Cryptococcal Meningitis with Cranial Nerve Neuropathies: Predictors of Outcome and Review of ART Initiation
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Cryptococcal Meningitis with Cranial Nerve Neuropathies: Predictors ofOutcome 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
HistoryPMH: FHx: HTN in mom, Diabetes• Prior treatment for in dad Tuberculosis as a child• Diagnosed with HIV in SHx 2/2012 at North Park • MSM • No IVDU. Used to snortMeds: None meth/coke. No EtOH • 5 pack-year smokingAll: None 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.
Labs126 88 11 1203.6 29 0.71 Albumin 3.2 11.7 AST 23 5.8 194 ALT 38 Alk Phos 67 T Bili 0.396% 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 leftglobus pallidus. Numerous punctate foci of T2 prolongation within periventricular and subcorticalwhite matter and confluent areas of T2 prolongation in posterior perventricular WM. Dilatedperivascular spaces and diffuse T2 prolongation within the basal ganglia b/l c/w gelatinouspseudocysts. Increased signal on FLAIR within subarachnoid space b/l with mildly increasedleptomeningeal enhancement
CSF CSF CrAg Culture7/22 1:1024 C. Neoformans7/24 1:65,536 C. Neoformans7/26 1:131,072 C. Neoformans7/27 1:131,072 C. Neoformans7/31 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
What are the predictors ofpoor clinical outcome of CM in HIV-infected patients? •Do high CrAg titers predict elevated ICP?
•Aims: Prevalence and predictors of AIDS-related complicatedCM•1990-2009, 82 patients with first episode CM identified, 14(17%) met predefined criteria•Findings: focal neuro exam, abnormal head CT and largecrypto burden measured by CrAg titer in CSF were a/woutcome 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 CSFopening pressure AIDS Research and Therapy 2010, 7:29
•Aims: Impact of serial LPs on association between CSF opening pressure andprognosis, time course and relationship of opening pressure with neurofindings, CSF fungal burden, immune response and CD4 count•163 HIV-positive ART-naive patients in trials of ampho B-based txfluconazole in Thailand and South Africa•Patients with higher baseline fungal burden (as measured by CSF CFU) hadhigher baseline opening pressure•High fungal burden NECESSARY but not sufficient for developing highpressure•Baseline opening pressure not a/w CD4 count, CSF CrAG, CSF cytokines orAMS 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 followedby 56d of fluconazole 400 vs 70d fluconazole 400 vs 70dfluconazole 800•At D14, characteristics a/w poor composite outcome: lowbaseline weight, high baseline CSF CrAg titer and low baselineCSF WBC•At D70, characteristics a/w poor composite outcome: baselineCSF 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. Immediately2. After completion of CM induction therapy3. In 1 month4. In 3 months5. 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 J Acquir Immune Defic Syndr. 2009. 51: 130-134.
No significant difference in death in IRIS group J Acquir Immune Defic Syndr. 2009. 51: 130-134.
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 J Acquir Immune Defic Syndr. 2009. 51: 130-134.
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•Median Interval from HAART initiation to IRIS was 63 days•3/13 (23%) IRIS patients versus 16/88 (18%) non-IRISpatients started HAART on or before day 42 (p=.71) CID. 2009. 49:931-934.
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• 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 Lancet Infectious Disease 2010. 10: 251-261.
• 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<50Fungal 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 delayedART (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 vs54%, 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) CID 2010, Vol 50 (June 1)
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 CID 2010, Vol 50 (June 1)
• 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
Risk Factors for IRIS • Pre-ART serum CrAg associated with increased likelihood of IRIS PLoS Medicine 2010. 7: e1000384
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) PLoS Medicine 2010. 7: e1000384
Are there other markers to predict IRIS?•Are there biomarkers a/wdevelopment of IRIS?•Can we reliably use them topredict 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 PLoS Medicine 2010. 7: e1000384
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 PLoS Medicine 2010. 7: e1000384
CRP> 32 mg/L alone associated with decreased survival PLoS Medicine 2010. 7: e1000384
Elevated IL-17, CRP>32 and low GM- CSF associated with increased mortality PLoS Medicine 2010. 7: e1000384
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 PLoS Medicine 2010. 7: e1000384
•Prospective cohort of 199 HIV-infected, ART-naïve Ugandans with firstCM 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 CNSmanifestations 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 inflammationwith decreased CSF leukocytes, protein, INF-γ, IL-6, IL-8 and TNF-α•CM relapse a/w persistent lack of viable organisms or inflammation inCSF 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. Atripla2. DRV/r + FTC/TDF3. RAL + FTC/TDF4. RAL + DRV/r + ABC/3TC5. Stribild6. 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, RichardHaubrich and Jennifer Dan.