HIV Opportunistic Infections

Michael P.Dubé, MD

Professor of Medicine

Division of Infectious Diseases

PNEUMOCYSTIS JIROVECI PNEUMONIA

HistoryHistory

Chronic cough (non-prod or clear)Low grade fever, may be absent or highChest tightnessExertional dyspneaDyspnea at rest - lateProphylaxis history

PNEUMOCYSTIS CARINII PNEUMONIAPNEUMOCYSTIS JIROVECI PNEUMONIA

ExaminationExamination

Low-grade fever (may be HIGH, or absent)Lung exam not very helpful, rales LATEThrushSeborrheaLymphadenopathy not seen (>1cm)

Multiple infections common

PNEUMOCYSTIS JIROVECI PNEUMONIA

LaboratoryLaboratory

• LDH > 300 in >90% of moderate to severe cases• CD4+ < 200 in >90%• CXR normal in 10-30%• (A-a) DO2 will be > 15 torr in >80%• DLCO, Ga scanning, exercise testing

may help

Admission criteriaAdmission criteria

• PO2 < 70-80

• (A-a)DO2 >30-35

• RR > 20

• Diagnosis uncertain

• Unreliable patient

• Unable to take po

PNEUMOCYSTIS JIROVECI PNEUMONIA

PNEUMOCYSTIS JIROVECI PNEUMONIA

DiagnosisDiagnosis

• If patient is ill, start empiric therapy• Induced sputum

30-60% sensitive• Bronchoscopy

BAL positive in ~90%TBBx is positive in 85-95%Yield of two tests is additive

• "Presumptive" diagnosis not reliable

• Late bronchoscopy associated with increased

complications and mortality

Conditions Mimicking PCP

No. Cases Histologic Description

16 Nonspecific Interstitial Pneumonitis

16 Normal Histology

13 Inadequate Histology (<30 alveoli)

7 Bronchial Abnormalities

2 Pyogenic Pneumonia

2 Pulmonary Lymphoid Hyperplasia

2 Caseating Granuloma

2 Talc Pneumonitis

1 Caseasting Granuloma with AFB

1 Pulmonary Anthracosis

1 Non-caseating Granuloma

1 Pulmonary Hemosiderosis

1 Cytomegalovirus Pneumonia

1 Eosinophilic Pneumonia

1 Squamous Cell Dysplasia

PNEUMOCYSTIS JIROVECI PNEUMONIA

TreatmentTreatment

• Drug of choice is TMP-SMXIV 15 mg/kg/d (5 mg/kg q8h)Oral 2 DS tabs TID for 70kg person

• Adverse effects in 40%RashElevated transaminasesNausea and vomitingNeutropenia

PNEUMOCYSTIS JIROVECI PNEUMONIA

Treatment - General principlesTreatment - General principles

• If sick enough to be hospitalized, sick enough to get IV therapy

• Total duration of 21 days

• Change to oral therapy when:Taking regular dietDiagnosis is confirmed AND/ORClear-cut, objective improvementOtherwise ready for discharge

PNEUMOCYSTIS JIROVECI PNEUMONIA

Treatment - Alternative agentsTreatment - Alternative agents

• Pentamidine IVDrug of choice for severe episodes in

TMP-SMX intolerant patients

• Dose 4 mg/kg qd X 21 days in hospital

• Many side effects

PancreatitisLife-threatening hypoglycemia

Neutropenia

Hyperglycemia

Renal failure

PNEUMOCYSTIS JIROVECI PNEUMONIA

Alternative therapy

• Dapsone-trimethoprim

All oral therapy for mild episodes

Dapsone 100 mg/d, trimethoprim 20 mg/kg/d

Less side effects than TMP-SMX

Rash, methemoglobinemia

• Clindamycin-primaquineMild to moderate episodes

IV or po clinda 450-600mg q6h + primaquine

30mg po daily

Rash, LFT abnormalities, methemoglobinemia

and leukopenia also common

PNEUMOCYSTIS JIROVECI PNEUMONIA

Alternative agentsAlternative agents

• Atovaquone (Mepron)Less toxic, less effective therapy for mild PCP

• Dose 750 mg suspension BID• Do not give to patients with diarrhea• Good for prophylaxis (1500 mg daily)

PNEUMONIAPNEUMOCYSTIS JIROVECI PNEUMONIA

Adjunctive therapyAdjunctive therapy

• CorticosteroidsIndicated for PO2 <70, AAD >35

Prednisone (or SoluMedrol 75% of dose)40 mg BID X 5 days

40 mg QD X 5 days20 mg QD till end of treatment

Increased incidence of herpes, thrush

• No increase in TB, CMV but may make

pulmonary Kaposi sarcoma progress rapidly

PNEUMOCYSTIS JIROVECI PNEUMONIA

ProphylaxisProphylaxis

• TMP-SMX is drug of choiceDose - One DS a day (or TIW)Prevents other infectionsSafe to rechallenge

• Dapsone less effective (inadeq. for toxo)Dose - 100 mg/d (screen for G6PD)

• Atovaquone comparable to dapsoneDose - 1500 mg/d (expensive)

• Inhaled pentamidine last resortDose - 300 mg/month nebulized

Workup of unexplained fevers

• Thorough history and physical exam

• History

– Travel, area of residence, ingestions,

social history, imprisonment

– Medications and adherence

– Prior medical care, CD4 counts, HIV RNA

– Focus on duration of symptoms

Workup of unexplained fevers

• Physical examination– General

– Careful oral exam

– Skin

– Lymph nodes

– Liver and spleen

– Perirectal area

– DILATED EYE EXAM FOR CMV when CD4 < 50

Workup of unexplained feversLaboratory studies

• Chest x-ray and LDH; liver tests

• UA with micro, CBC

• Fungal and mycobacterial blood cultures

– Especially when CD4 <50

• Serum cryptococcal antigen

• Urine histoplasma antigen (CD4 <50)

• IF affected organ is ABNORMAL: Skin, bone

marrow, liver biopsy

Workup of unexplained feversSTUDIES YOU SHOULD NOT BE DOING

• CMV antibodies

• Toxoplasma antibodies

• “Panculturing”

• LP, CT if no neurologic findings

• Sputum cultures with no pneumonia

• Multiple CD4 cell counts

• β-d-glucan

Histoplasmosis - Clinical syndromes

Site Findings

Pulmonary Cough, infiltrates, cavities

CNS Mass lesion, sometimes meningitis

Disseminated

Fever, night sweats, weight loss,

hepatosplenomegaly (1/3), skin/mucous

membrane lesions, pancytopenia, incr.

alk phos and LDH

Diagnosis of Disseminated

Histoplasmosis in AIDS

• Proper host

– CD4 < 50, central to southern Mexico,

Central American (in SoCal anyway)

• Fungal blood cultures

• Urine histo Ag high sensitivity ~95%

– When the test done in Indianapolis

• Bone marrow biopsy if buffy coat neg.

– IMMEDIATE if patient is severely ill

(pancytopenia, diffuse infiltrates, shocky)

Disseminated Histo in AIDS - Treatment

• Moderate to severe – Liposomal Ampho B

– Sepsis syndrome

– Severe pancytopenia

– Marked liver test abnormalities

– Wasting

– CNS disease

• Mild – Itraconazole 200 mg BID

– Taking regular diet well

– Asking to go home

Disseminated MAC in AIDS

• Proper host

– CD4 < 50, but usually <20

• Findings

– Fever, abdominal pain, diarrhea, severe

anemia, pancytopenia, HSM, ↑alk phos

– Localized findings (big nodes, lungs) rare

• Diagnosis

– Mycobacterial blood cultures (10-21 days)

– Bone marrow biopsy if buffy coat neg.

Disseminated MAC in AIDS - Treatment

• Treatment

– Azithromycin or clarithromycin +

– Ethambutol 15 mg/kg/d

– ± Rifabutin 300 mg/d

• Prophylaxis

– Azithromycin 1200 mg/wk

– Rarely use clarithro or rifabutin15 Feb 2019 DHS guidelines• NOT indicated if ART started immediately

• NOT if suppressed on ART even if CD4<50

• ONLY give if not on ART (eg. crypto

meningitis induction) or viremic in spite of

ART

CNS Toxoplasmosis

Differential diagnosis

• CNS lymphoma

• Tuberculosis

• M. kansasii

• L. monocytogenes

• T. pallidum

• N. asteroides

• Rhodococcus equi

• Cryptococcosis

• Histoplasmosis

• Blastomycosis

CNS Toxoplasmosis

Differential diagnosis

• Phaeohyphomycosis (IDU)

• Zygomycosis (Rhizopus, Absidia, Mucor)

• C. albicans

• Bacterial brain abscess (IE, sinusitis)

• Intracranial T. cruzi

• Amebic meningoencephalitis

• Bacillary angiomatosis

• Herpes simplex

• Varicella zoster

Empiric therapy when patients

are failing anti-toxo therapy

• Sulfadiazine 2gm q6h

• Pyrimethamine 75mg/d

• Leucovorin 10 mg/d

• INH 300 mg/d

• Rifampin 600 mg/d

• Ethambutol 1200 mg/d

• Pyrazinamide 1500 mg/d

• Penicillin G 4MU q4h

• Gentamicin 1.5 mg/kg q8h

• Ceftazidime 2 gm q8h

• Metronidazole 750 mg q8h

• Oxacillin 2 gm q4h

• Vancomycin 1 gm q12h

• Azithromycin 500 mg/d

• Acyclovir 10 mg/kg q8h

• Amphotericin B 50 mg IV/d

• Flucytosine 100 mg/kg/d in 4 divided doses

When to get a brain biopsy

• Always recall that only 50% of brain

abscess will be CNS toxo

• When the toxo IgG is negative

– 50x more likely to be something else

• If the CSF EBV PCR is positive

– Favors CNS lymphoma

• If there is not a radiographic response

after 2 weeks of anti-toxo therapy

Initial CNS toxo treatment

• First-line– Sulfadiazine 1-1.5gm qid

– Pyrimethamine 50-75 mg qd (200 mg loading dose)

– Leucovorin 25 mg/d

• Alternatives– Clinda-pyrimethamine-leucovorin

– TMP-SMX 5 mg/kg bid

– Atovoquone-pyrimethamine-leucovorin

– Atovaquone-sulfadiazine

– Azithromycin-pyrimethamine-leucovorin

• Re-scan at 2 and 6-8 weeks; to maint. doses

Diagnosis of cryptococcal infection

• Serum cryptococcal polysaccharide antigen

– >95% sensitive in AIDS

– Antigen may be negative in CSF

– Tends to decrease with successful therapy

• CSF cultures virtually always positive

• Lung infection often requires BAL

– 1/3 will have negative serum antigen

Treatment of cryptococcal infection

• Meningitis requires hospitalization

– Control of increased ICP is paramount

– Goal of therapeutic LP is OP < 250 mm

– DAILY LP until < 250

– Ampho B 0.7 mg/kg/d + 5FC 100 mg/kg/d for 2 wks

• Monitor K+, Mg++, creatinine; CBC esp. platelets

– Follow with fluconazole 400 mg/d for 8 weeks

– Cont. on 200/d until on effective ART and >200 CD4

for at least 6 months

• No ART for 6-8 weeks

• Mild-moderate non-CNS fluconazole 400/d

Candida

infections

Site Treatment

Oral Clotrimazole lozenges

Short-course fluconazole

Oesophageal Fluconazole 100 mg/d

Bloodstream Echinocandin (until speciated)

Resistant Echinocandin or amphoB

CMV Retinitis

• Clinical– Usually CD4 count <50

– Unilateral, then bilateral if untreated

– Asymptomatic, floaters, scotomata, decreased

acuity, field defects, PAINLESS

– Retinal exam: hemorrhage & exudates

• Treatment

– IV Gancyclovir, IV Foscarnet, PO Valganciclovir

• Monitoring

– Annual eye exam if CD4<50

Timing of ART initiation with

opportunistic infections and malignancies

• Tuberculosis

– Within 2 weeks if CD4 <50

– Within 8 weeks if CD4 >50

• PCP: As soon as patient is stable

• CNS infections

– Due to risk of immune reconstitution inflammatory

syndrome (IRIS), delay ART until major improvement

• Lymphoma and Kaposi sarcoma

– Will respond better to chemo if ART is initiated

IRIS – Immune reconstitution

inflammatory syndrome

• Exuberant inflammatory response to an infection

or malignancy that occurs early during effective

ART with increasing CD4 cells

– Unmasking: unrecognized infection present at baseline

– Paradoxical: exaggerated response occurring in patient

already undergoing treatment for underlying condition

– Manifestations depend on the organ system involved

– Range 2 weeks-1 year but most 4-12 weeks of ART

• Treatment is generally antiinflammatory (NSAIDs,

prednisone) with DC of ART only if life-threatening

Presentation of MAC with HAART

(Immune Reconstitution Inflammatory

Syndrome)

Cryptococcal Meningitis Following HAART

contrast enhancement indicating significant inflammatory changes