latent infection after acute infection, reactivation HIV patients relate to primary infection T cells control Prevalence increase with age Sexual, close contact, blood/tissue exposure, occupational, perinatal

CMV Resembles infectious mononucleosis -High fevers, lymphadenopathy, tonsillopharyngitis; EBV more common

Systemic diseases rare

CMV Hepatic manifestation: -Subclinical transaminitis -Elevated alkaline phosphatase /bilirubin -Granulomatous hepatitis (non-caseating epithelioid granulomas, portal triaditis, focal necrosis)

CMV Neurological manifestations: 2% of patients with AIDS -Encephalitis -Guillain-Barre syndrome -Branchial plexus neuropathy, diffuse axonal peripheral neuropathy, transverse myelitis, Horner’s syndrome, cranial nerve palsies

CMV GI manifestation: -Esophagitis (fever, odynophagia, nausea, bleed) -Gastritis (chest pain, GI hemorrhage) -Enteritis (abdominal pain, diarrhea, perforation) -Colitis (low grade fever, wt loss, anorexia, diarrhea, hemorrhage, perforation)

CMV Other involvements: -Cardiovascular (atheroma formation) -Pulmonary (pneumonitis) (rare) -Ocular (retinitis) 20-40% -Dermatologic (macular, papular, morbilliform eruptions) 30%

CMV Diagnosis: -PCR, antigen assays, cultures -Biopsy of GI lesions

CMV Treatment: -Mononucleosis syndrome Self limiting -Systemic syndrome IV Ganciclovir (3 to 6 wks) IV Foscarnet Oral Valganciclovir

Tuberculosis -AIDS defining condition -7-10% per year in HIV patients with +PPD -40% of TB patients with HIV -Both reactivated latent & exogenous infection -TB increases viral load: a. increase CD4 for targets b. increase expression of CCR5 & CXCR4

Tuberculosis Clinical manifestation: -Weight loss, FUO, malaise -Pulmonary as primary site (Pleural involvement) -Blood & extrathoracic lymph nodes (20%), bone marrow, GU tract, CNS, GI, skin

Tuberculosis Diagnosis: CXR -Primary infection: 36%. Pleural effusion, intrathoracic lymphadenopathy, middle/lower lobe consolidation without cavitation.

-Secondary infection: 29%. Apical/posterior consolidation of upper lobes or consolidation of superior segments of lower lobes without lymphadenopathy or effusion, endobronchial spread, bronchiectasis

Tuberculosis Diagnosis CXR -Miliary pattern – 4%. -Abnormalities atypical for TB – 13%. -Minimal changes – 5%. -Normal – 14%. *most patients with CD4 Productive cough, dyspnea, hypoxia >Abnormal CXR in 70% -lobular/ acinar bronchopneumonia -enlarged hilar/mediastinal lymph nodes with focal infiltrates (patchy, nodular, diffuse, miliary) >Chronic histo x-ray resemble reactivation T.B. >Broncholithiasis, mediastinal granuloma, fibrosing mediastinitis

Histoplasmosis GI involvement: 70% disseminated histoplasmosis 10% recognized -Ulceration, masses, dysphagia, GI bleed, colonic perforation

Histoplasmosis Skin involvement: 10% - 20% African strain -Nodules, papules, plaques, ulcers, vesicles, pustules, abscesses, dermatitis, exfoliative erythroderma, necrotizing vaxculitis, cellulitis, petechaie, purpura, ecchymoses

Histoplasmosis Adrenal involvement: 80% to 90% 10% adrenal insufficiency Adrenal infarcts or hemorrhage

Histoplasmosis CNS involvement: 5% to 20% Underlying immunosuppressive disorders -Meningitis + other symptoms of dis. Histo.(40%), -Isolated chronic meningitis(25%) -Focal brain lesions(25%) -Encephalitis(10%) -Localized involvement of spinal cord(2.5%)

Histoplasmosis Other involvements: -Hypercalcemia, chorioretinits, pleuritis, percarditis, endocarditis, peritonitis, pancreatitis, cholecystitis, prostatitis, panniculitis, mastitis, osteomyelitis, septic arthritis, epididymitis

Differential Diagnosis Usual Bugs – Salmonella Other „ „

CMV Mycobacteria Tuberculous MAC

Histo – or other fungus Cancer „ „

Lymphoma ?KS

Histoplasmosis Diagnosis: -Laboratory results suggestive: pancytopenia, LFT’s, CXR, CSF 1. Serological antibodies and cultures 2. Antigen and histopathology

Histoplasmosis Serological antibodies and cultures Antibody tests (60-70%) Immunodiffusion & complement fixation Falsely positive and negative Cultures Blood: 50-70% +, lysis centrifugation vs. BACTEC Urine: 40% + Sputum/ lavage/ lung tissue: 70% Bone Marrow: >70%

Histoplasmosis Antigen and histopathology Urine antigen 95% sensitive Serum antigen 86% sensitive Tissue biopsy (41 -63%) Hematoxylin & eosin stain, methenamine silver / PAS

Histoplasmosis Treatment:

1. Liposomal Amphotericin B (abelcet) 81 with AIDS 88 vs 64 clinical success 2 vs 13 mortality 25 vs 63 infusion side effect 9 vs 37 nephrotoxicity

Histoplasmosis Treatment: 2. Itraconazole Less ill/ maintenance Capsule vs. liquid Measure serum level after 2 weeks 6 months to 1 year of therapy 3. Fluconazole 4. Posaconazole, voriconazole, caspofungin

Our Patient Pulmonary infiltrates Severe sepsis Pancytopenia HIV hx GI Bleed Abnormal LFT Skin Lesions Renal failure Neurological decline

Our Patient Sputum collected for mycobacteria & fungus Thrush treated with Diflucan Blood transfused; Hct to 24 ANC to 50,000 Remain afebrile A diagnostic test returned positive A second test returned several hours later was confirmatory

CMV- rarely as sole pathogen for pul. abnormality TB/MAC- no lymphadenopathy, skin manifestation rare, normal x ray with low CD4 Kaposi’s Sarcoma – possibility as a co-infection, biopsy confirmatory Histoplasmosis – location and symptoms consistent Mixed diseases a consideration

Diagnosis

Disseminated Histoplasmosis

REFERENCES 1. Evans, AS, Niederman, JC, Cenabre, LC, et al. A prospective evaluation of heterophile and Epstein-Barr virus-specific IgM antibody tests in clinical and subclinical infectious mononucleosis: Specificity and sensitivity of the tests and persistence of antibody. J Infect Dis 1975; 132:546. 2.Evans, AS. The history of infectious mononucleosis. Am J Med Sci 1974; 267:189. 3.Sprunt, TP, Evans, FA. Mononucleosis leukocytosis in reaction to acute infections (infectious mononucleosis). John Hopkins Hosp Bull 1920; 31:409. 4. Joseph Wheat, L. Current diagnosis of histoplasmosis. Trends Microbiol 2003; 11:488. 5. Corcoran, GR, Al-Abdely, H, Flanders, CD, et al. Markedly elevated serum lactate dehydrogenase levels are a clue to the diagnosis of disseminated histoplasmosis in patients with AIDS. Clin Infect Dis 1997; 24:942. 6. Conces, DJ Jr, Stockberger, SM, Tarver, RD, Wheat, LJ. Disseminated histoplasmosis in AIDS: findings on chest radiographs. AJR Am J Roentgenol 1993; 160:15. 7. Poulsen, A. Some clinical features of tuberculosis. 2. Initial fever 3. Erythema nodosum 4. Tuberculosis of lungs and pleura in primary infection. Acta Tuberc Scan 1951; 33:37. 8. Nichols, CM, Flaitz, CM, Hicks, MJ. Treating Kaposi's lesions in the HIV-infected patient. J Am Dent Assoc 1993; 124:78. 9. Danzig, JB, Brandt, LJ, Reinus, JF, et al. Gastrointestinal malignancy in patients with AIDS. Am J Gastroenterol 1991; 86:715. 9. UpToDate® 10. Cecil Essential of Medicine (4th edition)

Differential Diagnosis Usual Bugs – Salmonella Other „ „

CMV Mycobacteria Tuberculous MAC

Histo – or other fungus Cancer „ „

Lymphoma ?KS

The End