Download Cryptococcal meningitis Melicent Peck MD, PhD Stanford University Department of Medicine

Cryptococcal meningitis
Melicent Peck MD, PhD
Stanford University
Department of Medicine
Case One
HPI: 73 y/o male admitted for 3-week h/o acute memory loss. Per pt’s wife, pt getting lost, repeating
same story over and over, unable to recall details of recent events. No F/C, no HA, no recent illness.
Patient had acute-onset aphasia in 07/09 and 09/09 with resolution over several weeks. Found to have L
temporal stroke on MRI brain.
PMHx: IDDM, HLD, HTN, vertigo (x 2 years, attributed to Meniere's disease)
Meds: Metformin, Lantus, Nicardipine, Citicholine SR
SHx: No etoh, tobacco. Retired administrator, lives in Bangalore, India but travels to US ~ 1x/year to see
family. No rural contacts, no hiking, no pets.
FHx: NC
PE: VSS. AAO x 3. Exam unremarkable.
Labs: Na 133, CRP < 0.2, ESR 38, HIV negative, serum CrAg 1:4
LP: OP 22cm, 116 wbc ((N28L66M6)), 12,625 rbc, xanthochromia, g
glucose 69, TP 536, CrAg
g 1:4
Gram Stain: small number polys, small number PMNs, small number rbc, no organisms, Cx: NGTD
MRI brain: new temporal lobe CVA
Case Two
HPI: 55 y/o male with h/o HIV (CD4+ 2 cells/l, VL 1850 copies/ml) not on HAART with OI disseminated KS
and Candidiasis, homeless admitted for abdominal pain, SOB. Pt found to have SBO s/p lysis of
adhesions, PNA 2/2 KS vs CAP. +HA primarily in morning, diffuse.
PMHx: HIV (1990), disseminated KS (lung, skin), Candidiasis (esophageal), polysubstance abuse
Meds: Atazanavir, Truvada, Ritonovir, Bactrim, Fluconazole, Azithromycin
SHx: Homeless, + etoh, + crack cocaine
FHx: NC
PE: VS: RR 24 Chronically ill-appearing male, cachectic OP: oral thrush, areas of mild ulceration on hard
palate, CV: RRR no mrg Lung: diffuse coarse crackles, decreased BS in RLL Abd: TTP RLQ with voluntary
guarding Skin: 2 x 2 cm violaceous macule on dorsum of L foot Neuro: non-focal
Labs: Hct 29, Na 132, albumin 2
BCx +Cryptococcemia, CrAg 1:256
LP <1
LP:
1 wbc,
b <1
1 rbc,
b Glucose
Gl
66,
66 TP 24
24,CrAg
C A 1:8
18
GS: no polys, no orgs Cx: NGTD Fungal Cx: Cryptococcus neoformans (liquid media, not on plate)
CT Head: unremarkable
DDX: Chronic Meningitis
 Bacteria




Mycobacterium Tb
Syphilis
Lyme disease
Nocardiosis
 Parasites


Cysticercosis
y
Acanthamebiasis
 Fungal





•
Cryptococcosis
Coccidiomycosis
Histoplasmosis
Candidiasis
Aspergillosis
Viral
•
•
HSV
VZV
•Sarcoid
•Tumor
Cryptococcal Meningitis
 Signs/Symptoms
 HA,, F,, nuchal rigidity,
g
y, p
photophobia
p
 Decreased vision, unsteady gait, CN palsies
 Confusion, lethargy, memory loss over several weeks
 Seizure or strokes in multiple vascular territories
 Causative Agent
Strain
Global
Distribution
Environmental
Reservoir
C. neoformans
Global
Temperate
climates
Pigeon droppings/
guano/ birds nests
Rotting
g vegetation
g
Epidemiology
 Occurs
O
in
i ~ 1 million
illi people
l per year
 ~600,000 deaths annually
 3-month mortality rate ~20% in developed countries, ~70% in Africa
 Primarily seen in immunocompromised patients
 Newly diagnosed HIV patients


Most common OI in AIDS (CD4+ < 50 cells/l)
 Incidence 0.04%-12% per year
Look for co-morbid CNS processes (Toxoplasma, Nocardia, lymphoma)
 Solid organ transplant patients


Median time to disease onset 21 months after transplantation
g transplant
p
recipients
p
Documented in 2.8% of sold-organ
 High dose CS, monoclonal Abs, other immunosuppressants
 Global disease burden
 Sub-Saharan
Sub Saharan Africa > S and SE Asia > Latin America >
E Europe and Central Asia > > N America > N Africa
and Middle East> W and Central Europe
 95% of cryptococcal meningitis cases in developing countries
are HIV associated
i t d

Account for 10-20% of all deaths in HIV infected patients in Africa (> Tb)
Pathogenesis
g
 Virulence Factors
 Capsule
 Antiphagocytosis barrier, depletes complement, dysregulates
cytokine secretion
 Melanin
 Antioxidant (UV light, toxic free radicals), interferes with T-cell
response
 Growth at high-temperature (37o C)
Mechanism of Infection
 Yeast spores enter host through lungs via inhalation
 Spores deposited in alveoli
 Phagocytosed by macrophages
 Granulomatous inflammation
 CD4, CD8, NK cells inhibit growth

Immunosuppressed
Yeast proliferates/
disseminates
Immunocompetent Yeast produce small
Yeast eliminated
lung-lymph node complex
Remain dormant (latency)
Host asymptomatic
y p
Clinical Manifestations
 Lung


1/3 pts asymptomatic (abnormal CXR with single or multiple pulmonary nodules)
PNA (F, chest pain, SOB, productive cough)

CXR: lobar infiltrate, hilar LAD, pleural effusions, lung cavitations
 CNS

Subacute meningitis or meningoencephalitis
 Skin

Ulceration, cellulitis, abscess
 Prostate


Usually asymptomatic
Can serve as reservoir of infection
 Eye


Ocular p
palsies,, p
papilledema
p
Can lead to blindness


Optic neuritis
Cerebral edema 2/2 elevated ICPs
 Bone/joint (osteolytic lesion)
Diagnosis
 CSF
 Elevated opening pressure
 Mononuclear pleocytosis
 Elevated protein
 Decreased glucose (< 40mg/dl)
 Cryptococcal antigen
 Direct detection (India Ink)
 Spherical, narrow based, budding, encapsulated yeast
 50% of non
non-AIDS
AIDS pts, 80% of AIDS pts CNS positive
 Culture
 Growth 48-72 hours on laboratory media at 20-37o C
 Routine
R ti blood
bl d culture
lt
can d
detect
t t cryptococcemia
t
i (3
(3-7
7 days)
d )
 CSF fungal culture
Diagnosis
 Serology
 Cryptococcal polysaccharide antigen (sera and CSF)
 Latex agglutination and enzyme immunoassay
>90% sensitive and specific
CSF titer ≥ 1:4 positive
Titer ≥ 1:1024
-High burden of yeasts, poor host immunity, greater chance of
therapeutic
h
ffailure
l
Serial titers imprecise but can be used for disease follow-up
Can be negative in pulmonary disease
 Radiology
 No pathognomonic scan
 CT brain: cryptococcomas (single/multiple), hydrocephalus, gyral
enhancement
 50% of CT scans normal
 MRI brain: hyperintense clustered foci in basal ganglia or midbrain
 Follow-up scans may show worsening of lesions
 Represents enhancement by inflammation as yeast being eliminated
 Not necessarilyy treatment failure
Treatment: Drugs
 Amphotericin B
 Amphotericin B deoxycholate (0.7 mg/kg/day)
 Nephrotoxic
 Acute infusion rxn (F/C, N/V, SOB)
 Liposomal amphotericin B (Ambisome:3-6 mg/kg/day)
 Amphotericin B lipid complex (Abelcet:3-6
(Abelcet:3 6 mg/kg/day)
 Flucytosine (100 mg/kg/day) (FC)
 MIC ≥ 128 g/ml associated with treatment failure
 Drug resistance as monotherapy
 Monitor for cytopenias
 2hr post-dose level 30-80 g/ml 3-5 days after initiation of treatment
 Fluconazole (200-1200 mg/day)
 MIC ≥ 16 g/ml
g/ml associated with treatment failure
 Resistance emerging problem when used as monotherapy (Africa)
Treatment: HIV
 Induction phase
 Amphotericin B + FC x 2 weeks
 Continue up to 6 weeks if pt sx (AMS),
(AMS) persistent increased
ICP, CSF culture remains positive
 Consolidation phase
p
 Fluconazole 400 mg Qday (6 mg/kg) x 8 weeks
 Suppressive phase
 Fluconazole 200 mg Qday
 Initiate HAART 2-10 weeks after commencement of initial
antifungal treatment
 Stop if CD4+ > 100 cells/l, VL ND x ≥ 3 months, CrAG
negative, minimum 12 mos of antifungal therapy
 Reinstitute maintenance therapy if CD4+ < 100 cells/l or
C A iincreases
CrAg
 Primary antifungal prophylaxis not recommended
IDSA Guidelines, 2010
Treatment: Organ Transplant
 Induction phase
 Amphotericin B + FC x 2 weeks
 Consolidation phase
 Fluconazole 400 mg-800 mg Qday (6 mg/kg) x 8 weeks
 Suppressive phase
 Fluconazole 200-400 mg Qday x 6-12 months
 Reduce immunosuppressants
 Lower prednisone to < 20 mg/day
IDSA Guidelines, 2010
Treatment: Normal
 Induction phase
 Amphotericin B + FC x 4 weeks
 No neurological
l
l complications
l
 CSF culture results negative after 2 weeks of treatment
 Extend treatment to 6 weeks if neurological complications
 If low-risk for therapeutic failure can shorten treatment to 2
weeks
 Consolidation phase
 Fluconazole 400 mg Qday (6 mg/kg) x 8 weeks
 Suppressive phase
 Fluconazole 200 mg Qday x 6-12 months
IDSA Guidelines, 2010
Elevated ICP
 Seen in ~ 50% of HIV infected patients
 Linked to high burden of yeast in CSF
 Opening CSF pressure ≥ 25 cm H2O + symptoms
 CSF drainage to reduce OP by 50% or to ≤ 20 cm H2O
 Repeat LP daily until CSF pressure and sx stabilized for > 2 days
 Consider placement of temporary CSF shunt or lumbar drain
IDSA Guidelines, 2010
Treatment in Resource-Limited
S tti
Settings
 Induction/Consolidation
 Amphotericin B (1 mg/kg/day) x 2 weeks -> fluconazole (800
mg/day) x 8 weeks
 Amphotericin B (0.7 mg/kg/day) + fluconazole (800 mg/day) x 2
weeks -> fluconazole (800 mg/day) x 8 weeks
 Fluconazole (1200 mg/day) + FC (100 mg/kg/day) x 2-10 weeks
 Fluconazole (1200 mg/day) x 10-12 weeks
 Maintenance
M i t
 Fluconazole 200-400 mg/day
 Open-labeled
p
RCT in Malawi ((2008))
 HIV positive adults (mean CD4+ count 21 cells/l, VL 99,000 cells/ml)
with first episode of cryptococcal meningitis
 Patients with ANC < 500, plt < 50K, ALT > 200, or on ART excluded
 Randomized to fluconazole (1200 mg/day) (n
(n=20)
20) vs fluconazole + FC
(100 mg/kg/day) (n=21) x 14 days -> 800 mg fluconazole Qday
 ART started after 4 weeks of antifungal therapy
 Monitored LP at t =0, 1, 3, 7, 14 days
 More frequent LP if OP > 30 cm H2O (mean OP at baseline 34 cm H2O)
 Followed LFTs, creatinine, CD4+ cells, HIV VL at baseline, LFTS and
cbc at weeks 1,2,4,6,10.
 Primary outcome: mean rate of decrease in CSF cryptococcal counts
 Secondary
S
d
outcomes:
t
serious
i
adverse
d
events,
t d
drug S/E
S/E, mortality
t lit att 2
& 10 weeks
Results/Conclusions
Fungicidal Activity: High-dose
fluconazole + FC > than high
high-dose
dose
fluconazole alone (p< 0.001).
Four patients in combination arm and
one in monotherapy arm had sterile
cultures
lt
att D14
D14.
10%
37%
43%
58%
Survival: Trend toward improved survival at 2 and 10 weeks among patients
who received combination therapy.
Results/Conclusions
Safety: Combination regimen safe w/o
monitoring
g FC levels
Limitations:
-FC not available in most of developing world, including Africa
-Underpowered to detect mortality benefit
References
1.
2.
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5.
6.
7.
8.
9.
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10.
11.
12.
Buchanan K & Murphy
p y J ((1998)) What makes Cryptococcus
yp
neoformans a p
pathogen?
g
Emerging Infectious Diseases 4(1):71-83.
Idnurm A, et al. (2005) Deciphering the model pathogenic fungus Cryptococcus neoformans.
Nat Rev Microbiol 3(10):753-764.
Longley N, et al. (2008) Dose response effect of high-dose fluconazole for HIV-associated
cryptococcal meningitis in southwestern Uganda.
Uganda Clin Infect Dis 47(12):1556-1561.
47(12):1556 1561
Mandell G, Bennett J, & Dolin R (2010) Principles and Practices of Infectious Diseases,.
(Churchill Livingstone) 7th Ed p 4320.
Makombe SD, Nkhata A, Schouten EJ, Kamoto K, & Harries AD (2009) Burden of cryptococcal
meningitis in Malawi. Trop Doct 39(1):32-34.
Mayanja-Kizza H, et al. (1998) Combination therapy with fluconazole and flucytosine for
cryptococcal meningitis in Ugandan patients with AIDS. Clin Infect Dis 26(6):1362-1366.
Nussbaum JC, et al. (2010) Combination flucytosine and high-dose fluconazole compared with
fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in
Malawi Clin Infect Dis 50(3):338
Malawi.
50(3):338-344
344.
Pappas PG (2010) Cryptococcosis in the developing world: an elephant in the parlor.
Clin Infect Dis 50(3):345-346.
Park BJ, et al. (2009) Estimation of the current global burden of cryptococcal meningitis
among persons living with HIV/AIDS. AIDS 23(4):525-530.
P f t JR,
Perfect
JR ett al.
l (2010) Cli
Clinical
i l practice
ti guidelines
id li
ffor th
the managementt off cryptococcal
t
l
disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 50(3):291322.
Sloan D, Dlamini S, Paul N, & Dedicoat M (2008) Treatment of acute cryptococcal meningitis
in HIV infected adults,, with an emphasis
p
on resource-limited settings.
g Cochrane Database Syst
y
Rev (4):CD005647.
Sloan DJ, Dedicoat MJ, & Lalloo DG (2009) Treatment of cryptococcal meningitis in resource
limited settings. Curr Opin Infect Dis 22(5):455-463.