Cryptococcal Meningitis with Cranial Nerve Neuropathies: Predictors of Outcome and Review of ART...

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AIDS CLINICAL ROUNDS

Cryptococcal Meningitis with Cranial

Nerve Neuropathies: Predictors of

Outcome and Review of ART Initiation

AIDS Rounds

11/16/12

Jill Blumenthal, ID Research Fellow

History of Present Illness

• RG is a 39M with HIV (CD4 14/4%, VL 40,519 VL) not

on ART presents with worsening HA, neck stiffness,

diplopia, n/v x1 week

• Noticed diplopia 1 week ago while driving, worse when

looks left

• HAs intermittent, pulsaltile worse with movement.

• + photophobia and phonophobia; lightheaded

• Intermittent “sparkles” in vision

• No fevers (but subjective warth), chills or sweats

• ROS: +20lb weight loss over 7 months. Thrush and

dysphagia. Rash on soles of feet x2 months. No CP,

SOB or diarrhea

History

PMH:

• Prior treatment for

Tuberculosis as a child

• Diagnosed with HIV in

2/2012 at North Park

Meds: None

All: None

FHx: HTN in mom, Diabetes

in dad

SHx

• MSM

• No IVDU. Used to snort

meth/coke. No EtOH

• 5 pack-year smoking

history, quit 6 months ago

Physical Exam

• VS: T 99.5 BP 145/90 HR 107 RR 18 O2 99% RA

• General: NAD, AOx3

• OP with thrush and pustular lesions on OP

• Neck: LAD on anterior chain, supple, no meningeal signs

• CV: RRR, no m/r/g

• Lungs: CTAB

• Abd: soft, NT, ND +BS

• Back: No spinal or paraspinal tenderness

• Extremities: no edema

• Skin: violaceous macular non-painful, non-pruritic lesions on medial aspect of right foot and along lateral malleolus of L foot

Ophthalmologic Exam

• Visual Acuity: 20/20

• EOMI Full on OD, OS no full abduction

• Sclera: Without lesions

• Fundoscopic exam: Mild blurring of disc margins but flat macula

• Cotton wool spots in superior left eye

• No vitritis or retinitis

Neurologic Exam

• CN: II-XII intact with the exception of bilateral 6th

nerve palsies, left slightly worse than right.

• Motor: Normal bulk, power and tone in all four

extremities. No tremors or drift.

• Sensory: Normal light touch, proprioception, pin

sensation, and temperature sensation in all four

extremities.

• DTRs: 2/4 all 4 extremities, downgoing toes b/l

• Coordination: Normal. Gait stable with narrow base.

Labs

5.8

11.7

194

126

3.6

88

29

11

0.71

120

Albumin 3.2

AST 23

ALT 38

Alk Phos 67

T Bili 0.3

96% PMNs, 3% Lymphocytes

Imaging

• 7/22 CT head non-con: No evidence of

intracranial hemorrhage, mass effect or midline

shift. White matter hypoattenuation involving the

bilateral corona radiata may represent ischemic

changes, demyelination versus gliosis.

However, small parenchymal mass lesions

cannot be excluded.

CSF

• Opening Pressure in ED recorded as 18cm H20

• Tube 4: WBC 19 (82L, 3N, 14M) RBC 2 Glc 2 Prt 20

• Culture, India Ink, VDRL, CrAg, Cocci serologies, AFB, HSV sent

2 small foci of restricted diffusion, one within right corona radiata and the other within the left

globus pallidus. Numerous punctate foci of T2 prolongation within periventricular and subcortical

white matter and confluent areas of T2 prolongation in posterior perventricular WM. Dilated

perivascular spaces and diffuse T2 prolongation within the basal ganglia b/l c/w gelatinous

pseudocysts. Increased signal on FLAIR within subarachnoid space b/l with mildly increased

leptomeningeal enhancement

CSF

CSF CrAg Culture

7/22 1:1024 C. Neoformans

7/24 1:65,536 C. Neoformans

7/26 1:131,072 C. Neoformans

7/27 1:131,072 C. Neoformans

7/31 Negative

Microbiology

• Bcxs at admission 7/21 grew C.

neoformans 2/4, cleared 7/22

• 7/22 Serum CMV PCR 1854

• 7/22 mouth lesion: Herpes simplex +

• 7/23 Hepatitis B cAb Positive

• 7/23 Hepatitis B sAb 538

• 7/25 Serum CrAg 1:262,144

Regimen

Cryptococcal Meningitis: Ampho B 300mg daily and flucytosine 1500mg q8h x2 weeks fluconazole 400mg daily

HSV Esophagitis: Acyclovir 800mg TID

CMV viremia/CNS disease: Ganciclovir induction 5mg/kg IV q12 x2 weeks valgancyclovir 900mg daily

Prophylaxis: Azithromycim, Bactrim

What are the predictors of

poor clinical outcome of CM in

HIV-infected patients?

•Do high CrAg titers predict

elevated ICP?

•Aims: Prevalence and predictors of AIDS-related complicated

CM

•1990-2009, 82 patients with first episode CM identified, 14

(17%) met predefined criteria

•Findings: focal neuro exam, abnormal head CT and large

crypto burden measured by CrAg titer in CSF were a/w

outcome of complicated CM

•Opening pressure >30 cm not significant when controlling

for focal neuro deficit, CT abnormality and CSF Ag titer

•CrAg (serum and CSF) moderately correlated with initial CSF

opening pressure

AIDS Research and Therapy 2010, 7:29

•Aims: Impact of serial LPs on association between CSF opening pressure and

prognosis, time course and relationship of opening pressure with neuro

findings, CSF fungal burden, immune response and CD4 count

•163 HIV-positive ART-naive patients in trials of ampho B-based tx

fluconazole in Thailand and South Africa

•Patients with higher baseline fungal burden (as measured by CSF CFU) had

higher baseline opening pressure

•High fungal burden NECESSARY but not sufficient for developing high

pressure

•Baseline opening pressure not a/w CD4 count, CSF CrAG, CSF cytokines or

AMS AIDS 2009, Vol 23 No 6.

•Aims: Baseline prognostic factors for clinical outcomes

•Prospective, randomized controlled trial

•140 subjects in Thailand and USA ampho B x 2 weeks followed

by 56d of fluconazole 400 vs 70d fluconazole 400 vs 70d

fluconazole 800

•At D14, characteristics a/w poor composite outcome: low

baseline weight, high baseline CSF CrAg titer and low baseline

CSF WBC

•At D70, characteristics a/w poor composite outcome: baseline

CSF CrAG >1:1024 and low baseline Karnofsky

•Patients with + CSF culture at D14 of tx had worse survival

Intern Jour STD & AIDS Vol 22 Nov 2011

What about HAART?

•Incidence of IRIS?

•Mortality associated with ARV

initiation during CM treatment?

•When to start?

When would you start HAART in

this patient? 1. Immediately

2. After completion of CM induction therapy

3. In 1 month

4. In 3 months

5. At follow up when patient is clinically

stable

• Aim: Incidence, characteristics, risk factors for CM-IRIS

• Cape Town, South Africa

• February 2005–July 2006

• 118 patients and followed for 1 year

• 18 were on ARVs at start, 35 died before ART, 65 started 47 days (38-65) from CM diagnosis (prospective)

• HAART: (stavudine, lamivudine and nevirapine or efaviernz) 4 weeks from CM diagnosis

J Acquir Immune Defic Syndr. 2009. 51: 130-134.

11 of 65 patients with IRIS at 4

weeks from starting


No significant difference in death in

IRIS group


Conclusions

• Patients developing IRIS had more rapid immune

restoration in response to ART

• Trend in those who developed IRIS to have a higher

fungal burden at end of induction therapy

• No difference in mortality

• No difference in cytokine profiles in CSF

• Deferring ART based on risk of mortality from IRIS must

be weighed against risk of mortality from advanced HIV,

esp in low-income countries

• Based on this cohort, authors conclude that ART should

be started between 2 - 4 weeks from start of antifungals


Limitations

• Data from 2 different studies (CID 2007.

45: 76-80. and CID 2008. 47: 123-130)

but there was no difference in rate of IRIS

(3/18 and 8/47)

• Aim: Incidence, Relationship between timing of HAART and

IRIS, Risk Factors for IRIS

• Prospective, Phase II, Multicenter, Randomized Clinical Trial

• Patients followed for 6 months

• Standard therapy: Amphotericin for 14 days + fluconazole 8

weeks (either 400 or 800mg)

• Encouraged to delay HAART for up to 6 weeks

CID. 2009. 49:931-934

No association between timing of

HAART initiation and IRIS

CID. 2009. 49:931-934.

•Median Interval from HAART initiation to IRIS was 63 days

•3/13 (23%) IRIS patients versus 16/88 (18%) non-IRIS

patients started HAART on or before day 42 (p=.71)

CSF characteristics of the 13/101

patients developed IRIS

CID. 2009. 49:931-934

Conclusion: Clinical outcome better

with HAART

• Risk Factor: Baseline serum CrAg titer was associated with increased risk of IRIS (1:512 vs 1:128)

• No difference in mortality between IRIS and non-IRIS, though more adverse effects in IRIS patients (papilledema and decreased levels consciousness)

• Probabilities of successful outcomes at days 14, 42, and 70 and survival to 6 months was higher for HAART.

• Limitations: Followed for only 6 months

CID. 2009. 49:931-934.

• Review of studies from 1996 to 2009

• Aim: To define mortality in patients with IRIS in different income countries

• 54 cohort studies from 22 countries

• High Income: Australia, France, Ireland, Japan, South Korea, Spain, UK, Germany, Taiwan, US

• High-Middle Income: Argentina, Brazil, Mexico, Poland, Serbia, South Africa, Venezuela

• Low-Middle: India and Thailand

• Low Income: Cambodia, Mozambique, Senegal

Lancet Infectious Disease 2010. 10: 251-261.

Rates of IRIS with Cryptocococcal

meningitis

Lancet Infectious Disease 2010. 10: 251-261.

• 21% of IRIS with patients diagnosed with cryptococcal meningitis

• IRIS 28% of patients with CD4<50

• IRIS 2% of patients with CD4>50

• IRIS greater in higher income than lower income countries

• Open-label, randomized, phase IV with 283 subjects who presented with AIDS-related OIs or serious bacterial infections

• May 2003 to August 2006, recruitment at 39 ACT Units in US and South America

• Early Arm – Start ART within 48 hours of study enrollment, within 14 days (n=142)

• Deferred Arm – Start ART between week 6 and 12 (n=141)

• Followed for 48 weeks

• HAART: PI/r + 2 NRTIs vs NNRTI+ 2NRTIs (3TC or FTC)

PLoS One. 2009. 4: e5575

Findings

• Most common OIs (not including TB)

– PCP 63%

– Cryptococcal Meningitis 12%

– Bacterial Infections 12%

• 20 cases of IRIS in this study (7%)

• 35 cases of cryptococcal meningitis (13 in

early arm and 22 in deferred arm)

• The difference in the primary endpoint did

not reach statistical significance

PLoS One. 2009. 4: e5575

Early ART favored

in patients with:

CD4<50

Fungal OIs

(including

cryptococcus

and

histoplasmosis)

PLoS One. 2009. 4: e5575

Lower Likelihood of AIDS progression

or death in Early Arm

PLoS One. 2009. 4: e5575

•Prospective, open-label randomized trial in Zimbabwe

•1st CM dx, randomized to early ART (within 72h after CM dx) or delayed

ART (after 10 weeks of tx with fluconazole alone)

•All subjects were inpatients taking fluconazole 800mg daily

•ART: d4T, 3TC and nevirapine twice daily

•Duration of follow up 3 years, primary endpoint all-cause mortality

•54 enrolled (28 in early, 26 in delayed)

•3 year mortality differed significantly between early and delayed ART (88 vs

54%, p<.006)

•Study terminated early by DSMB

CID 2010, Vol 50 (June 1)

Early treatment a/w increased mortality


Risk of

mortality

almost 3X as

great in early

ART group vs

delayed (AHR

2.85, CI 1.1-

7.23)

Conclusions/Limitations • In resource-limited settings where CM management may

be suboptimal, early initiation of ART results in increased

mortality

• Possible reasons: suboptimal management of CM via

monotherapy with fluconazole, inadequate CSF pressure

management, drug-drug interactions and IRIS

• Early initiation ?alteration of CNS and peripheral

cytokine profiles, limiting CNS clearance

– Early ART results in pro-inflammatory state IRIS

• Limitations: small sample size, lack of blinding, overall

CM management suboptimal, no drug resistance testing

• Recommendation: Wait at least 10 weeks for ART after

starting CM tx in resource-limited settings


• Aims: Incidence, Clinical presentation, Outcomes and Cytokine profiles of CM-IRIS

• Kampala, Uganda May 2006 to September 2009

• 101 ART naïve patients

• CM: Amphotericin B x 2 weeks 400mg fluconazole daily

• ART: Started median 34 days (24-41 days)

• ART: AZT, 3TC, efavirenz OR d4T, 3TC and nevirapine

PLoS Medicine 2010. 7: e1000384

• Pre-ART

serum CrAg

associated

with increased

likelihood of

IRIS

PLoS Medicine 2010.

7: e1000384

Risk Factors for IRIS

Increased Mortality with IRIS

•Overall Mortality 28/101 (27%)

•45 patients with IRIS

•16/45 (36%) with IRIS died

•12/56 (21%) without IRIS died

•NO difference in incidence of

IRIS in those starting ART 11-28d

and those who waited >28d (44

55%, p=0.4)


Are there other markers to

predict IRIS?

•Are there biomarkers a/w

development of IRIS?

•Can we reliably use them to

predict occurrence?

• Mathematical Model to predict IRIS and Mortality using other serum biomarkers

• Future CM-IRIS associated with elevated pre-ART CRP, IL-4,and IL-17.

• Increased IL-4 ineffective antigen clearance predisposition to develop IRIS

• IL-17 in the Th17 pathway previously hypothesized as important in IRIS pathogenesis

• Lower levels of TNF-alpha (part of innate immune response, pro-inflammatory), VEGF and GCSF had an increased risk of IRIS


Can we predict IRIS risk?


Mathematical model based on pre-ART serum levels of IL-4, IL-

17, G-CSF, GM-CSF, CCL2 (MCP-1), TNF-alpha, and VEGF

CRP> 32 mg/L alone associated

with decreased survival


Elevated IL-17, CRP>32 and low GM-

CSF associated with increased

mortality


Conclusions/Limitations

• Pre-ART increases in Th17 and Th2 responses

(e.g., IL-17, IL-4) and lack of proinflammatory

cytokine responses (e.g., TNF-α, G-CSF, GM-

CSF, VEGF) predispose individuals to

subsequent IRIS

• Biomarkers could be an objective tool to stratify

risk of CM-IRIS and death and guide when to

start ART

• No causality, heterogeniety of inflammatory

profiles, validation required


•Prospective cohort of 199 HIV-infected, ART-naïve Ugandans with first

CM episode, 170 had clinical data copllected

•July 2006-2009

•Ampho for 14 days fluconazole 400mg daily

•Of 170 patients, 85 survived to initiate ART at median 5 weeks

•33 (39%) developed paradoxical CM-related IRIS with CNS

manifestations at median 8 weeks

•Another 9 with likely crypto-related IRIS with non-CNS manifestations

•At CM dx, subjects who went on to develop IRIS had less inflammation

with decreased CSF leukocytes, protein, INF-γ, IL-6, IL-8 and TNF-α

•CM relapse a/w persistent lack of viable organisms or inflammation in

CSF

JID 2010 vol 202 Sept 15

Can we use CSF cytokine profiles to

clinically risk stratify HIV-infected

patients starting ART?

JID 2010 vol 202 Sept 15

General Conclusions

• Baseline high serum CrAg and fungal burden

associated with increased risk of IRIS.

• IRIS is not associated with increased mortality in

patients, except perhaps in resource-limited

settings.

• Patients with CD4<50 may benefit from

immediate ARV therapy

• Serum and CSF cytokine profiles show less

initial inflammation in those who develop IRIS

2010 IDSA Guidelines

• The precision of when to start HAART to avoid IRIS

remains uncertain

• Recommendation 2-10 wks

• Studies by Sungkanuparph (CID 2009) and Zolopa

(PLoS ONE 2009) may favor earlier start but small n’s

• In some settings, long delays in HAART can place

patient at risk of dying from other complications

• Important to anticipate interactions with HAART and

antifungal meds

CID 2010; 50:291–322

Back to RG…

• 7/24: Developed L-sided Bell’s Palsy

• 7/27: Low opening pressure, High CrAg CSF

• 7/28: Increasing confusion, Cr 1.8

• 7/30: Tm 101.1. More lethargic and delirious. CT with

progression of meningeal enhancement.

• 7/31: LP with low OP, CSF culture negative

• 8/1: Mentation improved. CSF CMV 2025, Serum CMV

1854, started IV ganciclovir. Cr 1.6

• 8/6 Serum CrAg 1:65,536

• 8/13 CSF CrAg 1:2048 GS mod yeast, culture negative

• 8/16 CSF GS rare yeast, culture negative

What ART regimen would you

start? 1. Atripla

2. DRV/r + FTC/TDF

3. RAL + FTC/TDF

4. RAL + DRV/r + ABC/3TC

5. Stribild

6. No clue– help!

ART regimen

• Given low CD4 count, high serum and CSF CrAg, KS on feet and CMV viremia in CSF Started after anti-fungal induction at 2 weeks

• DVR/r + 3TC/ABC + RAL vs. FTC/TDF + RAL

• No HLA test back +

Desire for simple regimen +

Blood brain barrier porous with several CNS infections so penetrating regimen less important +

No reports of IRIS with RAL yet…

• FTC/TDF + RAL started 8/7

Hospital Course continued

• Worsening headaches 8/12, repeat LP

8/13 with opening pressure 34

• CSF CrAg 1:2048

• Glucose 39, Protein 50

• WBC 9 (95L, 1S) Glc 39, Prt 50

• CSF GS with rare fungal elements, culture

no growth

• CMV CSF<500

Outpatient follow up

• 7/24 Genotype clean

• 8/3 HLAB57 neg

• 9/10 Outpatient visit: Switched to

ABC/3TC + RAL given Cr now 2. CD4

65/9%, VL undetectable (undetectable

8/21)

• Still with facial droop, b/l 6th nerve palsies

improving

• Doing well

The plot thickens…

• 10/11 L wrist pain swelling x2 weeks. XR

shows possible occult fracture

• 10/29 MRI: 3 x 2 x 5.5 soft tissue mass

involving scaphoid with extension along

flexor carpi radialis tendon and radial

artery into soft tissues

• 11/5 ortho appointment, bx/aspiration

scheduled for 11/8

Fluid aspiration results

• By 11/9, fluid aspirate with HEAVY smear

positivity for AFB!!

• Awaiting culture results but in the

meantime, planning to start 4-drug therapy

+ MAC therapy

Thank you! Special thanks to Gigi Blanchard, Richard

Haubrich and Jennifer Dan.

Cryptococcal Meningitis with Cranial Nerve Neuropathies: Predictors of Outcome and Review of ART...

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