Neelay Kothari, MD March 12th, 2015

Estimated 1.18 million people living with HIV (2008)

20% believed to be unaware of their infection

Males 75%, Females 25%

Rates of infection 8x higher amongst blacks than whites

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Prevalence

34 year old Somali female with negative PMH

Two month history of progressive dyspnea, dry cough, headache, loss of appetite

Acutely worse over the past 3 days

Exam (pertinent positives)

Febrile to 102.9 degrees

Dyspneic and tachypneic

Scattered crackles on lung exam

There is a very extensive diffuse hazy ground-glass opacity in virtually all the lungs, more severely involving the dependent portion of the lower lung fields, atelectases, as well as mild air bronchogram

Rapid HIV Test positive CD4+ count = 14 HIV Viral Load = 649,000

Which of the following is most likely?

(A) Pulmonary tuberculosis

(B) Pulmonary MAI infection

(C) Pneumocystis infection

(D) Toxoplasmosis pneumonia

(E) Cryptococcal pneumonia

How should diagnosis of pneumocystis pneumonia be made?

(A) Blood fungal cultures

(B) Sputum stain for pneumocystis

(C) Sputum fungal cultures

(D) Serology

Sputum stain positive for pneumocystis organisms

CD4 < 200 in 90%; Mean CD4 = 79

Before HAART: 70-80% got PCP without prophylaxis

Incidence markedly down with HAART

Risk of relapse 65 % w/o secondary prophylaxis

Symptoms usually of insidious onset Fever

Dyspnea

Non-productive cough

Often have oral thrush co-infection

Findings

Hypoxemia

Diffuse bilateral interstitial infiltrates (can have normal CXR)

LDH elevation (non-specific)

Pneumothorax

Histopathologic examination

PCR Testing

Beta-d-glucan assay

Not able to culture organism

Organisms persist for days to weeks

OK to start empiric treatment if high index of suspicion

Histopathology (microscopy with staining): Sensitivity in HIV patients

Induced sputum 50-90%

Bronch with BAL 90-99%

Transbronch biopsy 95-100%

Open lung biopsy 95-100%

Lower yield in non-HIV patients

Lower organism burden

PCR testing

Increased diagnostic yield, especially in non-HIV patients

Beta-d-glucan in serum

Up to 92% sensitivity

Not specific for pneumocystis

TMP-Sulfa is drug of choice

15-20 mg/kg q6-8h x 21 days

Intolerance common (rash, pancytopenia, hepatitis)

Survival rate 91% if complete treatment, 31% if change to pentamidine

Other options (mild-to-moderate disease)

Dapsone + TMP (similar efficacy, more pills)

Primaquine + clindamycin

Pentamidine

Atovaquone

Other options (severe disease)

IV Pentamidine (more toxic – hypoglycemia, metabolic, hepatitis, pancreatitis, neutropenia)

Primaquine + clindamycin

Trimetrexate (not available anymore)

Allow 7-10 d for response; PATIENCE! May deteriorate early Keep dry! Follow glucose on pentamidine Steroids: If PO2 < 70 or A-a gradient > 35 mmHg

Reduced early deterioration in oxygenation, decreased early and intermediate mortality

Prednisone 40 mg bid x 5d,20 mg bid x 5 d, 20 mg qd to day 21

Indications for primary prophylaxis CD4 < 200 (consider if 200-250 and dropping fast) Oropharyngeal candidiasis

Secondary prophylaxis History of pneumocystis (until immune

reconstitution)

Atovaquone 1500 mg po daily

Dapsone + pyrimethamine + leucovorin

Atovaquone + pyrimethamine + leucovorin

TMP-SMX 1 DS or SS daily Dapsone 100 mg daily Pentamidine Inhalation-300 mg q mo by neb

Non-compliant pts

More peripheral PCP and pneumothoraces

Atovaquone 1500 mg po daily Dapsone + pyrimethamine + leucovorin Atovaquone + pyrimethamine + leucovorin

2 years later….

Patient presents with difficulty swallowing, mouth ulcers, weight loss, fever, and pain in chest

Has been non-adherent to HIV treatment and prophylactic medications, missed several clinic visits

CD4 count 20, HIV viral load > 100,000

Exam: several ulcers in mouth, + thrush

Possible causes of patient’s symptoms?

Admitted to hospital for evaluation EGD

Multiple esophageal ulcerations

Perforation with possible tracheo-esophageal fistula

Biopsy -> CMV

Typically causes disease with CD4 < 50 Chorioretinitis

30% incidence in AIDS patients (before HAART)

Initially unilateral – will spread to other eye

Floaters, visual loss, decreased acuity

Diagnosis: clinical ophthalmology evaluation

Treatment: systemic and local (val)ganciclovir

Esophagitis / colitis Fever, weight loss, diarrhea, odynophagia

Can have hemorrhage / perforation rarely

Neurologic disease: dementia, ventriculoencephalitis, ascending polyradiculomyelopathy

Pulmonary disease: significance often unclear

66 year old Native American male Presenting with partial seizure with left face

twitching, left arm rhythmic movements, and slurred speech

Past Medical History: CAD, hyperlipidemia, hypertension

Social History: divorced, works as mechanic and farmer, lives alone

12 mm in diameter focus of ring

enhancement at the corticomedullary

junction of the lateral aspect of the

precentral gyrus of the posterior right

frontal lobe in the expected location of the

primary motor cortex. There is vasogenic

edema in the adjacent white matter of this

gyrus

Differential Diagnosis?

Further workup?

12 mm in diameter focus of ring

enhancement at the corticomedullary

junction of the lateral aspect of the

precentral gyrus of the posterior right

frontal lobe in the expected location of the

primary motor cortex. There is vasogenic

edema in the adjacent white matter of this

gyrus

1.1 cm peripherally enhancing lesion within

the posterolateral right frontal lobe that has

developed worsening non-enhancing

increased T2 signal in the subcortical white

matter compatible with edema

3 Days Later

Laboratory Evaluation

HIV antibody POSITIVE

CD4 count = 32

HIV viral load = 315,000

Toxoplasma IgG POSITIVE

EPIDEMIOLOGY

Variable seroprevalence 15% in United States

50-75% in parts of Europe

Transmission Undercooked meat with tissue

cysts

Oocysts in cat feces (sporulation requires 24 hours)

Not person-to-person

CLINICAL

Disease risk CD 4 count usually < 50

33% will get disease without prophylaxis

Symptoms Focal encephalitis

Headache, confusion, focal motor weakness

Fever

Seizures

ExtraCNS disease rare

Clinical presentation Serology 95 % sensitive CT or MRI-Multiple, bilateral,hypodense,

ring-enhancing mass lesions with predilection for B.G. and corticomedullary junction

Commonest cause of focal brain lesion in AIDS

Reduced in HAART Era

Clinical and radiographic response to Rx

Usually better in 2 wks

Differential Diagnosis

CNS Lymphoma

Toxoplasmosis

Tuberculosis

Cryptococcus

Other: Bacterial / PML / Chagas disease

Often treat empirically for toxoplasmosis

Biopsy if fail to respond

Pyrimethamine(200mg x 1 then 50-100 mg qd) + Sulfadiazine(1-2 g q 6h) Leucovorin to prevent BM suppression

80-90 % respond in 2-6 wks

Relapse 90 % w/o maintenance

f/u CT or MRI in 2-4 wks

Treatment at least 6 weeks, often longer if incomplete response

Chronic maintenance / secondary prevention: Pyrimethamine 25-50 mg daily + sulfadiazine 2-4 grams daily + leucovorin

Other regimens Pyrimethamine + Clindamycin Pyrimethamine + Azithromycin or Clarithromycin Atovaquone +/- Pyrimethamine

Indication: CD4 < 100 and Toxo IgG + TMP-SMX 1 DS tab daily is first line Other options

TMP-SMX 1 DS PO tiw

TMP-SMX 1 SS PO daily

Dapsone 50 mg PO daily + pyrimethamine 50 mg PO weekly + leucovorin 25 mg PO weekly

Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly

Atovaquone 1,500 mg +/- pyrimethamine 25 mg + leucovorin 10 mg) PO daily

43 year old female originally from Kenya 2-4 week history of

Left sided weakness

10 lb weight loss

Mental slowing

Fatigue and sleepiness

Past medical history: anemia Exam: slow to respond to questions, mild left

sided weakness, white coating on tongue

Laboratory Evaluation

HIV Antibody POSITIVE

CD4 count = 16

HIV Viral Load = 3,220,000

RPR Negative

CSF

▪ 1 WBC, 1 RBC, protein 26, glucose 54

▪ Cryptococcal antigen negative

▪ JC virus PCR POSITIVE

Patient was started on HIV treatment

Unfortunately her mental status continued to deteriorate

Transitioned to comfort care and died

JC Virus – 85% of population seropositive CD4+ count usually < 100 Clinical Presentation

Demyelinating lesions

Focal neurologic deficits

Progressive over weeks to months

Seizures in 20%

Imaging: Multiple nonenhancing white matter lesions

No mass effect

CSF analysis: PCR positive in 70-90% if not on HAART

Treatment

No specific treatment

Reverse immunosuppression ▪ Start HAART immediately

Prognosis

High morbidity and mortality

Half get better with HAART, though often have residual deficits

Lower CD4 count at presentation associated with poor outcome

46 year old male previously healthy Chief complaint: headache

Present for approximately one month

Sudden onset, with gradual worsening since

Bilateral, retro-orbital and into top of head Initially seen in Minute Clinic

Presumed sinusitis, prescribed amoxicillin

Not better, prescribed azithromycin

Not better, then prescribed Vicodin 6 days prior to admission

Associated symptoms Nausea and vomiting x 2 weeks

15 pound weight loss

Brief 30-60 second episodes of dizziness

Intermittent photophobia

Ringing sensation in right ear

Feels somewhat depressed Per family

Slow mentation and speech

Increased sleepiness

Works as nail technician, unable to work recently

No tobacco, occasional cigar, occasional alcohol (2 drinks per week), denies other drug use

Travel: recent travel to England No pets, animal or tick exposures, sick

contacts Enjoys gardening

VS Temp 98.1, P 75, R 16, BP 131/90 Weight 130 lb General: flat and depressed affect, slow

speech HEENT: whitish patches on tongue Skin: 3-4 mm skin colored papules present on

forehead, shoulder, sternum Remainder of exam unremarkable

HEAD MRI Focally increased signal intensity on

FLAIR and T2-weighted images involving the caudate nuclei, putamina, globus pallidus nuclei and the thalami bilaterally.

No associated hemorrhage, midline shift or hydrocephalus.

Patchy restricted diffusion in the same distribution, but to a lesser extent than the areas of T2 prolongation.

HEAD MRI Focally increased signal intensity on

FLAIR and T2-weighted images involving the caudate nuclei, putamina, globus pallidus nuclei and the thalami bilaterally.

No associated hemorrhage, midline shift or hydrocephalus.

Patchy restricted diffusion in the same distribution, but to a lesser extent than the areas of T2 prolongation.

HEAD MRI Focally increased signal intensity on

FLAIR and T2-weighted images involving the caudate nuclei, putamina, globus pallidus nuclei and the thalami bilaterally.

No associated hemorrhage, midline shift or hydrocephalus.

Patchy restricted diffusion in the same distribution, but to a lesser extent than the areas of T2 prolongation.

HEAD MRI Focally increased signal intensity on

FLAIR and T2-weighted images involving the caudate nuclei, putamina, globus pallidus nuclei and the thalami bilaterally.

No associated hemorrhage, midline shift or hydrocephalus.

Patchy restricted diffusion in the same distribution, but to a lesser extent than the areas of T2 prolongation.

WBC 4.3, Hgb 12.7, plt 202 Creatinine 0.97 Liver function tests normal Rapid HIV test positive Lumbar puncture

Opening pressure 31cm

0 RBC, 74 WBC (90% L)

Protein 76, glucose 45

Gram stain: no PMNs, 2+ yeast

RPR negative

Cryptococcal antigen positive (1:2048)

Can infect any organ Most common sites of

infection

Lungs: nodules, masslike infiltrate, adenopathy, lung cavitation, lobar infiltrates

CNS: subacute meningitis or meningoencephalitis

Skin: papules with soft or ulcerated center

CD4 count usually < 50 Usually subacute presentation

Meningitis or meningoencephalitis

Fever, malaise, headache

CSF findings

Opening pressure > 20 cm in 75%

Mildly increased protein, glucose low to normal

Lymphocytic pleocytosis or normal WBC

Positive serum cryptococcal antigen (93-99%)

Altered mental status Positive cryptococcal BC CSF Ag titer > 1:1024 + CSF India Ink CSF Cell Count <20

Initial Treatment Amphotericin + flucytosine x 2 weeks minimum Monitor flucytosine levels Monitor renal function / can use liposomal ampho Serial therapeutic lumbar puncture to reduce ICP

Follow up therapy Lumbar puncture at 2 weeks to check culture Once clinically better and if culture negative, can switch to

fluconazole 400 mg po daily x 8 weeks

Chronic maintenance therapy Fluconazole 200 mg po daily Until immune reconstitution

Randomized trial in 64 patients

Ampho monotherapy

Ampho + Flucytosine

Ampho + Fluconazole

Ampho + Flucytosine + Fluconazole

Ampho + Flucytosine had more rapid CSF sterilization (0.15-0.23 log CFU per day)

No association with clinical outcomes

Brouwer et al, Lancet, 2004.

Observational Study

208 patients

Outcome: death or mycologic failure at 2 weeks

Ampho + flucytosine: 26% failure

Other treatments: 56% failure

Dromer et al, PLOS One, 2008

Treatment:

Amphotericin B 0.7 mg/kg IV daily

Flucytosine 25 mg/kg po q6hours

Repeat lumbar puncture

Opening pressure = 8 cm

Additional laboratory testing

CD4 count 68, viral load 1,090,000

After 4 days of therapy, creatinine increased from 0.97 to 1.92

Changed amphotericin to Abelcet 5 mg / kg

Creatinine subsequently improved gradually

Subsequently developed severe nausea, vomiting, and bloody diarrhea

Underwent EGD and colonoscopy with biopsy

Results: 1. Atypical colitis, suspicious for drug induced (possibly flucytosine). This is a

morphologically unusual colitis, which is histologically very similar to the colitis one sees in patients with mycophenolate mofetil colitis.

2. No viral inclusions noted

3. No evidence of idiopathic inflammatory bowel disease or opportunistic infection

Headache improved, mentation improved Repeat lumbar puncture at ~2 weeks

Cryptococcal antigen 1:256

Culture with 1+ cryptococcus

▪ Fluconazole MIC = 16

▪ Flucytosine MIC > 32 (RESISTANT)

Antifungal therapy was changed to fluconazole

Gradual improvement in CNS and gastrointestinal symptoms

Eventually started HAART approximately 2 months after initial diagnosis

Now doing well

CD4 count improved from 38 to 263

No CNS sequelae

Ubiquitous in environment Typically CD4 count < 50 (20-40% incidence) Clinical presentation

Often non-specific

Fever, night sweats, fatigue, weight loss, diarrhea

Pulmonary presentation less common

Anemia, elevated alkaline phosphatase

Hepatomegaly, splenomegaly

Diagnosis: culture from sterile site

Treatment: multi-drug therapy

Clarithromycin (or azithromycin)

Ethambutol

Rifabutin

Prophylaxis – rule out active infection first

Azithromycin 1200 mg weekly is preferred

Rifabutin is an option

▪ More drug interactions

▪ Rule out active TB

Most common HIV-related illness globally Cause of death for 13% of those with AIDS CD4 most often 300-500 Reactivation most common 10 % risk per yr of reactivation v 10% lifetime risk if

immunocompetent Presentation typical of reactivation only if intact

immune system In AIDS extrapulmonary in 2/3 Only 30-50 % with AIDS have + PPD(>5mm)

Retest once CD4 count >200

Most common neoplasm in AIDS Usually gay males HHV-8-DNA + > 90% HIV + KS Localized or widespread visceral disease

GI,Lung, LN Violaceous lesions Bx-mimics BA

Rx = IFN, Vinblastine, VCR,VP-16,Adriamycin Responses Poor

HAART-good responses, sometimes complete remission

CD4 100-200

PCP Cryptosporidiosis

CD4 < 100

NHL PML Toxoplasmosis Cryptococcus CMV MAI Wasting Syndrome HIV Encephalopathy Recurrent PCP

Candida Tuberculosis HSV Zoster Pneumococcus

CD4 200-350

Infection Indications Preferred Discontinue

Pneumocystis AIDS diagnosis

CD4< 200

Thrush

TMP-sulfa SS or DS daily CD4 > 200 x 3 months

Toxoplasmosis CD4 < 100 + positive

toxo IgG

TMP-sulfa DS daily CD4 > 200 x 3 months

MAC CD4 < 50 Azithromycin 1200 mg

weekly or 600 mg

2x/wk

CD4 > 100 x 3 months

Histoplasmosis CD4 < 100 and lives in

endemic area

Itraconazole 200 mg CD4 > 150 x 6 months

Parodoxical clinical worsening after starting HAART despite improved immune function

Due to inflammatory response against infectious antigen CD 4 count usually < 50 Usually within 6 weeks, though can be several months Common pathogens: MAC, TB, CMV, cryptococcus,

pneumocystis, JC virus Can have atypical presentation Treatment: continue HAART if possible, treat infection,

anti-inflammatory therapy

Opportunistic infections are often the initial presentation of persons with undiagnosed HIV infection

Important to recognize syndromes, test for HIV infection when indicated

Treatment of HIV infection reduces risk for opportunistic infections